PharmTech Sept 2011

The Authority on Drug Development & Manufacturing

PharmTech.com

September 2011

Volume 35

Number 9

Regulators Debate WFI Production

EU Debt Crisis Affects CMOs

Facility Biocontainment and Inactivation

Viewpoint: Is USP Obsolete? USP Responds

FDA Evaluates QbD ProgramAgency Identifies Areas for Improving Quality by Design

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4 Pharmaceutical Technology september 2011 PharmTech .com

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James P. Agalloco

President,

Agalloco & Associates

Michael J. Akers, PhD

Senior Director,

Pharmaceutical R&D,

Baxter BioPharma Solutions

Larry L. Augsburger, PhD

Professor, Department of

Pharmaceutics,

University of Maryland

David H. Bergstrom, PhD

COO, NovaDel Pharma Inc.

Rory Budihandojo

Director, Quality Systems Audit,

Boehringer-Ingelheim Shanghai

Pharmaceuticals Co. (China)

Todd L. Cecil

Vice-President

Compendial Science

United States Pharmacopeia

Metin Çelik, PhD

President,

Pharmaceutical Technologies

International (PTI)

Zak T. Chowhan, PhD

Consultant, Pharmaceutical

Development

Suggy S. Chrai, PhD

President and CEO,

Chrai Associates, Inc.

Roger Dabbah, PhD

Principal Consultant,

Tri-Intersect Solutions

iSanjay Garg, PhD

Associate Professor and

Deputy Head,

School of Pharmacy,

University of Auckland

R. Gary Hollenbeck, PhD

Chief Scientific Officer,

UPM Pharmaceuticals

Ruey-ching (Richard) Hwang, PhD

Senior Director,

Pharmaceutical Sciences,

Pfizer Global R&D

Mansoor A. Khan, PhD

Director, FDA/CDER/DPQR

Russell E. Madsen

President, The Williamsburg

Group, LLC

Heidi M. Mansour, PhD

Assistant Professor,

College of Pharmacy,

University of Kentucky

Jim Miller

President,

PharmSource Information

Services Bio/Pharmaceutical

Outsourcing Report

R. Christian Moreton, PhD

Vice-President,

Pharmaceutical Sciences,

Finnbrit Consulting

Fernando J. Muzzio, PhD

Director, NSF Engineering

Research Center on Structured

Organic Particulate Systems,

Dept. of Chemical and

Biochemical Engineering,

Rutgers University

Moheb M. Nasr, PhD

Director,

Office of New Drug Quality

Assessment, CDER, FDA

Garnet E. Peck, PhD

Professor Emeritus of Industrial

Pharmacy, Purdue University

James Polli, PhD

Professor,

School of Pharmacy,

University of Maryland

Gurvinder Singh Rekhi, PhD

Director,

Research and Development,

Elan Drug Delivery Inc.

Susan J. Schniepp

Pharmaceutical Consultant,

Schniepp & Associates, LLC

David R. Schoneker

Director of Global Regulatory

Affairs, Colorcon

Eric B. Sheinin, PhD

President,

Sheinin and Associates

Charles A. Signorino, PhD

CEO, Emerson Resources, Inc.

Alan J. Smith, PhD

President,

Pharmaceutical Quality &

Technology Consulting

Heinz Sucker, PhD

Professor Emeritus,

Pharmaceutical Institute,

University of Bern

Scott Sutton, PhD

Microbiology Network

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Principal Statistician,

Torbeck & Associates

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On

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Continued on page 10

September 2011 Volume 35 Number 9

➲ On PharmTech.com

Issue extras➲ Pfizer’s Brian Johnson discusses

the company’s view of supply-chain

security PharmTech/com/PfizerJohnson

➲ This month’s Packaging Forum

features information on Michigan

State University’s anticounterfeit-

ing projects PharmTech.com/Michigan

Video➲ View a sneak-peak of the 2011

USP Science and Standards Sympo-

sia on PharmTech.com/PharmTechTV

Reader comment “Don’t we need to see this trend continue for a decade or more to say with certainty that we have turned the corner on the R&D drought of the pharma industry?” on the blog post “Woodcock Cites a ‘Turning Point’ in Drug Development.” blog.PharmTech.com.

Free eNewsletters Visit PharmTech.com/enews for:• ePT : Weekly industry news

and business notes.

• Sourcing and Management: The September edition focuses on supply-chain integrity.

• Equipment & Processing: The September issue examines redundant filtration.

Most popular articles• “Is Six Sigma Still Relevant for Drug-makers?” PharmTech.com/SixSigma

• ”China’s SFDA Following Through on GMP Efforts” PharmTech.com/ChinaGMPs

• “Big Pharma’s Manufacturing Blueprint for the Future” PharmTech.com/Blueprint

Custom content• PharmTech.com/regulation

• PharmTech.com/outsourcing

• PharmTech.com/formulation

SupplementBe sure to check out this month’s

API, Excipient, and Manufacturing

special issue.

Features

Pharma IngredIents

54 In Pursuit of Single-Enantiomer Drugs

Patricia Van Arnum

Chiral technologies continue

to attract investment.

Plus: Microscale hydrogels.

PharmaceutIcal Water

48 Regulators Debate WFI Production Methods Erik Greb

European officials may revise

acceptable production methods.

Peer-reviewed research

ProteIn PurIfIcatIon

66 Surface Neutralization System Mark A. Snyder, Daniel Yoshikawa, and Larry J. Cummings

The authors describe a new,

robust method for protein elution from

ceramic hydroxyapatite.

fda on qbd

60 Understanding Challenges to Quality by Design Helen N. Winkle and Moheb M. Nasr

Center for Drug Evaluation and

Research directors summarize an

FDA-commissioned report on QbD.

PqrI case study

74 Facility Biocontainment and Inactivation Ted Frank, Stephen Brooks, Kristin Murray, Steve Reich, Ed Sanchez, Brian Hasselbalch, Kwame Obeng, and Richard Creekmore

The authors aim to advance the appli-

cation of quality risk management.

Departments/Products

18 In the Field

26 In the Spotlight

84 Pharma Capsules

85 Industry Pipeline

88 Showcase/Markeplace

94 Ad Index

Cover story

44 Continuous Progress in Continuous ManufacturingPatricia Van Arnum and Rich Whitworth

Industry buy-in is increasing as pharma compa-

nies proceed with select projects and research.

Image: John Rensten/Getty Images. Pill Illustration by Dan Ward.

Pharmaceutical Technology is the authoritative source of peer-reviewed research and

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Continued from page 8

Columns

from the edItor

12 Retrospection and Introspection at FDA

Michelle Hoffman

An FDA report evaluates

the quality-by-design paradigm.

Pharmtech talk

14 Web 2.0 for Pharma Innovation

Patricia Van Arnum

Internal and external Web-based

communities are changing how

pharma companies can innovate.

agent-In-Place

16 Knowing is Half the Battle

Control, a senior compliance officer

Being aware of how a product was

made can make a big difference.

WashIngton rePort

28 Manufacturers and FDA Gear up for User-Fee Action

Jill Wechsler

PDUFA renewal legislation

sets stage for new policies.

bIoforum

38 The Case for Pediatric Exclusivity

Christopher Milne

Reauthorization of pediatric

exclusivity provisions looms in 2012.

PackagIng forum

40 Verification through Telecommunication

Hallie Forcinio

Smartphones could become the

product-authentication tool of choice.

InsIde Ich

78 Harmonization Continues

Georges France and Jean-Louis Robert

A summary of the June ICH meeting.

outsourcIng outlook

80 The EU Debt Crisis and CMOs

Jim Miller

The EU debt crisis portends of possible

negative repercussions for CMOs.

VIeWPoInt

92 Where in the World is the US Pharmacopeia?

Susan J. Schniepp,

with a response from Roger L. Williams Is USP undergoing an identity crisis?

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From the editor

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PharmTech.com/forum

i have often gotten the impression that FDA’s quality-by-design (QbD) initiative remains somewhat mysteri-

ous to pharmaceutical manufacturers, even though it’s been about seven years since FDA first introduced the concept in its 2004 report, Pharmaceu-tical Quality for the 21st Century: A Risk-Based Approach. FDA must have had that impression as well, since the agency commissioned a study to gauge the industry’s rate of adoption of the concept as well as its understanding of it, the results of which FDA officials present in this issue of Pharmaceutical Technology. The study findings sup-port anecdotal accounts of industry attitudes towards QbD.

The report quantifies the degree of adoption among different industry sec-tors. Not surprisingly, innovator com-panies (called “New Drug” in the re-port) have embraced the program most fully. Twenty-two percent of new drug companies are categorized as “fully implemented” in the report, mean-ing that these companies incorporate QbD principles in almost all of their development programs. These compa-nies also have a “systematic, compre-hensive review and redesign of in-line products.” In contrast, no generics or

biologicals manufacturers fall under the fully implemented category.

At the other end of the spectrum, generic-drug manufacturers appear to be most resistant to the program, with 40% of them being characterized as “novice,” which is defined as a com-

pany “that is skeptical about the value of QbD,” and uses “conventional devel-opment practices and has no QbD plat-forming.” In other words, they’re non-adopters. Biological manufacturers lie somewhere in the middle, with an im-pressive 67% venturing tentatively into “pilot” territory, defined as companies trying it out, but uncertainly. These results mirror responses PharmTech obtained in our 2011 Equipment and Machinery Survey (published in our March 2011 issue), where approxi-mately 58% of innovator companies, and 55% of biotech companies, but only 35% of generic-drug manufactur-ers reported that QbD had a high or medium impact on their equipment-purchasing decisions.

The reasons for skepticism reported in the FDA article also mirror what we’ve heard anecdotally. Quality pro-fessionals have a hard time getting

management to buy into the con-cept—what the report referred to as a “disconnect between leadership and middle management.” An additional misconception, which the report at-tempts to squelch—is that QbD is costly to apply.

But there’s also great uncertainty within industry, bordering on frus-tration, about what FDA wants. The report notes—and we’ve heard this ourselves—that industry perceives in-ternal inconsistencies within FDA as to how the agency assesses a company’s QbD efforts. Companies also express some degree of discomfort about talk-ing with FDA at all. And again, I’ve heard individuals say that FDA might ask people to implement QbD in the-ory, but gives them a hard time when they try to put it into practice. FDA for its part intends to spend the next five years developing more internal consis-tency and clarifying expectations both within FDA and the industry. In other words, the agency will work to demys-tify QbD and nudge more companies towards implementation.

At its core, the QbD initiative asks manufacturers to understand how vari-ables—temperature, pressure, humidity, for example—govern the behavior of their reagents and their effects on prod-uct quality, principles we all learned in our high school science classes when we were first introduced to the experimental method. And that’s the most mysterious thing of all. How did a science-based in-dustry manage to unlearn these concepts in the first place? PT

retrospection and introspection at FdA

There’s great

uncertainty within

industry, bordering

on frustration, about

what FDA wants.

A report commissioned by FDA

evaluates the QbD paradigm.

Michelle Hoffman

Michelle Hoffman

is editorial director of

pharmaceutical technology.

Send your thoughts

and story ideas to

[email protected].

PharmTech.com/forum

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14 Pharmaceutical Technology SEPTEMBER 2011 PharmTech .com

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Web 2.O for Pharma InnovationPatricia Van Arnum

Innovation. Any company looks to new products and services to drive value and competitive advantage. Our emphasis

in innovation typically focuses on what is made new or improved, but not on how we innovate. In facing shortfalls in achieving

innovation, one may ask: “Was the problem the idea or the process used to generate the idea?” The short answer: it is both.

The practical ways to improve innova-tion in sourcing/procurement was dis-cussed at a recent educational program of the Drug, Chemical, and Associated Technologies Association. Pharmaceuti-cal companies, their suppliers, and other experts shared ways on how to cultivate and systemize innovation for generating actionable ideas for new or improved pro-cesses, products, or services, a particularly challenging task in sourcing/ procurement, where cost reduction is a primary and re-strictive emphasis.

An interesting thread in this dialogue was the growing use among pharma com-panies of “innovation communities.” These communities consist of employees in mul-tiple functional areas, suppliers, customers, and other stakeholders that use Web-based platforms as a means to share ideas, infor-mation, and lessons learned. The premise is simple but important: engage people, internally and externally, in a structured, but accessible way to cultivate innovation.

A model for open innovation is Procter & Gamble’s (P&G) “Connect + Develop” platform. According to P&G, more than 50% of its product initiatives involve col-laboration from outside innovators. For pharma companies rethinking their in-novation strategy, consider inside–outside innovation enabled by Web 2.0. PT

For additional insight, see “Strategies for Innova-tion in Pharmaceutical Sourcing and Procurement,” at PharmTech.com/strategiesinnovation and “Innovation in Sourcing” at PharmTech.com/strategiesinnovation.

Internal and external Web-based communities

are changing how pharma companies innovate.

S

Patricia Van Arnum

is a senior editor of

Pharmaceutical Technology.

»Read Patricia’s blogs at

blog.PharmTech.com.

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16 Pharmaceutical Technology September 2011 PharmTech .com

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PharmTech.com/aipCautionary Tales from the Files of “Control,”

a Senior Compliance Officer

it’s cheaper to give than to sell“Some countries require audits before ap-proving a product for their market,” noted our GMP Agent-In-Place. “They also re-quire the host company to pay for the audit and travel expenses. So when our favorite Southern Hemisphere country audited, the bill was $200,000. Two years later, we had sold a total of 15 vials of product in that country. Whose idea was that anyway? We should have just made a gift of the vials.”

Preparation is key“We had a central computer system in use around the world at all of our manufactur-ing sites,” our GMP Agent-In-Place began. “It’s location was in the United States. A foreign inspector wanted to see the hard-ware and hardware qualification docu-ments, so he visited our site. Because such inspections are scheduled, we had a chance to retrieve and review all the pertinent re-cords. Key employees were well briefed in their explanations, especially where there might be difficult questions.

“One potentially difficult topic was training because some employees with impressive longevity had been grandfa-thered for certain activities, and had no training records. When the inspector asked for a training record, he didn’t specify a position or person, so we naturally handed him a new employee’s folder with a complete record. It’s these little things that can make a difference. We ended up with no findings.”

i made that“Fifteen years ago, I was traveling to Brazil for a meeting with some of our affiliates,” recalled our GMP Agent-In-Place. “Before

traveling, I had to get a couple of immu-nizations, so I went to a travel specialist medical group to get them. One required injection came in a vial. The nurse flipped off the seal and was going to stick the sy-ringe through the stopper without disin-fecting the stopper. I yelled, and requested

her to stop and disinfect the stopper first. After a discussion, it was clear that she thought the stopper was sterile, but I knew that the seal was merely a dust cover. Yes, the stopper starts sterile, but the flip-off seal does not assure sterility. How did I know this, you might ask? The product was one that I made.”

i made that, take 2“For me, it’s always fun to have the prod-ucts I help make administered to me,” smiled our GMP Agent-In-Place. “I know the adverse-event profile and complaint profile, and I can hold a productive discus-sion with the healthcare professional. Some time ago, I was at the eye doctor and he used some orange-dye strips. I had made them and we had an interesting conversa-tion about them. There’s a certain comfort level knowing all of the steps we had taken

to assure the product’s identity, safety, po-tency, purity, and quality.”

Saved“At my previous company, there was a huge emphasis on cost savings,” our GMP Agent-In-Place reported. “I ran the stabil-ity program and, every year, the director of quality would ask whether I had any savings for him. The first time he asked, I wasn’t sure how to answer, but he ex-plained. Anytime that we canceled a sta-bility test or discontinued a program, these were savings, and we should total them up.

“After that meeting, our team regularly determined whether we needed to per-form all the post-expiration date testing that had been requested. Another fruit-ful area turned out to be testing that was requested by certain development project managers —often, the first lots were left in stability testing areas well after the prod-uct’s development had moved on; these early lots were no longer needed. A few years later, I was informed that these sav-ings were directly related to the bonus the director received. Non-directors did not qualify for such a bonus.” PT

Being aware of a forthcoming inspection or how a

product was made can make a huge difference.

Knowing is Half the Battle

Pharmaceutical Technology’s monthly

“Agent-in-Place” column distills true-

life cautionary tales from the files of

Control, a senior compliance officer.

If you have a story to share, please

email it to Control at AgentinPlace@

advanstar.com. We won’t use any

names, but if we do use your experi-

ence in the column, you’ll receive a

Pharmaceutical Technology t-shirt.

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18 Pharmaceutical Technology mONtH 2011 PharmTech .com18 Pharmaceutical Technology September 2011 PharmTech .com

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18 .....Market Report

from Latin America

22 .....Global Healthcare

on the Ground: IFPMA’s Efforts

24 .....Corporate Sustainability Forum

24 .....Upcoming Events

Growth and change in Brazil and Mexico offer key opportunities for the region’s pharmaceutical industry.

Report from:

Latin America

Opportunities for growth as well as favorable regulatory measures within the pharmaceutical market in Latin America are making the region more attrac-tive than ever. According to IMS Health, the entire Latin-American region is expected to grow to $51.3 billion by 2014.

“Latin America’s pharma market in general has shown a growth trend similar to Asian markets in terms of sales, around 12% to 16%,” says Carlos Kiffer, operations director for GC2, a pharmaceutical R&D company based in São Paulo, Brazil.

Demand for pharmaceuticals and other products is increasing across the region, despite the global credit crisis, according to the Economic Commis-sion for Latin America and the Caribbean (ECLAC), a United Nations orga-nization with headquarters in Santiago, Chile. As a result, Latin American countries are expected to grow in total approximately 4.7% this year, projects ECLAC. In 2010, the region grew 5.9%.

contin. on page 20.

Hellen Berger

THE

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IN THE FIELD

contin. from page 18This economic performance is attracting global attention.

Trade and manufacturing practice are also playing a role in the region’s success. For example, the seven largest Latin American countries—Brazil, Mexico, Venezuela, Argentina, Colombia, Chile, and Peru—have all become signatories to international trade treaties such as the Trade-Related aspects of Intellectual Property Rights (TRIPS) treaty. Brazil and Mexico have been ap-plying GMPs in their pharmaceutical industries for years. These practices are positive factors for investors, according to Carlos Kiffer, who also works as a researcher for the Federal University of São Paulo.

Brazil increases healthcare access Brazil, in particular, has the largest pharmaceutical market in Latin America and “leads in terms of gross sales with an average of $12 billion per year,” according to Kiffer. The country’s R&D market represents approximately 5% of total gross sales, he adds.

This year looks good so far. IMS Health projects the pharma-ceutical industry in Brazil alone will grow approximately 10% and report total revenues of $25.6 billion in 2011. By the year 2015, the market is projected to reach $32.8 billion, according to Business Monitor International (BMI).

Brazil’s potential lies in its population of nearly 200 million inhabitants, many of whom are just gaining access to private healthcare and generic drugs. During the past decade, the gov-ernment has put controls into place to end sky-rocketing infla-tion, consolidated its economy, and opened the door to goods and services for millions of Brazilians, many of whom had been living in poverty. As a result of the changes, private healthcare firms based in the southeast of Brazil—the most developed region of the country—have reported double-digit growth in profits in the past few years.

Government measures regarding fiscal adjustments have in-creased Brazil’s competitive edge and boosted investments from the private sector as well. According to BMI, imports of goods produced outside South America, including pharmaceuticals, are expected to drop due to legislation passed in 2010 (Law number 12.349/2010). The new law gives preference to goods and services provided by domestic or foreign companies installed within the Mercosur economic bloc. Mercosur, also known as the South-ern Common Market, is made up of Argentina, Brazil, Paraguay, and Uruguay. Bolivia, Chile, Colombia, Ecuador, and Peru have associate-member status in the bloc.

“We therefore expect growth in the generic-drug sector to outpace the rest of the industry, especially in terms of sales vol-ume,” according to a February 2011 BMI report titled, Industry Trend Analysis.

Generic-drug sales in Brazil represented 17.2% of the phar-macy sector by value and 21.3% by volume in 2010. The sector is expected to increase to around 25% by 2015, according to in-dustry data.

Market consolidation is underway as well. Recent acquisitions

of domestic firms by giant multinationals have changed the local market considerably. And despite growing market share by for-eign investors, growth and opportunities for smaller biotech firms are still expected, primarily because of the country’s rich biodiversity, according to Brazil’s National Pharmaceutical Labo-ratories Association.

Mexico strengthens regulatory measuresMexico has the second largest pharmaceutical industry in Latin America, with average gross sales around $9 billion per year, ac-cording to Kiffer. The R&D market in Mexico, like Brazil, cor-responds to approximately 5% of the country’s total gross sales, he explains.

Looking ahead, Mexico’s annual growth rate for the pharma-ceutical industry is projected to be 11.7% between 2009 and 2014, and will likely reach close to $14.9 billion, according to BMI.

According to Kiffer, Mexico’s pharmaceutical market plays a relevant role in Latin America because it is located in North America and is closer to the US than any other Latin American country. The proximity allows Mexico to do business with the US and use the logistics infrastructure available in the region, adds the researcher.

“Mexico has been developing its infrastructure and logistics for research, while good quality universities and [recently] improved pharma regulations offer opportunities,” says Kiffer.

The country’s business environment has indeed become more competitive, according to IMS Health. The Mexican government, for example, abolished requirements for pharmaceutical com-panies to establish a local plant in order to obtain import per-missions. As a result, public and private customers are no longer forced to purchase medicines from drug manufacturers that have plants operating in the country.

In addition, according to Espicom Business Intelligence, the number of people accessing public healthcare in Mexico is ex-pected to increase as the country implements universal health-care coverage. The change could slow down growth in the private pharmaceutical sector, but will likely increase the sale of generic drugs. In fact, generic-drug spending is projected to comprise 7.5% (by value) of the total drug market in Mexico by 2014, according to BMI.

To prepare for this growth, the country lowered its import tax rate and is supporting generic-drug company license deals with multinational firms. The government is also collaborating more with the US FDA, including by simplifying authorizations for im-ported products into Mexico. Additional improvements include the introduction of regulations aimed at controlling the quality of generic drugs in the country.

Although Mexico is technically trailing behind other countries in Latin America with regard to the generic-drug sector, it is ex-pected to continue to outrank overall pharmaceutical markets in many other countries in the region.

Hellen Berger is a business correspondent based in São Paulo, Brazil.

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IN THE FIELD

Global Healthcare on the GroundIFPMA Engages Global Bodies

to Push Health Efforts Forward

The complexity of global health con-cerns requires the engagement of national and regional governments, the private sector, nongovernmental organizations, and other civil-society organizations. For the pharmaceuti-cal industry, this involvement can be through individual companies and collective industry actions. The Inter-national Federation of Pharmaceuti-cal Manufacturers and Associations (IFPMA) is an important instrument of collective participation on global health concerns. IFPMA represents 29 multinational research-based phar-maceutical companies and 45 national industry associations in North Amer-ica, Western Europe, Japan, Austra-lia, Central and South America, Asia, and Africa. Eduardo Pisani, IFPMA’s director general, recently spoke with Pharmaceutical Technology to discuss the association’s policy objectives and action plans in global health.

IFPMA’s scope of action“The mission of the IFPMA is to en-gage with international organizations to build mutual understanding and to find effective and sustainable so-lutions to major global health issues

with a focus on medicine quality, in-n o v a t i o n , and access,” says Pisani. To that end, I F P M A , b a s e d i n G e n e v a , has formal

consultative status with the United Nations, UN specialized bodies, in-cluding the World Health Organiza-tion (WHO), the World Bank, and the World Trade Organization.

Three core areas—quality, innova-tion, and access—serve as the frame-work for IFPMA’s specific work in global health, which increasingly requires partnerships between the private and public sector. “Nowadays, most of the work accomplished in the global public health arena is collaborative in nature, so multistakeholder partnerships are encouraged,” says Pisani, pointing to partnerships in R&D, capacity-building, training, or technology transfer.

He points to the collaborative focus inherent in the UN Millennium De-velopment Goals (MDGs), a set of eight time-bound targets for address-ing extreme poverty, hunger and dis-ease, gender equality, education, and environmental sustainability. “MDG Goal 8 specifically mentions the need for cooperation with pharmaceutical companies in the development of a global partnership to provide access to affordable, essential drugs in devel-oping countries,” says Pisani. To illus-trate IFPMA’s role in the MDGs, Pisani noted that IFPMA member companies have approximately 210 projects in place, worth an estimated $9.2 billion that address the health-related MDGs. By 2015, the date set for the MDGs to be realized, if the present trend is maintained, the value of these projects is expected to increase to $20 billion (excluding companies’ expenditures on R&D for diseases of the developing world), he adds.

Noncommunicable disease. Noncommuni-cable diseases, particularly cancer, cardio-vascular disease, respiratory disease, and diabetes, are a growing health problem in the developing world. Noncommuni-cable diseases have become a problem in certain countries as lifestyle choices, such as an unhealthy diet and tobacco use, ac-company a rise in the overall standard of living for middle-income countries as the economies of these countries improve.

To address the problem, the UN is holding a first-ever UN General Assembly high-level meeting on noncommunicable diseases this month (September 2011) in New York. IFPMA will be responsible for conveying the research-based pharmaceu-tical position on chronic diseases. “We be-lieve that the experience in the developed world demonstrates the crucial role of changing risky behaviors and prevention,” says Pisani. “We also will be advocating for the effective, multistakeholder strate-gies at the global, regional, and national levels that are fully integrated into health-care systems.”

In this multistakeholder framework, Pisani says that governments, the research-based pharmaceutical industry, civil soci-ety organizations, and health profession-als can play a role in increasing education and awareness, improving early detection and disease surveillance, and facilitating implementation of prevention programs.

Inf luenza pandemic preparedness.

Influenza pandemic preparedness, in-cluding access to vaccines for develop-ing nations, is a crucial issue in global public health and was one of the topics addressed by the World Health Assem-bly, the decision-making body of WHO, which met in May 2011, in Geneva. At the meeting, the World Health Assem-bly agreed to the Pandemic Influenza Preparedness (PIP) framework. IFPMA contributed to the deliberations of the WHO Open-Ended Working Group (OEWG) of Member States on PIP, which was tasked with improving the global system for responding to future influenza pandemics. The OEWG ad-

Patricia Van Arnum

Eduardo Pisani

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IN THE FIELD

opted an agreement in April 2011 for a PIP Framework, which was endorsed by the World Health Assembly in May.

IFPMA supported the OEWG’s plan, in particular for addressing key chal-lenges, such as increasing the capacity of vaccine production and enabling access in developing countries. IFPMA also supports the WHO’s financial parame-ters for the industry for the WHO Global Influenza Surveillance Network (GISN).

The OEWG recommendation in-cludes specific requirements for users of the GISN to ensure that vaccines and antivirals are made available to developing countries in the event of a future pandemic. During the most re-cent H1N1 pandemic, IFPMA vaccine manufacturers committed 166 million doses to meet the WHO target of 200 million vaccine doses for developing countries, according to IFPMA.

In commenting on the PIP frame-work, IFPMA recognized the impor-tance of local production of vaccines and antivirals in pandemic prepared-ness and said it would continue to ex-plore local production, pointing to in-vestment made by member companies in several countries, including Mexico, Brazil, China, Indonesia, and Thailand. During the OEWG/PIP consultations,

individual IFPMA members confirmed that they also were willing to voluntarily undertake a selection of actions in the event of a future pandemic, including production-capacity expansion and ac-cess to reverse-genetics technology, de-pendent upon skills, knowledge, finan-cial management, public-health policy, and national regulation.

Counterfeit drugs. Counterfeit drugs in the developing world are a large pub-lic health concern and represent a key strategic focus for IFPMA. In 2010, 1735 incidents of fake medicines were reported by the Pharmaceutical Secu-rity Institute, a Washington, DC-based nonprofit organization, a nearly 10% increase compared with the prior two years. One third of these cases reached licensed wholesale distributors and/or pharmacies in 37 different countries.

In 2010, IFPMA partnered with its member association, PReMA, the na-tional pharmaceutical industry asso-ciation in Thailand, the International Associat ion of Patients Organi-zation, and the US Pharmacopeia to raise patient awareness about the health risks

imposed by counterfeit medicines in Southeast Asia. IFPMA also chairs the working group on anticounterfeiting technologies of the International Medi-cal Products AntiCounterfeiting Task Force (IMPACT). WHO established IMPACT in 2006 as the organization’s drug anticounterfeiting group.

Looking forwardIFPMA has additional initiatives under-way in the areas of neglected tropical diseases and antimicrobial resistance. Pisani emphasizes that the pharma-ceutical industry’s participation in solving global health concerns is part of a larger collaborative, multistake-holder approach. In that effort, he says transparency, cooperation, and trust are key. “We have to walk the talk,” he concludes, underscoring not only the in-dustry’s participation in the dialogue on global health concerns, but its specific involvement in solutions.

» Worth Attending

PDA-FDA Joint Regulatory ConferenceSept. 18–21, Washington, DC

www.pda.org/pdafda2011

INTERPHEX Puerto RicoOct. 20–21, San Juan

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2011 Annual AAPS ConventionOct. 23–27, Washington, DC

www.aaps.org

CPhI Worldwide Oct. 25–27, Frankfurt, Germany

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USP Science & Standards Symposia: Bringing Science and Industry Together WorldwideOct. 3–6, Seattle

www.usp.org/meetings/asMeetingIntl/

INTERPHEX China*Featuring a special program on GMP-compliant

equipment, put together by Pharmaceutical Technology

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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

nongovernmental organizations. In the September issue (available at

www.PharmTech.com/PTSM):

• Analysis of proposals calling for stronger environmental standards for

the manufacturing of pharmaceuticals sold in Europe

• 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,

senior editor, at [email protected].

Watch the pieces fall into place when you work

with the experts.

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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,

[email protected].

IN THE SPOTLIGHT: MANUFACTURING

Tablet press enables adjust-ments to precompression forceBosch–Manesty’s Xpress 100 R&D

rotary tablet press incorporates a

hybrid turret that uses four stations

of B- or D-format punches and dies.

The turret’s four unused stations

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Lower punches can be removed

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The tablet press includes load

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displacement, which tells personnel

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all times. One paddle feeder fills the

necessary amount of powder into

the dies and replicates powder feed

behavior at production scale.

Biocontainers providechemical resistanceThe FluoroFlex biocontainers are the most recent addition to Meissner’s One-Touch series of single-use systems. Based in polyvinylidene fluoride, the biocotainers are made of a recently developed, multilayer coextruded film that was designed to meet the demanding requirements of the pharmaceutical industry. The FluoroFlex products can be used for all applications for which traditional polyolefin-based biocontain-ers are appropriate. The film was designed to provide thermal stability, chemical resistance, and robustness that exceed those of traditional polyethylene-based biocontainers.

Xpress 100 rotary tablet press

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FluoroFlex biocontainer

Meissner Filtration Products

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As science advances and regulations evolve, new classes of products become

available. Recent years, for example, have witnessed increased emphasis

on highly potent products and biopharmaceuticals. As patients’ demands

change, drugmakers must have the proper equipment to produce needed

medicines. This month’s products help manufacturers respond to public

demand and regulatory requirements. A tablet press from Manesty produces

scalable results. Biocontainers from Meissner provide thermal stability for

sensitive products. Emerson’s pinch valve helps provide precise flow control.

Pinch valve automates control of sterile liquidsThe Baumann 85000 sanitary pinch valve

from Emerson Process Management offers

an automated solution for control applica-

tions within single-use manufacturing. The

valve is designed to enable consistent qual-

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batch control. Its Fisher Fieldvue digital

valve controller provides an installed equal-percent flow characteristic for preci-

sion control. Combining the valve with a PlantWeb system facilitates technology

transfer for process scale-up.

The Baumann 85000 can clamp around existing disposable tubing, which

enables the user to bypass extractables and leachables testing on the liner, thus

ensuring compatibility with the liquid-control process and compliance with FDA

requirements. Its tube–shell design eliminates the need to replace the liner with

each batch, which simplifies changeout of disposable tubing between batches and

reduces users’ inventory. Its epoxy-coated actuator features stainless-steel fasteners

that enhance corrosion resistance. Also, the valve plunger does not contact the pro-

cess fluid and operates with a shutoff rating equal to ASME/FCI 70-2, Class VI.

Baumann 85000 pinch valve

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The United States may be in danger of losing its leadership position in bio-pharmaceutical research due to cer-

tain regulatory policies and reductions in reimbursement for new breakthrough therapies. Prescription-drug user fees are scheduled for reauthorization by Congress next year, and all parties antici-pate a push for new policies to improve the drug-approval process. Although the broader goal is to spur biopharmaceuti-cal research and new drug development, manufacturers fear that cost-cutting ef-forts by the Obama administration and Congress will curb resources for FDA and squeeze drug-payment policies. The rhetoric is heating up as industry moves to deflect measures it fears will limit support for discovery and for regulatory oversight of new medical treatments.

Industry underminedA main message from pharmaceutical companies is that US policies that under-mine investment in biopharmaceutical innovation will prompt manufacturers to shift R&D to more hospitable climes. The European Union’s Innovative Medicines Initiative has earmarked $2 billion to fund collaborative research projects and build expert networks to support pharmaceu-tical innovation in Europe. The Chinese government is targeting the biopharma-

ceutical industry as part of a five-year economic development campaign, which includes providing $1.5 billion to invest in startup companies.

At a press briefing in July 2011, John Castellani, president of the Pharmaceuti-cal Research and Manufactures of America (PhRMA), explained how the biopharma-ceutical industry has thrived in the US because of policies that protect intellectual property, support scientific research, and place a high value on medicines. Now, other countries, such as Germany and France, want to attract back biopharma-ceutical firms, he warned. At the same time, Singapore and other emerging econ-omies have identified the biopharmaceu-tical sector as crucial to their economies. Merck President Kenneth Frazier similarly observed in a Wall Street Journal op–ed in July, that the designation of the US as the “medicine chest to the world” and its claim to be home to 82% of the world’s biotech R&D activity will be undermined if the federal government imposes price controls on the Medicare drug program and estab-lishes the Independent Payment Advisory Board (IPAB) (1). (See sidebar, “Campaign to dismantle IPAB”).

The price controls mentioned by Frazier refer to additional rebates on drugs covered by the Medicare Part D drug benefit, spe-

cifically those medicines consumed by low-income seniors who previously obtained medicines from state Medicaid programs that negotiate rebates with pharmaceu-tical manufacturers. The shift of those “dual eligibles” to Part D plans eliminated those rebates, and industry critics, led by Rep. Henry Waxman (D-CA), have been pressing to recoup this pharmaceutical “windfall” for several years.

The Congressional Budget Office (CBO) estimates that rebates on drugs for some 10 million seniors who receive low-income subsidies under Part D would save $112 billion over the next decade, or $10 billion a year. That’s a big number that will be hard for budget-cutters to ignore.

PhRMA is fighting the rebate policy and other actions with analysis claim-ing that the policy could prompt bio-pharmaceutical companies to shift op-erations, and thus US jobs, overseas. A Battelle study for PhRMA calculates that a $10-billion reduction in on industry revenues would kill 130,000 high-paying jobs, thereby exacerbating the nation’s al-ready high unemployment rate.

WASHINGTON REPORT

Jill Wechsler

is pharmaceutical

technology’s Washington

editor, 7715 Rocton Ave.,

Chevy Chase, MD 20815,

tel. 301.656.4634,

jwechsler@advanstar.

com.

PDUFA renewal legislation sets stage for new

policies affecting revenue, research, and oversight.

Jill Wechsler

Manufacturers and FDA Gear Up for User-Fee Action

The most notable

PDUFA change gives

FDA an extra two

months to review

applications.

In Washington this month

• PhRMA fights rebate policy

and other actions that may

drive biopharmaceutical

companies to leave the US.

• Medicare Part D faces

instability as deficit-

reduction plans are debated.

• Congress considers

a range of pet programs

to incorporate into the

pending PDUFA renewal.

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Washington Report

Even more troubling are suggestions that the rebate plan could destabilize the Part D program which has been a huge success in providing less costly medicines to seniors. Another report for PhRMA by the IMS Institute for Healthcare Informat-ics documents how Part D has led to lower spending on medicines for seniors. More important, a separate study published in the Journal of the American Medical Asso-ciation finds that increased use of prescrip-tion drugs due to the Medicare drug ben-efit significantly reduced medical spending by seniors on hospital and nursing home care (2). Medicare reports that the pro-gram’s total cost is 41% less than initial CBO estimates, partly because plans have negotiated hefty discounts from manufac-turers. Layering on another level of rebates, says PhRMA senior vice-president Rick Smith, would be “a double whammy.”

PDUFA extrasIf a Part D rebate plan does not end up in Medicare cost-cutting proposals as part of broad deficit-reduction legislation slated to

Many members of Congress and healthcare

providers want to dismantle the Independent

Payment Advisory Board (IPAB) before it gets

going, and pharmaceutical companies have

joined in the attack. Manufacturers fear that this

independent board will make significant cuts

in reimbursement for innovative medicines

as part of its charge to keep Medicare spending

in line with annual budget targets.

The Affordable Care Act (ACA) of 2011

gave IPAB authority to propose reductions in

Medicare outlays if expenditures grow faster

than certain spending levels, and the cuts go

into effect automatically unless the legislators

enact alternative changes that achieve similar

savings. The aim is to depoliticize the Medicare

cost-cutting process, but detractors complain

that the Board’s focus on short-term spending

reductions will lead to arbitrary cuts, instead of

effective strategies to improve reimbursement

and care delivery.

Both the House Budget Committee and the

Energy and Commerce Committee aired these

issues at hearings in July 2011. IPAB supporters

championed the program as the only ACA

provision that specifically imposes controls on

exploding healthcare costs. They emphasized

that IPAB proposals won’t kick in unless spending

soars too high and that Congress has authority to

make final decisions.

Providers complained that the process and

timeframes for calculating spending targets, for

developing IPAB proposals, and for Congress to

act are complex and confusing. The Healthcare

Leadership Council, which represents providers,

patients and pharmaceutical companies, ruled

out “legislative tinkering” to fix IPAB, due to its

focus on short-term budget reductions instead of

long-term Medicare improvements.

The first IPAB proposal for reducing

expenditures is due in 2014. Implementation is

supposed to start in 2015, but no one is rushing

to name board members or get IPAB up and

running.

Campaign to dismantle the Independent Payment Advisory Board

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Washington Report

come before Congress, it will be on the list of pharma-related reforms included in next year’s legislation to reauthorize the Pre-scription Drug User Fee Act (PDUFA V). After a year of consultation with industry and other stakeholders, FDA officials and manufacturers reached a new PDUFA agreement this past spring; it faces fur-ther public discussion before it is formally transmitted to Congress in January 2012. The current user-fee program expires on Sept. 30, 2012, and a new program has to be in place before then in order for FDA to be able to continue collecting industry payments, which now support more than 60% of the cost of the approval process for new drugs and biologics.

Members of Congress already are gear-ing up to add a range of pet programs to the user-fee legislation. A number of drug-related policies calculated to generate sav-ings for government health programs will include bills to legitimize drug reimporta-tion, reduce exclusivity for biosimilars, and curb brand–generic patent settlements. There will be a strong push to extend steep

340B discounts on drugs used by safety-net hospitals to include inpatient treatment and orphan medicines.

The basic PDUFA proposal is not radi-cally different from the current user-fee program and by itself should win Congres-sional support fairly easily. FDA is looking to boost user-fee revenue by about $40 mil-lion per year, according to Center for Drug Evaluation and Research Director Janet Woodcock’s testimony to the Energy and Commerce Committee—that’s a “mod-est” 6% annual increase that will bring in nearly $700 million in fiscal year 2013. The most notable change gives FDA an extra two months to review applications, here in the guise of a 60-day “administrative filing period” after submission of an application; this timeframe will permit agency review-ers to fully vet the filing before starting the official review clock. More meetings will take place between reviewers and sponsors, with a new cadre of FDA liaison officials to enhance communications. FDA will assess meta-analysis methods, biomarkers, and patient-reported outcomes measures to im-

prove clinical studies. The plan also calls for standardizing risk evaluation and miti-gation strategies (REMS); boosting FDA’s Sentinel system to improve postmarket drug-safety surveillance; and implement-ing an electronic submissions system for clinical data, something that has been in the works for years.

Along with PDUFA, FDA and manu-facturers are working on a new user-fee program for generic drugs, while also discussing a formula for fees for new bi-osimilar-product applications. Support for renewing pediatric-drug development and research incentives is strong, preferably on a permanent basis. The aim is to move away from the five-year sunset-and-reauthoriza-tion process linked to PDUFA for the Best Pharmaceutical for Children Act and the Pediatric Research Equity Act to encour-age more pediatric product development.

The Medical Device User Fee Act (MDUFA) also is up for renewal, and nego-tiations on that program have been much more contentious than those for drugs. FDA is embroiled in evaluating proposals

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Washington Report

for overhauling its 510k regulatory process for low-risk devices, which has device mak-ers up in arms. A recent Institute of Medi-cine (IOM) report advises FDA to find a better way to assess the safety and efficacy of these products, an approach that indus-try feels will stymie medical device innova-tion and product development. FDA has to reduce fees for 2012 because it collected too much from industry this year. This situa-tion, along with the larger device regula-tory issues, has not smoothed the process for negotiating future fees.

As the PDUFA legislation emerges, pharmaceutical companies are looking to line up behind a number of drug-related measures, such as proposals to boost in-centives for the development of new anti-biotics and to update FDA’s orphan-drug program. Industry backs efforts led by Rep. John Dingell (D-MI) to strengthen oversight of imported drugs and active ingredients, with added FDA authority for recalls and import controls and required registration and fees on foreign manufac-turing facilities to cover the costs of over-

seas inspections. Companies also support Republican-backed efforts to make REMS requirements less burdensome and to re-vise FDA conflict-of-interest policies that exclude many qualified experts from seats on FDA advisory committees.

The Biotechnology Industry Organiza-tion (BIO) recently unveiled its own wish-list of policy changes to spur biotech R&D. BIO wants to make FDA an independent agency, more like the Federal Trade Com-mission, and to depoliticize it by appointing the FDA commissioner to a fixed six-year term, separate from the presidential elec-tion cycle. BIO wants to require FDA to tell sponsors specifically why it’s not approving an application, and also proposes a condi-tional or “progressive” drug-approval pro-cedure that permits therapies for diseases that lack any effective treatment to come to market on a limited basis while the sponsor completes clinical studies. The list also in-cludes reviving the Reagan–Udall Founda-tion, an independent research organization established by the FDA Amendments Act of 2007, but never funded by legislators.

Congress opens debateFDA laid out its goals for user-fee renewal legislation at House and Senate hearings in July 2011. Commissioner Margaret Hamburg outlined for the Senate Health, Education, Labor, and Pensions (HELP) Committee how user fees support patient access to new drugs and medical products. Panel leaders expressed strong support for renewing user fees for drugs and devices, hopefully by next spring. But Sen. Richard Burr (R-NC) threatened to block PDUFA reauthorization if FDA doesn’t change its approval process for medical devices. Hamburg acknowledged that devices raise problems, but blamed approval delays on poor quality applications that require re-viewers to ask manufacturers for additional data not found in the original filing.

Woodcock provided the House En-ergy and Commerce Health subcommit-tee with a fairly positive report on FDA’s drug approval process, describing how proposed PDUFA V enhancements will further address drug access and safety is-sues. Most Democrats and Republicans

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Washington Report

praised the fee program, as did industry and patient representatives.

Energy and Commerce Committee Chairman Fred Upton (R-MI) laid out top Republican concerns: REMS requirements may be thwarting new drug development, and “rigid and unrealistic” conflict-of-interest policies keep top scientists off ad-visory committees, thus preventing these panels from vetting new drug candidates in a timely manner. Marc Boutin, execu-tive vice-president of the National Health Council, backed conflict-of-interest policy changes, noting that the rules have created “alarming” committee vacancy rates.

Woodcock credited the 20-year-old user-fee program with establishing a more efficient, predictable drug approval process that has sped up the review pro-cess for new drugs and biologics “without compromising the agency’s high stan-dards for demonstration of safety, efficacy, and quality of new drugs.” FDA has pro-vided patients with access to more than 1500 new drugs during the past two de-cades, she commented, including impor-

tant cancer therapies that a recent study shows are available to US patients before reaching the market in Europe.

Woodcock also reported that FDA is on track to approve more new medicines in 2011 than in recent years, with 20 new drugs already okayed at the mid-year point; the number rose to 21—the 2010 total—soon after when FDA added As-traZeneca’s Brilinta to the list. Woodcock also noted that CDER’s rate of first-cycle approvals for priority new molecular enti-ties (NMEs) is going up, citing recent ac-tion on landmark treatments for hepatitis C and for late-stage melanoma. And she noted how the REMS program can facili-tate access to high-risk products, such as a new thyroid cancer treatment that FDA approved with a REMS to limit product use to truly needy patients.

The real problem, she said, is not slow approvals, but that too many experimental drugs continue to fail during development. PDUFA support for more FDA–sponsor meetings will help, along with added re-sources to develop further guidance and

new methods for testing and evaluating experimental drugs.

Many of these undertakings are in-cluded in a CDER report identifying science and research needs that can en-hance the development of new drugs and biologics. This July 2011 publication from CDER’s Science Prioritization and Review Committee builds on the Critical Path Opportunities reports of 2004 and 2006 in citing research projects that FDA would like to pursue, ideally in partnership with industry, academia, or other government agencies (3). The topics include ways to im-prove analysis of postmarket data, product-quality assessment, clinical trial design, and individualized treatments.

References

1. K. Frazier. Wall Street Jrnl., July 13, 2011. 2. J. McWillians et al., JAMA 306 (4), 402–409

(2011). 3. CDER Science Prioritization andReview

Committee, “Identifying CDER’s Science and Research Needs Report,” (FDA, Rock-

ville, MD, July 2011). PT

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Sometimes Congress actually gets it right, but keeping it that way is another matter. In late 1997, the FDA Modern-

ization Act was passed and among its many provisions was an incentive for pediatric exclusivity. Under the law, FDA requested that the pharmaceutical industry conduct pediatric studies in exchange for an ad-ditional six months of market protection against generic-drug competition for all the products containing the active ingredient for which the studies applied. A year later, a complementary and mandatory provision was added in a carrot-and-stick approach to ensure the broadest coverage for an es-timated 75% of drugs that were being used off-label for children. This incentive pack-age was reauthorized in 2002 and 2007, and reauthorization looms again in 2012. The debate already is taking shape, and the arguments and adversaries are lining up in a now predictable array.

There is little debate about the success of the program, which has been publicly lauded by regulators, industry, pediatric healthcare professionals, and public-health advocates. Its record after nearly 15 years is still noteworthy: more than 400 drugs have been labeled for pediatric use by hun-dreds of companies (1). Granted, there are still some challenges to be addressed, es-pecially with neonates and formulations, but the US program has been emulated worldwide. Europe, for example, adopted a similar approach in 2004, and Japan has been holding high-level discussions on pro-posals for such a program as well.

Nor is there much debate about the dif-ficulty of doing pediatric studies despite a report by the Tufts Center for the Study of Drug Development that showed that the scope of work, the length of time required to do pediatric studies, and the related costs

have increased significantly during the life of the program (2). Nor was there any con-cern that more than 40% of pediatric-study programs fail, which increases overall in-dustry spending on pediatric studies by about two-fold. Even if pediatric studies are accepted in time to garner the exten-sion of market exclusivity, many sponsors experience events, such as court challenges by generic-drug companies, product with-drawals or prescription-to-over-the-coun-ter switches that dramatically decrease sales during the exclusivity period.

Ironically, the debate always is about whether the industry is receiving too much benefit from the program despite that, nominally at least, Congressional in-tent was to incentivize the industry. Every five years, tired banners are waved about a profits cap, tying the length of the award to projected profits or reducing the exclusivity period to three months. All of this grand-standing starts anew even though neutral parties have considered these proposals in past debates and have rejected them.

For example, the European Commis-sion affirmed that a fixed six-month award is optimal both in terms of practicality and fairness (3). FDA testified in the last round of reauthorization hearings held in May 2001 that it does not really bring expertise in business matters to the table, but relies on reports from independent certified accountants or accepts a manufacturer’s certification when cost recovery data is re-quired (4). FDA added that it faces risk of litigation, especially if there is any ambigu-ity in the language tying length of exclusiv-ity to sales data. The agency is also troubled that using vital resources to analyze finan-cial data or police the sales of drugs would compromise FDA’s primary mission. Congress, too, has previously weighed the trade-off implicit in marketing exclusivity in the Orphan Drug Act and determined that the benefits exceeded the dangers (5).

Why does the pediatric studies incen-tive work? Because it does what an incen-tive program is supposed to do. It incites the intended audience to take action. Un-like many alternative incentive proposals, it is not too speculative or unsustainable, such as those dependent on the vagaries of government grant programs or prizes from charitable foundations nor is it too limited for the risks being taken, such as tax credits. A few other incentive programs have worked, but none are as effective as the carrot-and-stick approach used in pediatric exclusivity. It has withstood the test of time and is being emulated by other countries at a time when laws passed by Congress are considered good models for little else. Now and through 2012, we have and will continue to have debates on the presidential election, healthcare reform, and the national debt. Do we really need another divisive debate on something that actually works?

references 1. FDA, “Pediatric Labeling Changes through

July 18, 2011” (Rockville, MD), www.fda.gov/downloads/ScienceResearch/SpecialTopics/PediatricTherapeuticResearch/UCM163159.pdf, accessed Aug. 15, 2011.

2. C.P. Milne, Food Drug Law J. 57 (3), 491–518 (2002).

3. EC, “Proposal for a Regulation of the Eu-ropean Parliament and of the Council on Medicinal Products for Paediatric Use and Amending Council Regulation (EEC) No1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004. Extended Impact Statement Final” (Brussels, Sept. 3, 2004), http://ec.europa.eu/health/files/paediatrics/docs/extended_impact_assess-ment_final_3_september_en.pdf, accessed Aug. 22, 2011.

4. J. Woodcock, Statement, Senate Health, Edu-cation, Labor, and Pension Committee Hear-ing, May 8, 2001.

5. Code of Federal Regulations, Title 21, Food and Drugs(Government Printing Office, Washington DC. Part 316. PT

Christopher Milne is associate director

with the Tufts Center for the Study of Drug

Development, [email protected].

Reauthorization of pediatric exclusivity provisions

looms in 2012 and debates begin anew.

Christopher Milne

The Case for Pediatric Exclusivity

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Counterfeiting is becoming more sophisticated and widespread, but the number of overt and covert

tools to fight it is growing. As a result, the global market for anticounterfeit-ing products for pharmaceuticals and foods is expected to increase to $79.3 billion by 2014, reflecting a compound annual growth rate (CAGR) of 8.6% since 2009. According to this forecast, North America will account for almost two-thirds (62%) of this expenditure; however, the second-largest market, Asia, is expected to expand faster, with a CAGR of nearly 20% because of the low penetration of anticounterfeiting measures and a significant level of counterfeiting in the region (1).

Interest is particularly high in pro-tective technologies that rely on input from a smartphone. Readily available worldwide, smartphones can authenti-cate products in real time at the point of purchase or at home. In fact, global smartphone sales will top 420 million devices in 2011, accounting for 28% of all handsets. With the introduction of affordable “entry-level” smartphones, researchers predict that annual sales will surpass 1 billion devices by the end of 2016, or one of every two mobile handsets sold (2).

As well as being increasingly likely to own a smartphone, consumers also find the device familiar and easy to use. Smartphone authentication technology delivers an immediate “authentic” or “not authentic” response to a text or to the scan of a barcode or other package feature. Frequently, the authentication technology also can send product-related information, support track-and-trace or pedigree initiatives, or collect data about the purchase. Therefore, smartphone-based technology “is finding favor as an alternative to ‘specialist’ readers across the entire authentication market,” wrote William Llewellyn, vice-president and senior consultant at AWA Alexander Watson Associates, a Netherlands-based market-research firm (3).

Smartphone-based authentication technology is already in use in Nigeria and has been so successful that it will be commercialized in other countries in Africa, as well as in India. “Given the prevalence of mobile technology throughout the world, it made sense to use a technology that was already in every customer’s pocket,” explains Ash-ifi Gogo, cofounder and chief executive officer of Sproxil, a provider of brand-protection software and services.

In Nigeria, consumers remove a scratch-off overprint, similar to that used for lottery tickets, to reveal a one-time-use code. Then they text it to a phone number that works on all cellular networks within the country, and servers dispatch a response indi-cating whether the drug is genuine. Confirmation messages also can be customized to include information,

such as disease-management tips. Both outgoing and incoming text messages are free. If a fake product is found, the consumer is given a hotline number to call. Hotline personnel report fake products to the Nigerian Agency for Food, Drug, and Administrative Con-trol for further investigation (Mobile Product Authentication analytics, scratch-off labels, Sproxil).

A similar technology has been ad-opted by Unichem Laboratories to simplify the authentication of products made at two of its plants in India. Blister lidstock is printed with a unique bar-code and private virtual phone number. Implementation on the packaging line simply requires a printer to apply the barcode and a scanner at the end of the line to record it. Because the barcode-generating and -authenticating software is compatible with most printers, it’s possible to use existing units.

To authenticate a product, the con-sumer dials the phone number and texts the code. Response is immediate and can include targeted information, and the interactive connection makes it possible to collect unit-level sales data, including geographic location, time to market, and drug-authentication his-tory. The system also can send remind-

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Verification through TelecommunicationHallie Forcinio

Smartphones could become the

product-authentication tool of choice.

We’ll be seeing more ...

•Authentication by smartphone

•Anticounterfeiting options

•Nanotechnology-based

protection

3 in 1

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Packaging Forum

ers to take a dose, refill a prescription, or follow up with a doctor (Unique ID Mobile Verification, PharmaSecure).

Another smartphone-based prod-uct-authentication method relies on a custom two-dimensional (2D) code printed with visible or invisible ink. Scanning the code links the user to a web portal that confirms whether the product is authentic, as well as delivering other information, such as coupons, product videos, directions for use, or recall updates. The code also can be used during the packag-ing process to prevent label or product mixups, verify that kit components are correct and complete, and support track-and-trace initiatives. Like other smartphone-based authentication methods, the interactive, multilingual system allows manufacturers to com-municate directly with consumers and collect demographic information (Mi6 2D code and DigiTrack system, Com-plete Inspection Systems).

A similar closed-loop system se-curely generates a unique alphanu-meric code for each item so consumers can verify its authenticity by texting it or typing it in on a website. A con-sumer registering a code for the first time will receive confirmation by a return text message, but if the code

has already been registered or is not recorded in the database, an instant text message delivers a warning. The manufacturer also can send product or promotional information, reminders to take a dose, or alerts about product changes. As well as being suitable for use wherever cell service is available, the multilingual system automatically adjusts the language and message con-tent according to the message received (Pro-tex, Chesapeake).

Not all smartphone-based product authentication methods rely on alpha-numeric codes or barcodes. Another option involves printing or molding microdots on a product or package, cap-turing an image of the random pattern, and then storing it in a database. When it’s time to authenticate the product, the consumer scans the pattern with his or her smartphone, transmits the image, and receives confirmation seconds later (Cryptoglyph pattern, Fingerprint technology, and remote verification processes, AlpVision).

The fingerprint concept also is used for a security label that combines la-belstock with copper threads and a 2D barcode. A free mobile software appli-cation specifically developed for this technology enables end users to confirm authenticity without a network connec-

tion. As a result, authentication can be done for free anywhere in the world.

The random pattern formed by the copper threads is read by a camera, and a cryptographic key unique to each manufacturer converts it into a unique code. This code is then printed on the label next to the thread pattern using a digital drop-on-demand inkjet system. Cryptographic signature technology links the random pattern, code, and product information so they cannot be separated (1-Tag system and labelstock, Linoprint inkjet printer, Heidelberger Druckmaschinen).

When the label is scanned to confirm authenticity, the software immediately detects whether the content of the code matches the pattern of the neighboring copper threads. The application also dis-plays the corresponding brand, the prod-uct name, and the size of the packaging. It can supply additional product-specific information as well. For example, the expiration date or batch number can be integrated into the code and accessed in parallel to the authenticity check. If desired, weblinks also can be delivered to give consumers access to product or manufacturer websites.

A quota system prevents misuse and simplifies label reconciliation counts by specifying in advance how many items can be labeled at a time and what product information can be encoded. The quota is specified through a secure Internet connection and can be rede-fined quickly and easily each day.

Covert protectionOther anticounterfeiting methods cur-rently capturing attention incorporate tiny identifiers into the package, label, or the product itself. Some of these covert tools rely on smartphone scan-ning, while others require devices such as portable magnifiers.

One nanotechnology-based covert solution randomly distributes micro- and nanoparticles in a material to create machine-readable fingerprints. A proprietary, handheld scanning de-vice scans the fingerprint and instantly communicates the encrypted informa-tion to a secure server through mobil-

A Smartphone doesn’t have to be connected to the network to authenticate a product

with a 1-Tag label from Heidelberg.

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Pharmaceutical Technology September 2011 43

Packaging Forum

ity platforms such as GPRS, 3G, or Broadband, which returns a complete authentication report to a cell phone or computer (nonClonableID, Bilcare Technologies).

A pill-level solution blends micro-tags into immediate-release film coat-ings for solid dosage forms. The cus-tomized microtags can hold significant amounts of brand-owner-specific, en-crypted information, such as lot and batch numbers, logos, and other text, patterns, shapes, and symbols in a particle smaller than the diameter of a human hair. Invisible to the naked eye, the microtags are readily detect-able with portable magnifiers.

The microtags consist of materi-als generally regarded as safe or from FDA’s Inactive Ingredients Database. They have no effect on dissolution or stability and integrate seamlessly into the coating process. As a result, adding the microtags to an existing coating is considered a Level I annual report-able change under the scale-up and postapproval changes guidance. Drug manufacturers can adopt the technol-ogy without prior approval from FDA (mark On-Dose ID covert marker technology and vision Optical View-ing systems, ARmark Authentication Technologies, and coatings, Colorcon).

References 1. MarketsandMarkets, Global Anti Coun-

terfeit Market for Food and Pharmaceu-ticals report, (MarketsandMarkets, Dal-las, TX, 2011).

2. IMS Research, Mobile Handset Market Intelligence Service & Database (IMS Research, Austin, TX, 2011)

3. W. Llewellyn, Packaging Digest (2011), www.packagingdigest .com/ar t ic le/ 518765-New_technology_aids_ fight_against_counterfeiters.php, accessed Aug. 11, 2011. PT

For a look at Michigan State University’s anti-counterfeiting projects, visit PharmTech.com.


The adoption of continuous manufac-turing is proceeding at a step-wise pace in the pharmaceutical industry.

Facing a need to modernize manufacturing to reduce costs, improve production eco-nomics, increase manufacturing flexibility, and gain better process understanding and control, and encouraged by regulatory sup-port for continuous manufacturing as part of a quality-by-design (QbD) paradigm, pharmaceutical companies, academic–industry partnerships, and equipment vendors are moving forward with research, select projects, and product rollouts to en-able continuous manufacturing.

Regulatory frameworkAlthough full continuous manufactur-ing is still new to the pharmaceutical in-dustry, other industries, such as oil, gas, petrochemicals, polymers, and food his-torically and currently operate in a con-tinuous manufacturing mode to enable large-volume production at cost-effective levels (1). In the highly regulated pharma-ceutical industry, moving to continuous from batch manufacturing requires accep-tance of regulatory agencies to guide this transition. By its very nature, continuous processing lends itself to in-process moni-toring and control and is compatible with FDA’s process analytical technology (PAT)

initiative and the agency’s overall move to a risk- and science-based approach to pharmaceutical manufacturing and QbD principles. In its PAT guidance, FDA iden-tifies “facilitating continuous processing to improve efficiency and manage variability” such as through small-scale equipment that eliminates scale-up issues, as a way to im-prove quality, safety, and efficiency (2, 3).

“There are no regulatory hurdles for implementing innovation in pharmaceu-tical manufacturing,” said Moheb Nasr, director of the Office of New Drug Qual-ity Assessment, Center for Drug Evalua-tion and Research at FDA and member of Pharmaceutical Technology’s editorial ad-visory board. Nasr spoke at a panel discus-sion on continuous processing held at In-terphex in March 2011. A key point made by Nasr is that current regulations do not distinguish between batch and continuous manufacturing. “The regulations are silent about the mode that must be used,” he said. He emphasized that the term “batch” does not denote a mode of manufacturing but rather defines a specific quantity of a drug or other material that is intended to have uniform character and quality. The regulations specify: “A batch means a spe-cific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and

is produced according to a single manu-facturing order during the same cycle of manufacture.” (4). Moreover, a “lot” refers to a “batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by con-tinuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures it hav-ing uniform character and quality within specified limits” (4). Thus, the definitions of a lot and a batch are both applicable to continuous processing.

“We have no specific regulations or guidance for continuous manufactur-ing, other than the definition of lot,” said Nasr. “Nothing in the regulations or guidance prohibits continuous manu-facturing. Continuous manufacturing, in the agency’s view, is consistent with FDA’s QbD efforts as it allows for a more modern manufacturing approach [and of-fers] great potential to improve assurance of quality and consistency of marketed drugs” he said. Nasr also said that part of the barrier to advancing continuous man-ufacturing is a reluctance to change. “The challenge we have is the lack of experience and the fear of the unknown.” On a tech-nical basis, he acknowledged that control strategies need to be further developed and adjusted to consider the dynamics of continuous processing.

The business case Nasr also stressed the business case for continuous manufacturing given current challenges in batch manu-facturing. He emphasized two key advantages: elimination of scale-up and related challenges, and increased manufacturing flexibility. He noted the value of applying platform technologies in a modular approach to meet evolv-ing market product demand as a way to reduce manufacturing footprints, in terms of facilities and equipment, which would allow for more f lexible operations, lower capital costs, and less work-in-progress materials.

Alex Chueh, director/team leader of the technology, science, and operations group of Pfizer’s Global Supply Division, who also spoke at the Interphex panel, agreed.

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“From a new-product point of view, you really need to minimize the scale and take advantage of continuous manufacturing,” he said. He pointed to improved manu-facturing efficiency, reduced operating costs, reduced cycle time, lower invento-ries, a smaller manufacturing footprint, reduced capital expenditures as well as improved product quality and consistency by applying steady-state processes, QbD approaches, and real-time release. But he pointed to challenges as well, includ-ing the financial justification for invest-ment in continuous processing projects in light of excess existing batch capacity, declining production volumes as result of maturing products, potentially more costly continuous processes, and the existence of already optimized and lean batch-manufacturing processes.

In addressing these challenges, Chueh outlined the criteria that Pfizer uses in eval-uating a continuous processing project. He said the process must:•Provide a wide range of throughputs/

capacity to meet different product-volume requirements that meet the company’s financial models•Be easy to clean and allow for fac-

ile changeover for multiple product productions•Minimize scale-up and technology-

transfer complexity for new products•Be modular, portable, and transfer-

rable (i.e., plug-and-play approach and skid designs)•Provide interchangeability for plug-

and-play in different continuous processing unit operations for better processing and formulation flexibility•Be adaptive and amenable to con-

tinuous quality verification and real-time release• Improve specific product quality and

functionality (e.g., coating uniformity)•Require a smaller manufacturing

footprint with lower capital costs•Be hybrid in design (i.e., the process

can be used either in a batch or con-tinuous mode).

Project workUsing these proof-of-concept principles, Chueh offered several examples of spe-cific projects in continuous solid-dosage

processing at Pfizer. The first was a con-tinuous dry-granulation process that was implemented as a multiproduct platform at a cost of $16 million, which included $7 million for a new building housing the op-erations, and which produced $4 million in annual cost savings. The dry-granulation process consisted of several steps: meter feeding of excipients and lubricants, in-line blending, roller compaction, milling, and further in-line blending. The equipment train used in continuous dry granulation is not dissimilar to the direct compression process with the addition of roller compac-tion and milling steps, which is the most straight forward type of continuous man-ufacturing process for solid oral dosage forms, according to John Groskoph, senior director, global chemistry manufacturing and controls, also at Pfizer.

“From a PAT perspective, at a prese-lected processing point, we identified all of the critical process parameters (CPPs) as well as critical quality attributes (CQAs) that needed to be measured and controlled,” said Chueh. In continuous dry granulation, raw material variabil-ity, blend uniformity, compaction, and particle size are the key CQAs. PAT ap-plications, such as near infrared (NIR) and focused beam reflectance measure-ment (FBRM, for particle characteriza-tion) were developed to ensure good measurement, monitoring, and control with data fed into a supervisory control and data acquisition (SCADA) system. For blend uniformity, Pfizer developed an on-line PAT measurement system to sample, measure, and monitor the blend potency and uniformity in a continuous mode. Further, a three-way diverting sys-tem that interfaced with the on-line NIR was developed to validate rejection of de-tected nonconforming materials. A more robust on-line blend potency sampling and measurement system is currently being evaluated.

Pfizer applied a similar proof of con-cept approach for developing a continu-ous high-shear, wet-granulation–fluid-bed drying process. The $13-million project was for a high-volume product with an estimated annual savings of $7 million. Pfizer integrated metered feed-ing, blending, continuous granulation,

continuous drying, and final blending operations into a single-pass, first-in–first-out system. The company worked with an equipment vendor to develop the continuous granulator and continuous dryer aspects. In this process, the con-tinuous wet granulator and dryer units operate more like a tunnel rather than a sealed chamber. Dry powder can be fed into the entrance, fluidized, and sprayed with granulation solution in the initial portion of the unit. As the moist powder travels through the granulation unit, it forms granules that move onto the dry-ing unit and begin the drying phase. The now dry granulate passes through the exit and onto further continuous blending before being collected into an intermediate bulk container.

Chueh also pointed to the compa-ny’s interest in developing continuous direct-compression processes. “We are hoping that in the future we have more direct compressible formulations and processes because it is the most ef-fective, simplest and, easiest process. But it’s not easy to develop based on API characteristics,” he said. In using the same proof-of-concept criteria for its continuous processing operations, Pfizer integrated multiple loss-in-weight feeders, used a proprietary, in-house de-veloped continuous mixer, followed by lubrication, and on-line NIR monitor-ing of the blend potency and uniformity during the blending process. The proj-ect’s investment was $3.5 million with a projected annual savings of $1 million.

In developing these continuous man-ufacturing processes, Chueh outlined some specific technical considerations. “Since blend uniformity is always a crit-ical quality attribute, the feeding accu-racy and precision as well as the in-line blending and mixing efficiency became one of the [key] technical focus areas.” He also emphasized the importance of managing start-up and shutdown losses. “One of the disadvantages of a continuous process is the start-up and shutdown losses, so we have minimized [those] as much as we can,” offering as an example the company’s work with a vendor to develop a second-generation continuous coater that has minimal


start-up and shutdown losses. Achiev-ing more consistent and uniform spray-ing and drying conditions in the con-tinuous coating zone were other key focus areas during the development of the continuous coater, he added.

Process understanding and controlDespite the challenges, some feel that the divide between batch and continuous manufacturing can and should be over-come. “What we have now is not a batch paradigm,” said Fernando Muzzio, pro-fessor of chemical engineering at Rutgers University, president of Mixing Consul-tants, and a member of Pharmaceutical Technology’s editorial advisory board. “We mix in batch, we roller-compact continuously, we then lubricate in batch, and then tablet or capsule-fill continu-ously. Then we coat in batch and package continuously.” Muzzio, who also spoke at the Interphex panel discussion, is center director of the Engineering Research Center For Structure Organic Particulate Systems, a multi-university consortium consisting of Rutgers University, Purdue University, the New Jersey Institute of Technology, and the University of Puerto Rico at Mayagüez. The center, which is funded by National Science Foundation and industrial partners, including 35 pharmaceutical manu-facturers and equipment producers, is involved in research and development for continuous processing.

To move to continuous processing, Muzzio noted even the simplest route, continuous direct compression of tab-lets, requires many measurement points and data streams (e.g., feed rate, blend uniformity, humidity, shear, compres-sion, thickness) that need to be inter-preted in context. The key, he said, is building a predictive model that can relate all of the measurement points to the process variables to control product quality. Full closed-loop automated con-trol is a requirement to achieve reliable performance. For example, commercial technology for monitoring powder den-sity in real time is an issue, and there is currently nothing that is “plug and play,” he said. Muzzio’s team has continuous direct-compression and continuous dry-

granulation lines operating at the center and is currently working on developing a continuous wet-granulation line.

The feasibility of developing con-tinuous processes for specific unit operations requires advances in phar-maceutical equipment design and operation. “To make continuous mix-ing, granulation, and drying possible for small-scale operations, such as in the pharmaceutical industry, systems needed to be developed with very lim-ited or no start-up and shutdown waste that reach steady state in an extremely short time,” says Kris Schoeters, prod-uct manager of continuous processing at GEA Pharma Systems, a pharmaceu-tical equipment provider. He points to the company’s ConsiGma continuous granulation, drying, and tableting line as an example. Designed in a modular way, the system consists of a patented twin-screw granulator, a segmented continuous fluid-bed dryer, and gran-ule-conditioning unit to prepare dry granules for the tablet press.

“Each module has been optimized to achieve steady state very rapidly (some-times within seconds) and to ensure plug-f low of the product throughout the system. The whole system is con-trolled by an advanced process control system; all modules have to communi-cate with each other seamlessly to form an intelligent-control system with feed-forward and feedback loops. The con-trol system is, in fact, one of the major design challenges for continuous pro-cessing,” says Schoeters.

Another chal lenge is ensuring plug-f low while maintaining consis-tent mixing characteristics. The twin-screw granulator, for example, contains “tightly intermeshing corotating twin screws and kneading elements, which provides a self-cleaning and self-empty-ing effect and, hence, ensures real plug flow,” says Schoeters.

On the horizonDeveloping continuous processes for specific unit operations and coupling them is one way to achieve continuous manufacturing. In this approach, drug-substance manufacturing and solid-

dosage manufacturing are separate, and specific unit operations in solid-dosage manufacturing are developed as continuous processes and coupled. A more holistic or end-to-end approach is being considered by Novartis, through a 10-year, $65-million collaboration that the company formed with the Massachusetts Institute of Technology (MIT) in 2007, with the goal of developing a fully integrated platform for continuous manufacturing that would integrate drug-substance manufacturing with finished drug-product manufacturing.

Bernhardt Trout, director at the Novartis–MIT Center for Continuous Manufacturing and professor of chemical engineering at MIT, explained that the focus of the collaboration is not trying to redesign the process unit by unit, but rather to look at API and finished-drug product manufacturing as a whole. To that end, the center is researching and developing new technologies, including applying different chemistries to produce a desired API. Thus far, the center has developed a prototype, bench-scale integrated continuous manufacturing platform for API and solid dosage manufacturing. The fully integrated, end-to-end system has been run several times, and steady-state runs for up to a week at a time were planned for August 2011. The process and its control system will be used as a research tool to test start-up and shut-down strategies and to introduce new technologies for integration and further testing through 2011 and beyond.

References1. E. Greb, Equipment and Processing

Report, Mar. 17, 2010, PharmTech.com/

continuousquest, accessed Aug. 22, 2010.

2. F DA , G u i d a n c e f o r I n d u s t r y :

PAT—A Framework for Innovative

P h a r m a c e u t i c a l D e v e l o p m e n t ,

Manufacturing, and Quality Assurance

(Rockville, MD, September 2004).

3. A. Pellek and P. Van Arnum, Pharm.

Technol. 9 (3), 52–58 (2008).

4. Code of Federal Regulations, Title 21,

Food and Drugs, Part 121, Sec. 210.3,

www.accessdata.fda.gov/scripts/cdrh/

cfdocs/cfcfr/CFRSearch.cfm?fr=210.3,

accessed Aug. 23, 2011. PT


Special Report: Pharmaceutical Water

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officials’ emphasis on preventive medi-cine. This expanding market highlights the importance of water for injection (WFI), which is required to prepare parenteral solutions. Many vaccine ma-kers seek to sell their products to markets around the world, but regulatory officials still disagree about which methods for producing WFI are acceptable.

Pharmacopoeial specificationsThe US Pharmacopeia (USP) describes specifications for conductivity, total organic carbon (TOC), and bacterial endotoxin that WFI must meet. For years, USP only allowed companies to produce WFI through distillation. That process had a long history, and experts viewed it as a safe and robust method for producing water with a low bioburden. In the late 1970s, new language was adopted that enabled

manufacturers to use reverse osmosis, provided the water met the same speci-fications. USP now states that, “WFI is water purified by distillation or a pu-rification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms” (1).

Based on studies conducted by the US Centers for Disease Control and Prevention, FDA concluded that re-verse osmosis could produce WFI to USP specifications, provided that the process was operated adequately. FDA also recommends that the reverse- osmosis system be designed appropri-ately and include precautions such as regular sanitization and maintenance, and periodic validation.

In general, FDA seems to be con-cerned more about whether WFI meets USP specifications, and less about the type of process a firm uses to create the water, as long as it is based on sound science. “FDA requires that you have a validated system that demonstrates

Regulators Debate Methods for Producing Water for InjectionErik Greb

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that you consistently make water meet-ing the specifications in USP,” says Terry Munson, technical vice-presi-dent at consulting firm Parexel. “How you get there is not a major concern.”

The Japanese Pharmacopoeia (JP) has taken a similar approach. For more than a decade, it has allowed a combination of reverse osmosis followed by ultrafil-tration as an alternative to distillation, says Gary Zoccolante, pharmaceutical technical director of Siemens Industry.

The European Pharmacopoeia (EP) contains the same specifications for conductivity, TOC, and endotoxin as USP does, but it requires firms to pro-duce WFI through distillation. Accord-ing to the document, WFI “is obtained from water that complies with the reg-ulations on water intended for human consumption laid down by the compe-tent authority or from purified water by distillation” in a suitable device (2).

The EP seeks to ensure that WFI is produced through a robust process. “Eu-ropeans don’t consider reverse osmosis or equivalent processes to be a robust, proven process for long-term continu-ous removal of bacteria and bacterial endotoxins,” says William V. Collentro, senior consultant for ConcordiaVal-Source. Distillation changes water from its liquid phase to its steam phase. “The Europeans consider the phase change to be extremely important,” says Collentro, because it ensures that bacterial endotox-ins, bacteria, and other nonvolatile im-purities “are left behind with the water, ulitimately removed from the evaporator section by blowdown.”

EMA’s concerns about reverse osmosisBiofilm. Unlike distillation, reverse os-mosis is not conducted at temperatures that kill bacteria. Instead, this process is operated at ambient temperature, which gives rise to some of European regula-tors’ concerns. One major worry is that organisms can grow and form biofilm on both sides of the membranes. Biofilm consists of gram-positive, gram-nega-tive, and pathogenic bacteria, according to an EMA paper on WFI prepared by reverse osmosis. “The biofilm will build up and become increasingly resistant to

sanitization by hot water or chemicals because of the glycocalyx material,” it says. “Biofilms cannot be destroyed” (3).

But companies contain and manage biofilm formation routinely, accord-ing to a response to EMA cowritten by Theodore Meltzer, a consultant at Capitola Consultancy and member of Pharmaceutical Technology’s Edito-rial Advisory Board.* “The statement that biofilms will become increasingly resistant to sanitization by hot water or chemicals is untrue,” he wrote. Mi-crobial biofilms only resist chemical and physical treatment agents at much lower temperatures and chemical con-centrations than industry uses (4).

“Similarly, the statement that bio-films cannot be destroyed is also in-correct,” Meltzer added. Common agents such as peracetic acid, hydrogen peroxide, and combinations of the two hydrolyze biofilms (4).

Endotoxins. Another main concern among European authorities is that a biofilm may exist in product water tub-ing from any membrane process. The way that a reverse-osmosis system is operated and maintained can increase the risk that WFI will contain micro-organsms. About 25% of the feed water from a reverse-osmosis unit is directed to a waste line, and this waste is rich in bacterial endotoxins and bacteria. Usu-ally, a portion of the waste is diverted back to the system’s feed water in a process called waste recycle. This tech-nique is required to maintain velocities throughout the final membranes in an array to avoid precipitation of material within the membranes.

“If you’re going utilize waste recycle, consider the fact that the piping will contain a well established biofilm. At-tempt to remove microorganisms with a process such as ultrafiltration,” says Collentro. Firms could also operate the reverse-osmosis unit at a lower level of water recovery and send the recovered stream to a break tank of chlorinated water at the beginning of the system. “I try to eliminate waste recycle as much as I can,” says Collentro.

Microbial fouling. European regulators also have expressed concern that mem-branes are subject to microbial fouling. Impurities can build up on membranes in layers of biofilm, organic material, and scalants such as calcium or mag-nesium compounds. A preventative maintenance program is required to control microbial fouling, which sig-nificantly increases the probability of microorganisms in product water.

“When fouling occurs, firms must conduct a three-step cleaning process to remove scalants, the organic material, and the bacteria. Chemical sanitization is the only effective method of remove biofilm from the membrane surface and asso-caited microorganisms,” says Collentro.

But fouling can be avoided. “Ap-propriate chemical treatment regimes developed as part of the validation process prevent fouling and associated flux declines,” wrote Meltzer. In addi-tion, bacteria cannot grow through reverse-osmosis membranes, “which are permeable only to some ions and water molecules” (4).

European regulators often cite the heat associated with the distillation pro-cess as an advantage over reverse osmo-sis because it kills microbes and prevents contamination. But operators can heat-sanitize membrane systems frequently or operate them continuously hot. These techniques “will minimize or eliminate microbial problems to the same extent as distillation,” says Zoccolante.


*Theodore Meltzer, who served as a

respected member of Pharmaceutical

Technology’s Editorial Advisory Board for

more than 20 years, passed away in August

2011. He is dearly missed by his colleagues in

industry and on this magazine.

EMA’s state-

ment that bio-

films cannot

be destroyed is

‘incorrect,’ wrote

Meltzer.

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Metabolic byproducts. Biofilm concen-trates various metabolic byproducts, notes the EMA paper. If it forms on the upstream side of a membrane, “the con-centration is sufficient for these to pass through the membrane” (3).

But the scientific evidence does not support this assertion, according to Meltzer. “The minimum … molecu-lar weight … for the lipid-A portion of endotoxins (required to elicit a fever response) is on the order of 10,000; the approximate organic molecular weight cutoff for [reverse-osmosis] membranes is on the order of 300” (4).

Global concerns about distillationSeveral observers point out that dis-tillation raises some of the same con-cerns that European regulators have about reverse osmosis. For example, an FDA Inspection Guide describes various ways that stills have produced water contaminated with endotoxins. The log reduction of endotoxin that stills can provide is limited. In many failures, an insufficient pretreatment system produced an endotoxin feed to the stills that was greater than they could remove (5).

Also, biofilm formation can occur during distillation just as it can during reverse osmosis, wrote Meltzer. “Biofilm is an inevitable occurrence in all water systems except those continuously main-tained hot, at above at least 65 ∘C” (4).

Other observers have noted an appar-ent inconsistency within EP. The docu-ment lists the exact same water-quality specifications for highly purified water (HPW) as it does for WFI, but allows the former to be made through reverse osmosis and other processes, says Zoc-colante. “WFI may be used for more critical applications, but HPW is also used for applications where water qual-ity is extremely important. A process is either reliable or it is not. The applica-tion does not change that fact.”

Both distillation and reverse osmo-sis require water to be pretreated to protect the equipment and to provide acceptable results. Operating the pro-cesses at the proper temperature—or,

in the case of reverse osmosis, per-forming frequent sanitizations—and validating them properly should help ensure that they yield WFI that meets compendial specifications.

The prospects for harmonizationHarmonization of requirements would give pharmaceutical manufacturers a choice of technologies for producing WFI. Two-pass reverse osmosis could help firms reduce the capital costs, op-erating costs, and maintenance costs of their WFI system, which “would be of considerable benefit for world mar-ket needs,” says Michael Foster, water group lead at OBK, a provider of water-purification systems. Harmonization also would lower costs for drugmak-ers in emerging countries because one type of water would suffice for purified-water and WFI applications, he adds.

Events indicate that harmoniza-tion of EP, USP, and JP requirements for WFI is possible. During recent meetings of the Parenteral Drug Asso-ciation, European regulators showed openness to discussing the topic of pro-ducing WFI through reverse osmosis, says Maik Jornitz, senior vice-president of marketing bioprocess at Sartorius-Stedim North America.

On Mar. 24, 2011, the European Directorate for the Quality of Medi-cines and HealthCare (EDQM) held a water workshop with experts from JP, USP, the pharmaceutical industry, and equipment manufacturers. By the

end of the meeting, the experts saw sufficient reason to recommend that the European Pharmacopoeia Com-mission initiate discussions regarding the potential use of membrane systems for producing WFI, says Georg Roess-ling, senior vice-president of Parenteral Drug Association Europe. Regulators stipulated that the discussions should consider a potential revision of current specifications for WFI and the intro-duction of methods to deal with the contaminants likely to be present in reverse-osmosis systems to ensure the safety of the resulting WFI.

European regulators are looking for robust, long-term data that show that the quality of WFI produced by reverse osmosis is comparable to that produced by distillation, says Jornitz. They want to be sure that reverse os-mosis can produce WFI reliably, and sharing experience of reverse-osmosis WFI systems with them would be ad-vantageous, he adds.

In June 2011, EP decided that ad-vances in membrane systems since the late 1990s warranted a review of its previous policy. “However, the data collected in the past months still need to be reviewed to answer questions about new multimodule reverse-os-mosis systems and associated improve-ments (e.g., hot water and chemical sanitization) designed to overcome concerns linked to the microbiologi-cal quality of the water,” says Susanne Keitel, director of EDQM. It is likely that EP ultimately will receive a request for revision of the monograph on WFI, she added.

References 1. USP 34–NF 29 (US Pharmacopeial Con-

vention, Rockville, MD, 2011), p. 4596. 2. EurPh, General Text 01/2009:0169 (EDQM,

Strasbourg, France, 2010), p. 3219. 3. EMA, “Ref lection Paper on Water for

Injection Prepared by Reverse Osmo-sis,” Doc. Ref. EMEA/CHMP/CVMP/QWP/28271/2008, Mar. 5, 2008 (London).

4. T. Meltzer et al., PDA J. Pharm. Sci. Tech-nol. 63 (1), 1–7 (2009).

5. FDA, Guide to Inspections of High Pu-rity Water Systems (Rockville, MD, July 1993). PT

Distillation and reverse osmosis require water to be pretreated to protect equipment and yield good results.

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Technology differentiation is an important strategy in any business sector. It is partic-ularly crucial for fine-chemical producers and contract manufacturers of intermedi-ates and APIs, which face an increasingly competitive market. Strengthening capa-bilities in biocatalysis, chemocatalysis, and other technologies in support of pharma-ceutical companies’ interest in producing single-enantiomer drugs is an area of in-vestment by select fine-chemical compa-nies, CMOs, and technology providers.

Biocatalysis strengthBiocatalysis is a valued approach in pro-ducing intermediates and APIs of de-sired stereoselectivity. In building their toolboxes, companies are expanding their offerings in biocatalysts through

organic growth, industrial partnerships, and academic collaborations. For ex-ample, in May 2011, Almac launched its selectAZyme brand of biocatalysts, includ-ing reductases, transaminases, hydrolases, and nitrilases for use in synthesizing APIs and fine chemicals, including chiral com-pounds. The selectAZyme service also provides metabolite synthesis for oxidative and glycosylated products.

The launch of the selectAZyme line of biocatalysts follows Almac’s $4-million investment in biocatalysis R&D. Research areas include new biocatalytic platforms for producing chiral intermediates, hyper-activation of biocatalysts for reducing en-zyme loadings, developing drivers for co-factor recycling, and mitigating problems with equilibriums. In 2009, the company also launched carbonyl reductase, trans-aminase, hydrolase, nitrilase, and nitrile hydratase enzyme-screening kits.

As an example of biocatalysis at work, Almac carried out preliminary screening to show that a carbonyl reductase (CRED) bioreduction could replace a resolution for preparing a chiral alcohol. After identify-ing a CRED at small scale, the company IM

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Biocatalysis, chemocatalysis, and other chiral technologies continue to attract the investment dollars of CMOs and fine-chemical companies.

Building Toolboxes in Pursuit of Single-Enantiomer Drugs Patricia Van Arnum

Pharma Ingredients: APIs & Excipients

Patricia Van Arnum

is a senior editor at

pharmaceutical technology,

485 Route One South,

Bldg F, First Floor,

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tel. 732.346.3072,

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scaled up production and integrated the biocatalytic approach into the API process-development program and manufactured 30 kg for Phase I clinical trials, according to an Almac Oct. 7, 2010, press release.

In December 2010, DSM Pharmaceuti-cal Products, the custom manufacturing organization of DSM, formed a license agreement with c-LEcta, an industrial biotechnology company. The agreement grants DSM rights to c-LEcta’s propri-etary alcohol dehydrogenases for enzyme-screening programs and for developing manufacturing routes for APIs and inter-mediates. Alcohol dehydrogenases are used to synthesize chiral alcohols from ketones.

In September 2010, DSM launched InnoSyn, a route-screening service, which applies tools such as biocatalysis, homoge-neous catalysis, and continuous chemistry using microreactors to screen catalysts for feasibility studies for chemocatalytic and biocatalytic steps. The company earlier had introduced new enzymes, such as pig liver esterase (i.e., pharmaPLE), lyases, transam-inases, dehydrogenases and homogeneous catalysts for asymmetric hydrogenations, aromatic substitutions, and oxidations.

In January 2011, the biocatalysis firm Codexis and DSM Pharmaceutical Prod-ucts formed an enzyme-supply agreement. The agreement grants DSM rights to use Codexis’s custom biocatalysts and services and secures a supply of Codexis enzymes for commercialization of pharmaceuti-cal manufacturing routes developed by DMS’s InnoSyn route-scouting service. In October 2010, Codexis expanded its offerings in biocatalysis by introducing screening kits for a subset of the range of biocatalysts it offers. The kits contain 24 enzymes from Codexis’s collection of biocatalyst variants from two enzyme classes: ketoreductase and transaminase.

Codexis recently formed several bioca-talysis partnerships with pharmaceutical companies. In May 2011, the company suc-cessfully completed technology transfer of custom biocatalysts for the manufacture of three undisclosed pharmaceutical prod-ucts to Teva Pharmaceutical Industries. Two products were transferred to pilot manufacturing, and a third to full-scale commercial manufacturing. The original agreements covering the development of these processes were signed in 2009. In Jan-uary 2011, Codexis formed a collaboration

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with Dainippon Sumitomo Pharma (DSP) under which Codexis is supplying bioca-talysis screening products and services to DSP for use in selected undisclosed thera-peutic products in its development pipeline.

In 2010, researchers at Merck & Co. and Codexis reported on the biocatalytic asym-metric synthesis of chiral amines from ketones in the manufacture of sitagliptin, the active ingredient in Merck’s antidiabe-tes drug Januvia. The biocatalytic process replaced a rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of sitagliptin. The research-ers started from an (R)-selective trans-aminase that showed slight activity on a smaller truncated methyl ketone analogue of the sitagliptin ketone. After creating this transaminase, which had marginal activity for the synthesis of the chiral amine, they further engineered the enzyme through directed evolution to optimize its use for large-scale manufacturing (1–3).

The initial (R)-selective transaminase was a homologue of an enzyme from Arthrobacter sp., which previously was used for (R)-specific transamination of methyl ketones and small cyclic ketones. For the sitagliptin synthesis, the research-ers generated a structural homology model of this transaminase and found that the enzyme would not bind to the prositagliptin ketone because of steric in-terference and potentially undesired inter-actions. The evolved transaminase was a successful biocatalyst that synthesized the chiral amines that previously were acces-sible only through resolution (1–3).

Codexis and Merck were recognized in 2010 with an Environmental Protection Agency’s Presidential Green Chemistry Challenge Award, an annual recognition of advances in green chemistry. Codexis also submitted for consideration in 2010 and 2011 a biocatalytic route for making simvastatin, the active ingredient in Merck

& Co.’s anticholesterol drug Zocor, which is now off patent (3, 4).

Codexis licensed technology from Yi Tang, professor in the department of chemical and biomolecular engineer-ing at the University of California at Los Angeles. The previous synthetic routes to simvastatin involved converting lovas-tatin into simvastatin by adding a methyl group that required protecting and then deprotecting other functionalities in the lovastatin molecule in a multistep synthe-sis. In the first route, lovastatin was hy-drolyzed to the triol, monacolin J, followed by protection with selective silylation, es-terification with dimethyl butyryl chlo-ride, and deprotection. The second route involved protecting the carboxylic acid and alcohol functionalities, methylating the C2́ carbon with methyl iodide, and deprotecting the product. These routes were inefficient because they produced less than 70% overall yield and were

Microscale hydrogels are used in targeted drug delivery and tissue

engineering. The spatial organization of biological entities or chemical

compounds within hydrogel microstructures is important. Sequentially

patterned microgels can spatially organize either living materials to

mimic biological complexity or multiple chemicals to design functional

microparticles for drug delivery (1). Current methods for producing

such microparticles, however, restrict the type of shapes that can be

generated and the kinds of the materials that can be used to produce

the microparticles, thereby limiting their usefulness. Researchers at

the Massachusetts of Technology (MIT) and Harvard University recently

reported on new methods that address the challenges in producing

microscale hydrogels, according to an Aug. 16, 2011, MIT press release (2).

Most drug-delivering particles and cell-encapsulating microgels are

created using photolithography, which relies on ultraviolet light to

transform liquid polymers into a solid gel. This technique has certain

limitations. It can be used only with certain materials, such as polyethylene

glycol, and the ultraviolet light may harm cells. In another approach,

microparticles also can be used to fill a mold with a liquid gel carrying drug

molecules or cells. The gel is cooled until it sets into the desired shape. This

approach, however, does not allow for creation of multiple layers (1).

The researchers’ approach sought to address these two issues: the

restriction of using photocrosslinkable polymers as the materials to

pattern hydrogels and the limitation in the shapes that can be generated

using static molds as a micromolding approach. Specifically, they

reported on a dynamic micromolding technique to fabricate sequentially

patterned hydrogel microstructures through the thermoresponsiveness

of poly(N-isopropylacrylamide)-based micromolds. The researchers

reported that these micromolds were responsive and exhibited shape

changes under temperature variations, which facilitated the sequential

molding of microgels at two different temperatures. They fabricated

multicompartmental striped, cylindrical, and cubic microgels that

encapsulated fluorescent polymer microspheres or different cell types.

These researchers asserted that these “responsive” micromolds can be used

to immobilize living materials or chemicals into sequentially patterned

hydrogel microstructures (1, 2).

In addition to being used in drug delivery, the various particle sizes

also have potential for tissue-engineering applications. For example, the

long, striped particles may be useful for engineering elongated tissues,

such as cardiac tissue, skeletal muscle, or neural tissue. In their study,

the researchers created striped particles with a first layer of fibroblasts

surrounded by a layer of endothelial cells. They also created cubic and

cylindrical particles in which liver cells were encapsulated in the first layer

surrounded by a layer of endothelial cells, an arrangement for potentially

replicating liver tissue (1).

Such gels also could be embedded with proteins that help the cells

orient themselves in a desired structure, such as a tube that could form

a capillary. The researchers also are planning to create particles that

contain collagen for building large tissues and entire organs as vehicles

for laboratory testing of potential new drugs. “If you can create 3D tissues

which are functional and really mimic the native tissue, they are going to

give the right responses to drugs,” said Halil Tekin, an MIT graduate student

and lead author of a recent article detailing his team’s research, in the MIT

release (2). Such an advance would offer the potential of accelerating the

drug discovery and development processes.

Sources1. H. Tekin, J. Am. Chem. Soc. 133 (33), pp 12944–12947 (2011).

2. MIT, “Mimicking Biological Complexity in a Tiny Particle,” Press Re-

lease (Cambridge, MA, Aug. 16, 2011).

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mass-intensive due to protection and de-protection (3).

The route developed by Tang and his group circumvented protection and de-protection and resulted in greater atom economy, reduced waste, and overall less hazardous reaction conditions. First, they cloned LovD, a natural acyltransferase pro-duced by Aspergillus terreus that is involved in synthesizing lovastatin and that can ac-cept nonnatural acyl donors. Recognizing that LovD might be a type of simvastatin synthase and a starting point for creating a new biocatalytic process, they evolved the enzyme toward commercial utility (3–5). Codexis licensed Tang’s technology, engi-neered the enzyme further, and optimized the process for pilot-scale simvastatin man-ufacture. During 2010, Codexis scaled up enzyme manufacture to the 150-kg batch scale and manufactured simvastatin am-monium salt in 400-kg batches (4).

In June 2011, the biocatalysis com-pany Enzymicals launched a screening kit for (R)-selective transaminases. Tech-niques for the recombinant production of (R)-selective transaminases were developed under a collaboration with Lonza. The en-zymes can be used in the synthesis of chi-ral amines and other chiral intermediates. Process patents for transamination also are included in the license agreement, which allows Enzymicals to carry out customer- oriented laboratory testing. Enzymicals was founded in August 2009 by the re-search group of Uwe Bornscheuer, profes-sor in the department of biotechnology and enzyme catalysis in the Institute of Biochemistry at Ernst Moritz Arndt Uni-versity in Greifswald, Germany. In addition to (R)-selective transaminases, Enzymicals also offers other proprietary biocatalysts, such as PLE isoenzymes, several esterases, and Baeyer–Villiger-monooxygenases.

In November 2010, W.R. Grace com-pleted its $19.2-million acquisition of Syn-thetech, a manufacturer of fine chemicals, specialty amino acids, and chiral interme-diates, including capabilities in biocatalysis. W.R. Grace acquired Synthetech’s prodc-tion and R&D facility in Albany, Oregon, and a second R&D facility in San Diego.

In July 2010, Johnson Matthey acquired X-Zyme, a provider of enzymes, particu-larly oxidoreductases for producing chiral

intermediates. X-Zyme is a 2001 spin-off from Heinrich Heine University’s Insti-tute of Molecular Enzyme Technology in Germany. X-Zyme’s portfolio included enzymatic catalysts for scalable production of highly pure chiral amines and alcohols. And in March 2010, Cambrex acquired IEP, an industrial biocatalysis company in Wiesbaden, Germany. Cambrex gained IEP’s capabilities in customized biocata-lytic process-development and enzymes for pharmaceutical applications.

Expansion modeOther companies also are expanding their capabilities in chiral chemistry. In April 2011, the custom pharmaceutical services business of Dr. Reddy’s Labora-tories opened a new 33,000-ft2 Chirotech Technology Center in Cambridge, United Kingdom. The additional capacity will fa-cilitate an initial doubling of scientific staff and allow for further capacity additions, including capabilities in biocatalysis and chemocatalysis. In another development in 2010, Sigma Aldrich partnered with BASF to sell BASF’s ChiPros branded chi-ral molecules in small quantities of up to one kilogram. The partnership involves 80 products, including chiral amines, al-cohols, epoxides, and acids.

In a reorganization announced in Au-gust 2011, Evonik is combining its custom manufacturing business (i.e., exclusive syn-thesis) with its businesses for pharmaceuti-cal amino acids (i.e., Rexim product line) and pharmaceutical polymers in a new healthcare business line, effective Sept. 1, 2011. The company’s exclusive-synthesis business includes capabilities in bioca-talysis and chemocatalysis, and the phar-maceutical amino acid business includes natural and nonnatural amino acids for making chiral building blocks.

Tools for molecular characterization and chiral separations also play an impor-tant role in producing single-enantiomer drugs. Recent activity includes a collabo-ration, announced in July 2011, between Chiral Technologies, a provider of chiral separation products, and BioTools, a pro-vider of instrumentation for vibrational chiroptical spectroscopy. Vibrational circu-lar dichroism (VCD) technology is used in structural characterization of chiral drugs

and biopharmaceuticals. BioTools manu-factures and sells VCD spectrometers, which are used to determine the absolute configuration of single enantiomers.

In December 2010, BioTools, Ghent University in Belgium, and the University of Antwerp opened the European Center for Chirality. The center’s mission is to help academic and industrial scientists develop chirality-related applications by offering services ranging from the deter-mination of absolute chiral configura-tions, vibrational optical activity (VOA) measurements, and computational mod-eling by providing expert consultants, educational workshops, and open-access VOA instrumentation.

In chromatographic applications, in May 2011, Chiral Technologies launched a new immobilized chiral stationary phase, Chiralpak ID, the fourth addition to the company’s product line of immobilized chiral stationary phases. It can be used in high-performance liquid chromatography and supercritical fluid chromatography.

In September 2010, the European op-erations of Chiral Technologies, Chiral Technologies Europe, entered into a global licensing agreement with the University of Vienna under which Chiral Technologies Europe acquired exclusive manufactur-ing and marketing rights for Cinchona alkaloid-based zwitterion-exchange type chiral stationary phases invented and de-veloped by researchers at the University of Vienna. The zwitterion-exchange type chiral separation phases separate a broad range of ionizable chiral analytes, which range from acidic and basic molecules to zwitterionic molecules that bear basic and acidic moieties in the same molecule.

References 1. P. Van Arnum, Pharm. Technol. 34 (8) 42–44

(2010). 2. C.K. Savile et al., Science 329 (5989), 305–309

(2010). 3. EPA, “The Presidential Green Chemistry

Challenge Awards Program: Summary of 2010 Award Entries and Recipients” (Wash-ington, DC, 2010).

4. EPA, “The Presidential Green Chemistry Challenge Awards Program: Summary of 2010 Award Entries and Recipients” (Wash-ington, DC, 2011).

5. Y. Tang, Science 326 (5952), 589–592 (2009). PT


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To understand the challenges and opportunities

associated with implementing quality by

design (QbD), FDA contracted an independent

consultant to evaluate current industry adoption

of QbD. This article summarizes those findings

and proposes actions FDA can take to encourage

full-scale QbD implementation.

Helen N. Winkle is director of the Office of Pharmaceutical

Science (OPS) at the Center for Drug Evaluation and Research

(CDER) within FDA. Moheb M. Nasr, PhD,* is director of the

Office of New Drug Quality Assessment in OPS, CDER, at

FDA, 10903 New Hampshire Ave., Silver Spring, MD, 20993,

tel. 301.796.1900, [email protected].

*To whom all correspondence should be addressed.

FDA on QbD

In 2004, FDA released its final report on “Pharmaceutical Qual-ity for the 21st Century: A Risk-Based Approach.” The purpose of the initiative, which was launched in 2002, was to encourage innovation and implementation of new manufacturing tech-

nologies, focus the agency’s resources on those areas of pharma-ceutical manufacturing considered to pose the most risk, and im-prove on the consistency and predictability of the agency’s work in ensuring drug quality and safety. In the 2004 report, FDA outlined its initiation of quality by design (QbD)—a science- and risk-based approach that begins with predefined objectives for meeting the desired clinical performance and emphasizes product and process understanding and process control.

Working with regulators in the European Union (the European Medicines Agency and European Competent Authorities) and Japan, FDA has been instrumental in furthering QbD objectives through the International Conference on Harmonization (ICH), and industry has made progress in implementing QbD in terms of its corporate culture, operations, and quality systems. But, as is the case with many new endeavors, challenges still exist that inhibit full-scale implementation.

In an effort to understand these challenges and identify oppor-tunities for adoption, FDA contracted an independent consultant to objectively evaluate and develop a fact-based consensus view on the state of QbD adoption. The team got input from several sources—literature research, database searches, and interviews with industry leaders—to gauge industry’s current perspectives on QbD and its level of adoption. This article summarizes the con-sultant’s findings, to include key adoption challenges and imple-mentation issues, as well as actions that FDA can take to encourage full-scale implementation and ultimately ensure the production of high-quality products.

Evolution of quality by design QbD has continued to gain momentum during the past several years. One of the most striking factors has been an increase in the codification and practice of QbD in a standardized basis. More and more companies are experimenting with and using the concept, as well as developing mechanisms to support it. That being said, companies are at very different levels of maturity in terms of QbD adoption. Four levels of maturity were identified in the report.

Understanding Challenges to Quality by DesignHelen N. Winkle and Moheb M. Nasr


The first level of maturity, novice, is defined as a company that is skeptical about the value of QbD. The company uses conventional development practices and has no QbD platforming. The second level, pilot, defines a company that is trying QbD, but is still uncertain about the initia-tive’s potential value. This company tends to apply QbD to a small subset of projects and processes and has implemented limited or no QbD platform-ing. The third level, rollout, is a company that is convinced about QbD’s impact and is beginning to see some of the benefits. This company uses QbD techniques regularly, but not universally, and may engage in some life-cycle management with integrated QbD platform and network strategy. Finally, the fourth level, catego-rized as fully implemented, defines a company that is completely convinced about QbD’s positive impact and has seen the benefits. This company uses QbD in almost all development programs. It also has a systematic, comprehensive review and redesign of in-line products. Table I illustrates, by drug type, the level of maturity of those companies that were examined.

Key adoption challengesThere are still many challenges as FDA promotes the con-cepts of QbD. Industry, academia, and FDA need to work together to pursue the opportunities, overcome the chal-lenges, and realize the benefits that QbD implementation has to offer. This is necessary to ensure that QbD concepts are incorporated not only when the first activities are initi-ated around a product’s development, but also during the design of the process that is used to make the product and other activities associated with a product’s life cycle. In con-ducting its research, the team discovered 10 key challenges related to QbD adoption.

The first four, noted below, are challenges industry faces in-ternally as it attempts to implement QbD:

1. Internal misalignment. One of the most important fac-tors in successful implementation is the application of QbD across the entire operating model. The research, however, showed that several companies experienced misalignment horizontally across the organization, a disconnect between leadership and middle manage-ment, a culture of conservatism, an unwillingness to redesign certain aspects of their operating model, and the belief that QbD was low on the company’s prior-ity list because the initiative was not required and the benefits were not guaranteed.

2. Lack of belief in a business case. The majority of compa-nies believed that QbD has a strong business case, but skeptics felt that QbD would slow time to file (generic products) or that the amount of clinical trials neces-sary to implement QbD for drug substance production steps (e.g., upstream) made the business case negative until there were further advances in the actual science (biologic products).

3. Lack of technology to execute. Specific challenges that were identified included the belief that QbD was an insuffi-cient solution for controlling variability of raw materials, it would require companies to develop new skill sets and obtain new technology that are viewed as out of reach, and it would be difficult to gather, manage, and analyze all of the product data generated during development.

4. Alignment with third parties. Industry was concerned about how to bring QbD to fruition while managing a complex supply chain that includes both suppliers and contract manufacturers.

Based on interviews with industry, six challenges to QbD implementation specific to FDA and other regulatory bodies emerged. These include:

5. Inconsistent treatment of QbD across FDA. Companies felt that FDA understood QbD requirements differently both within and between offices. This inconsistency leads to the belief that FDA may not review filings in a consistent manner.

6. Lack of tangible guidance for industry. The majority of com-panies, especially those in the novice and pilot catego-ries, felt the need for a more tangible guidance on how to actually implement QbD. Companies wanted clarifica-tion from FDA on matters such as acceptable methods, criteria to select and deselect critical quality attributes, standards by which to judge adequacy of controls, and criteria for analytical method substitution.

7. Regulators not prepared to handle QbD applications. While FDA continues to take steps to remedy this, interviewees were still concerned about matters such as new reviewers’ level of experience and a perceived high turnover rate.

8. The way promised regulatory benefits are currently being shared

does not inspire confidence. This challenge is primarily the result of the lack of codification of real regulatory benefits from FDA. Without clear benefits, proponents of QbD in industry have expressed difficulty in promoting the idea within their companies.

9. Misalignment of international regulatory bodies. A concern con-sistently raised by companies at the rollout and fully imple-mented levels of adoption was whether QbD applications would be accepted by other regulatory bodies. Although no interviewees had experienced rejection by these groups, they did comment on the increased time and effort re-quired in other markets.

10. Current interaction with companies is not conducive to QbD. Com-panies felt that, historically, there was not a lot of comfort talking with FDA; however, companies are eager to open and improve on this communication.

Table I: Level of maturity and drug type of examined companies.Group Novice Pilot Rollout Fully implemented Total

New Drug 22% 33% 22% 22% 100%

Gx 40% 20% 40% 100%

Biologics 17% 67% 17% 100%

Gx is generic drug. Totals are rounded.


Table II provides an analysis of what challenges are most relevant for the different drug types, while Table III identifies what challenges are most apparent by stage of adoption.

Business case for quality by designThe team’s analysis shows a strong preliminary business case for QbD. Interviews proved false two commonly held beliefs that QbD is very expensive and will drive costs up and that QbD will take a long time and require much more analysis. Interviews provided evidence that the cost to im-plement QbD is in fact minimal and the increase in time, if at all, is negligible (see Figure 1).

Analysis also identified many potential benefits from QbD. In terms of quantifiable benefits, value comes from four main areas: a reduction of cost of goods sold and capi-tal expense, increased technical development productivity, improved quality (and lower risk), and increased sales.

Ultimately, for companies to experience the most business benefits possible, two things must be in place:

(1) companies must be aligned across the entire operating model to capture the full benefits that QbD enables in manufac-turing and quality control, and (2) FDA must ensure a high quality and consis-tency of review and compliance (e.g., train reviewers, provide stronger guidance and ground rules for QbD filings) and deliver on the regulatory benefits many compa-nies feel were promised.

Implications for FDAAs previously noted, the team’s re-search highlighted many challenges to QbD implementation. In response, several options were provided to en-courage and accelerate QbD adoption.

FDA policy options. Three options were provided under this category:

• Define and codify incentives. Many com-panies felt this was a powerful way to encourage QbD adoption. As such, FDA may want to consider whether to do this and, if so, what those incentives should be and what benefits could come from introduc-ing these incentives.

• Develop tangible guidance for QbD execution.

Companies—especially those in the early stages of adoption—were con-fused by what QbD means and how to execute such a huge endeavor. They strongly believed that they could ben-efit from more tangible guidance.

• Determine whether to mandate implementa-

tion of QbD. If, within certain segments, there is a possible public health risk due to lack of scientific understand-ing by industry and the incentive to increase that understanding is limited, mandating QbD could be considered.

Internal FDA change management. Two options were provided under this category:

• Ensure consistency of review process in terms of scientific knowledge and

quality of review. The desire for a consistent review process and well-trained reviewers is unanimous throughout industry. FDA is aware of this need and continues to train and pre-pare reviewers to adequately assess QbD applications.

• Harmonize how QbD is approached across FDA. FDA should present a unified approach to QbD to ensure that the momen-tum around QbD adoption in industry is strong.

External change management. Three options were provided under this category:

• Enhance communication with industry. Industry almost univer-sally asked for more frequent dialogs with FDA. The

FDA on QbD

Table III: Different challenges highlighted by different stages of adoption.

Challenges to implementation Novice Pilot Rollout

Fully

implemented

1. Internal misalignment

2. Lack of belief in a business case

3. Lack of technology to execute

4. Alignment with third parties

5. Inconsistent treatment of QbD across FDA

6. Lack of tangible guidance for industry

7. Regulators not prepared to handle QbD applications

8. The way promised regulatory benefits is currently

being shared does not inspire confidence (i.e.,

business case and regulatory benefits are not clear)

9. Misalignment of international regulatory bodies

10. Current interaction with companies not conducive to QbD

Source: Interviews. QbD is quality by design. represents a key challenge.

Table II: Key challenges according to industry segment.Challenges to implementation New drug Gx Biologics

1. Internal misalignment • “R&D is incentivized by shots on goal, not QbD”

2. Lack of belief in a business case • “Generics is all about file first, figure out later”

3. Lack of technology to execute • “We can’t prove the molecular parameters necessary in a

QbD file since we don’t really understand what effects what”

7. Regulators not prepared to handle QbD applications • “Huge amount of reviewer inconsistency”

9. Misalignment of international regulatory bodies • “It takes more effort to file in other countries—they

often take a while to ‘get it’”

Source: Interviews. Gx is generic drug. QbD is quality by design. represents a key challenge.

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companies who participated in the Office of New Drug Quality Assessment’s chemistry, manufac-turing, and controls (CMC) pilot programs felt they benefited from the increased, and often less for-mal, communications. While in-creased levels of communication may pose constraints on FDA as they relate to resources, a system should be crafted that allows for a level of communication that is ac-ceptable and manageable for both FDA and industry.

• Create more buy-in by disseminating case examples. Industry asked for real, tangible examples of what applications FDA has approved or denied and why those decisions were made. FDA can work with companies whose applications have been approved to develop examples that are sensitive to proprietary information, as well as disseminate findings and tips on successfully navigating challenges.

• Improve international harmonization. Companies felt that a lack of international harmonization was one of the consistent chal-lenges. FDA should continue to seek opportunities to work with other regulatory bodies and ensure alignment on what QbD means, what QbD requires, and how regulatory flexibil-ity can be granted.

Looking forwardThe independent report served as an excellent assessment of QbD implementation by the pharmaceutical industry and of FDA poli-cies and practices from industry’s perspective. We were extremely encouraged to see from the report that the understanding and practice of QbD is evolving, gaining momentum, and generating passion throughout industry. As a result of the report, we have accelerated our internal drive toward the implementation and adoption of QbD and are in a better position to determine what we need to support the process for the next 5 years.

Looking back, the first 5 years of the QbD initiative were spent developing the concept of QbD. This included set-ting the aspiration and getting stakeholders on board— something we accomplished by initiating a number of outreach

efforts; working with international regulators and industry to develop the ICH Q8, Q9, and Q10 guidelines on pharmaceu-tical development, risk management, and quality systems; and increasing our own internal knowledge and capability.

Looking forward, we plan to spend the next 5 years focusing on putting QbD into consistent practice, including ensuring the clarity of our vision, message, and aspirational targets and time-lines; clarifying expectations and benefits of QbD within FDA and industry; and ensuring a broad codification and guidances. As such, we are working toward consistency of concepts within FDA, including: (1) ensuring that other organizations involved in supporting QbD (e.g., inspectional components) are completely aware of the principles of QbD and how they need to be applied, and (2) enhancing collaboration among the organizational com-ponents that are responsible for the overall quality of drugs. We are in the process of developing and implementing our internal quality system to ensure the quality and consistency of all CMC reviews, including the review of QbD submissions.

We believe that the implementation of QbD has been signifi-cant in advancing FDA’s desired state for pharmaceutical manu-facturing: “A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight” (1). We look forward to continuing to work with industry and other stake-holders to ensure this desired state is reached.

Reference 1. J. Woodcock, “The Desired State: A Mutual Goal of Industry, Society,

and the Regulators” (October 2005). PT

Figure 1: Conceptual timeline showing quality-by-design (QbD) versus traditional development.

Clinical

development

Pre-proof

of concept

Post-proof

of conceptFiling

Traditional

technical

development

Early dev Late devTech

transferScale up

Launch

ready

Technical

development

with QbD

Early dev Late devTech

transferScale up

Launch

ready

+0 – 10% −10% – +10% −10 – 0% −10 – 0%

Note: QbD is quality by design. Dev is development.

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Hydroxyapatite is used for the fractionation

and purification of a wide variety of biological

molecules. At commercial scale, the release of

protons during elution can detract from ceramic

hydroxyapatite performance. The authors

developed a simple methodology using a

single additional buffer step called the surface

neutralization system (SNS) that removes these

protons at near-neutral pH. The insertion of

the SNS step does not alter the desirable basic

properties of ceramic hydroxyapatite.

Mark A. Snyder* is manager, process R&D applications,

Daniel Yoshikawa is product manager, and Larry J.

Cummings is a consulting scientist, all at Bio-Rad

Laboratories, 6000 James Watson Dr., Hercules, CA

94547. [email protected], tel. 510.741.4675.

*To whom all correspondence should be addressed.

Submitted: Apr. 14, 2011 Accepted: May 31, 2011.

Protein Purification

Hydroxyapatite is a unique form of calcium phosphate used for the fractionation and purification of a wide variety of biological molecules, such as subclasses of IgG, enzymes, antibody fragments, and nucleic acids (1). Hydroxyapa-

tite chromatography can be used as a polishing step to separate biomolecules that otherwise closely copurify (2–5, 6) or for the initial purification of crude samples (6). Ceramic hdroxyapatite is manufactured through sintering and heat treating hydroxyapa-tite crystals, thus forming a robust, easy-to-pack beaded form (7).

CHT is a mixed-mode resin. The calcium ions on the surface bind to either carboxyl clusters or phosphoryl groups on target molecules in a metal affinity-type mechanism. The phosphate groups on the surface, on the other hand, interact with amines or other positively-charged groups on the surface of proteins (or other molecules) through a classical cation-exchange mecha-nism. CHT is used to purify many manufactured biotherapeu-tics and for general proteins, owing to its superior removal of all process-stream impurities (e.g., aggregates, host-cell protein, viruses, endotoxin, protein A, and DNA).

At commercial scale, the release of protons during elution can hinder CHT performance. The surface of CHT under typical processing conditions has a high degree of protonation on the surface phosphate groups (see Figure 1) (8). These protons can change places with other cations in the mobile phase. When the concentration of cations increases (e.g., step gradients range from low ionic strength to high ionic strength), protons are released into the mobile phase, temporarily reducing the pH of the solu-tion. This release has been mathematically modeled (9). Such uncontrolled pH excursions can, in the long run, detract from CHT performance (10, 11).

The pH excursion could be eliminated if the protons were re-placed by other cations, thus converting all phosphate hydroxyls into their salt (e.g., sodium) form and forming water from the protons (see Figure 2). Taking this concept, a simple methodol-ogy was developed using a single additional buffer step immedi-ately before elution, which removes protons at a near-neutral pH. This patent-pending technology is called the surface neutraliza-tion system (SNS) and is mechanistically similar to the action shown in Figure 2, except that water provides the neutralizing hydroxyls. This article presents data demonstrating that the

Surface Neutralization System A New, Robust Method for Protein Elution from Ceramic Hydroxyapatite

Mark A. Snyder, Daniel Yoshikawa, and Larry J. Cummings

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SNS technique significantly extends the useful life of CHT (i.e., improves robustness) and prevents the pH drop during elution without desorbing the target protein when the target protein is a monoclonal antibody. Data also show that this technology does not affect the common quality outputs typically monitored dur-ing antibody purification.

Materials and methods

CHT (type I 40 μm), Unosphere Supra cartridges, Bio-Scale Mini CHT columns, Bio-Sil 250 HPLC-SEC columns, and the Biologic Duoflow chromatographic workstation are all prod-ucts of Bio-Rad Laboratories. Human polyclonal IgG antibody was purchased from Sigma-Aldrich. Chinese hamster ovary (CHO) ELISA immunodetection and Picogreen DNA analysis kits were purchased from Cygnus Technology and Invitrogen, respectively. All other chemicals were obtained commercially. Monoclonal antibodies (mAb) R and G were kindly provided by external collaborators.

SNS is implemented by adding a special buffer solu-tion immediately before elution. All other process buffers as originally developed in a given process can remain the same. The addition of low levels of calcium significantly enhances CHT stability by the same common-ion effect as phosphate stabilization, and should be included in all steps up to and including elution (9, 10). The exact composition of each buffer used for this study is detailed below. SNS solu-tions include a stabilizing buffer (25–50 mM, such as Tris, arginine, lysine, histidine, PIPES, HEPES, ACES MOPS, and MOPSO), 25 mM NaCl, and 5 mM sodium phosphate, pH 7.5–8.4. The stabilizing buffer maintains the slight alkalin-ity of the solution; the low amount of NaCl slowly removes protons from the surface of CHT without desorbing target proteins; and phosphate is added to improve CHT robust-ness through the common ion effect. Application of six column volumes (CV) is sufficient to neutralize the CHT surface charge; in the experiments that followed, volumes of at least 6 CV were employed.

MAb G was loaded at approximately 20 mg/mL onto a 3.2 × 20 cm CHT column equilibrated in 5 mM sodium phosphate, pH 6.5. The column was then washed with 3 CV of this buffer prior to the application of 8 CV of SNS solution (50 mM Tris, 25 mM NaCl, 5 mM sodium phosphate, pH 8.41). Elution was then carried out using 5 mM phosphate, 330 mM NaCl, 12 ppm calcium (added as CaCl

2), pH 6.5, followed

by regeneration with 0.5 M sodium phos-phate, pH 6.5. Note that all ppm measure-ments in this study were of calcium, so that 40 ppm calcium = 1 mM calcium (formula weight 40.08).

Results and discussion

The ultraviolet (UV) profile dem-onstrates that all applied IgG re-mained bound to the CHT dur-ing the SNS step (see Figure 3).

The pH trace shows no acidic excursion during the elution step; this contrasts with a drop to pH ~5.5 in the absence of SNS. The stable pH during elution, as mea-sured by the online probe, demonstrates that all protons have been exchanged for sodium ions on the surface of CHT.

The protective effects of SNS on CHT are shown in Figure 4. In Figure 4A, a 3.2 × 20 cm column of CHT was cycled 50 times in the absence of protein as above, but with an SNS solution that was 10 CV of 25 mM PIPES, pH 7.75, 25 mM NaCl, and 5 mM sodium phosphate. The picture indicates an absence of fines or broken particles after cycling; the presence of such species in-dicates reduced CHT robustness (9, 10). The ability of SNS to suppress an acidic excursion is further substantiated in Figure 4B, where the on-line pH trace is shown with concurrent off-line measurements. For comparison, the pH drop observed without the SNS step included is shown with a blue dotted line. Note that the pH of the eluant never drops below pH 6.5, and the output calcium content is near or lower than the input calcium level in the elution buffer. The input buffer calcium is thus sufficient to prevent virtually all calcium leaching into the effluent stream. In the absence of added buffer calcium, detectable calcium in the effluent represents loss of CHT into the solvent phase.

Off-line measurements are presented again in Figure 5, this time using a PIPES-based SNS solution. In this experiment pH and calcium values were measured during a protein-free cycle

Figure 1: Surface chemistry of ceramic hydroxyapatite with

reversible binding of protons to the surface under the influence of

increasing or decreasing amounts of cation, in this case, sodium.

Figure 2: Action of proton removal.

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for a 3.2 × 20 cm column of CHT. The equilibration buffer was 10 mM sodium phosphate, pH 6.8; the load buffer contained 20 mM Tris-Arginine, pH 7.4; the SNS solution was 25 mM Tris, 25 mM NaCl, 5 mM sodium phosphate; and the elution buffer was 10 mM sodium phosphate, 0.55 M NaCl, and 10 ppm (0.25 mM) calcium chloride, pH 6.8. The purple curve represents on-line pH measurements, while the red curve represents on-line conductivity. Again, the SNS solution maintained a stable elution pH of 6.5, and the calcium in the elution buffer was sufficient to prevent calcium leaching from CHT; in contrast, the calcium present in the pre-elution effluents resulted from slight dissolu-tion of the CHT itself because these buffers did not contain added calcium chloride.

To demonstrate the robustness of SNS at commercial scales, this protocol was repeated on a 20 × 20 cm column packed with CHT. At commercial scale, the primary endpoint for CHT use is unacceptable backpressure. Under control conditions where the SNS step was omitted, approximately 10 cycles were obtained before the backpressure in the column rose to > 3 bar. However, the addition of the SNS buffer allowed for at least 46 cycles before a significant increase in pressure. Not only could early failure be

easily demonstrated as a negative control, but the clear protective effect of SNS was also shown. This is a crucial validation of the usefulness of SNS technology for manufacturing processes.

The effectiveness of SNS in stabiliz-ing CHT, as well as a lack of general ef-fect on monoclonal IgG elution, is thus demonstrated. Monoclonal antibodies, however, provide more precise ways to examine specific chromatographic ef-fects. Accordingly, further work was performed with two available mono-clonal antibodies to determine whether SNS cycling would affect CHT itself or whether SNS would alter antibody elu-tion or impurity clearances.

A 1.1 × 21.7 cm column of either fresh CHT (see Figure 6A) or CHT from the 20 × 20 cm SNS experiment described above (see Figure 6B) was equilibrated with 10 mM sodium phosphate, pH 6.8 and loaded with ~10 mg mAb G/mL bed volume. The column was then washed either with 8 CV of SNS (25 mM Tris, 25 mM NaCl, 5 mM sodium phosphate, pH 7.75) or equilibration buffer before elution with 10 mM sodium phosphate, 330 mM NaCl, 10 ppm calcium (0.25 mM), pH 6.8. In both cases, the peak elution shape re-mains the same, even though the pH drop seen in Figure 6A is eliminated in Figure 6B. The yields were 83% and 86%, within historical values (80–88%). The similar peak shapes indicate that prior exposure

to SNS does not alter the ability of CHT to bind and elute this monoclonal antibody. Figure 6C shows HPLC-SEC chromato-grams of the load and eluate pools taken from experiment 6B. Even after almost 50 cycles of exposure to SNS, CHT still com-pletely retained its ability to remove aggregates to below the limit of detection (0.03%).

Peak retention times provide a more precise comparison of protein-matrix interactions. The previous experiment was re-peated, except that the elution was a gradient from 10 mM so-dium phosphate, pH 6.8 to 10 mM sodium phosphate, pH 6.8 with 1.5 M NaCl over 20 CV. Again, the elution time of the anti-body peak was unaltered even after exposure of CHT to multiple SNS cycles (see Figure 7). This is a precise demonstration that CHT-protein interactions are not affected by prolonged cycling with SNS solutions.

In further robustness studies, columns (1.1 × 21.7 cm) of either fresh CHT or CHT from the 20 × 20 cm experiment described above were equilibrated in 10 mM sodium phosphate, pH 6.5 and then loaded with a 1 mg/mL solution of human polyclonal IgG. The 5% and 10% breakthrough points were established based


Figure 3: Behavior of monoclonal antibody G during surface neutralizaton.

Ab

sorb

an

ce (

AU

)

Co

nd

uct

ivit

y (

mS/c

m)

Time (tenths of a minute)

Figure 4: Fifty cycles with PIPES-buffered surface neutralizaton: (A) visual

measurement of fines after 50 cycles; and (B) pH and calcium measurements.

Co

nd

uct

ivit

y (

mS/c

m)

Time (min)


on UV absorbance, using the absorbance of pure load material as the UV value for 100% breakthrough. The data demonstrate that repeated exposure to SNS does not demonstrably alter the binding capacity of the monoclonal antibody when two loading conditions were chosen (see Table I).

Finally, for SNS to be commercially viable it should not alter the ability of CHT to clear other process impurities. To study this, approximately 10 mg of mAb R was purified over a UnoSphere Supra cartridge using an eluant of 0.1 M glycine, pH 3.5, which was then neutral-ized to pH 6.8. The solution was then applied to a 1 mL Bio-Scale Mini CHT column equilibrated in 10 mM sodium phosphate and 10 mM NaCl, pH 6.8. The column was washed with 25 CV of equilibration buffer followed by 0 (con-trol) or 10 (SNS) CV of 25 mM Tris, 25 mM NaCl, 5 mM sodium phosphate, pH 7.75. The column was then devel-oped with 25 CV of a linear gradient of 10 mM sodium phosphate and 10 mM NaCl, pH 6.8, down to 10 mM sodium

phosphate and 1 M NaCl, pH 6.8. Antibody eluate pools were then analyzed for CHO host-cell protein and DNA. SNS did not alter the clearance of either type of impurity within the reproducibility limits of the assay (see Table II).

Figure 5: Calcium and pH measurements during surface neutralization.

The purple curve is on-line pH measurements, the red curve is on-line conductivity.

Figure 6: Protein elution using NaCl step gradient with and without surface neutralizaton system (SNS) step: (A) monomer yield

without SNS step; (B) monomer yield with SNS step; and (C) aggregate analysis of B by size exclusion chromatography.

Co

nd

uct

ivit

y (

mS/c

m)

Time (min)

Ab

sorb

an

ce (

AU

)

Ab

sorb

an

ce (

AU

)

Time (min)Time (min)

c

Ab

sorb

an

ce (

AU

)

Time (tenths of a minute)


ConclusionThe results of these experiments demonstrate several points. The application of a simple, inexpensive buffer immediately before elution of a protein from CHT mitigated uncontrolled pH excur-sions and dramatically extended the number of cycles that could be obtained prior to a significant backpressure increase. This result stemmed from the replacement of protons on the surface of the matrix with sodium ions. The positive effects of SNS were demonstrated visually and by pH and calcium measurements, and reproduced at a column scale (20 × 20 cm) that has been shown to produce early column backpressure failure in negative control experiments.

The insertion of the SNS step did not alter basic properties of CHT, such as binding capacity, target protein interaction, ag-gregate clearance, or host cell protein and DNA removal. Thus,

the highly desirable properties of CHT remain unaltered as its robustness was significantly increased. Also, the perfor-mance of CHT on a per-cycle basis seems to be equivalent with or without SNS. Taken together, these data suggest the desirability of this technology for devel-opment-phase processes, and also suggest that it is a reasonably straightforward reg-ulatory pathway for post-licensing modi-fication of an existing process.

The addition of calcium indepen-dently supports CHT robustness, and is expected to act through the common-ion effect in the same way as phos-phate (10–12). Unpublished studies demonstrate this as well. The presence of calcium in effluents from calcium-free buffers demonstrates that CHT is leaching this ion into solution. By add-ing calcium at appropriate concentra-tions to various buffers, this leaching can be dramatically diminished. The simple method for determining how much calcium to add, as well as further experimentation on the positive effects of calcium on CHT robustness, will be discussed in the future.

References1. L.J. Cummings, T. Ogawa, and P. Tunón, “CHT Ceramic Hydroxyapatite: New Life for an Old Chromatographic Technique,” Bulletin No. 1927 Rev. B (Bio-Rad Laboratories, Hercules, CA, 2005).2. P. Yachelini, I. Falk, and K. Eichmann, J. Im-munol. 145 (5), 1382–1389 (1990).3. K. Schott et al., J. Biol. Chem. 265 (8), 4204–4209 (1990).4. C.W. Mahoney, A. Azzi, and K.P. Huang, J.

Biol. Chem. 265 (10), 5424–5428 (1990). 5. A.C. Newton and D.E. Koshland Jr., Biochemistry 29 (28), 6656–6661

(1990). 6. B.R. Ganong, Biochemistry 29 (29), 6904–6910 (1990). 7. L.J. Cummings, M.A. Snyder, and K. Brisack, Meth. Enzymol. 463,

387–404 (2009). 8. K. Y. Kwon et al., J. Phys. Chem. Lett. C, 113 (9), 3369–3372 (2009). 9. L. Dattolo, E.L. Keller and G. Carta, J. Chrom. A. 1217 (48), 7573–7578

(2010). 10. M.A. Snyder, presentation at The Fifth Hydoxyapatite Conference

(Rottach-Egern, Germany, 2009). 11. L.J. Cummings, presentation at The Fifth Hydoxyapatite Conference

(Rottach-Egern, Germany, 2009). 12. CHT Ceramic Hydroxyapatite Instruction Manual, Bulletin LIT611

Rev. E (Bio-Rad Laboratories, Hercules, CA, 2006). PT

What would you do differently? Email your thoughts about this paper to [email protected] and we may post them on PharmTech.com.


Figure 7: Surface neutralizaton system step with protein eluted using NaCl linear gradient.

Table I: Effect of repeated use of surface neutralizaton system on binding capacity.

Sample Load buffer

5% Breakthrough

(hulgG, mg/mL)

10% Breakthrough

(hulgG, mg/mL)

Tris SNS, 46 cycle CHT Tris -Arginine pH 7.4 17.8 23.8

Control CHT Tris -Arginine pH 7.4 17.4 23.0

Tris SNS, 46 cycle CHT 5 mM NaPi, pH 6.5 45.5

Control CHT 5 mM NaPi, pH 6.5 40.6

Table II: Effect of surface neutralizaton system (SNS) on process impurity clearance.Chinese hamster ovary host cell protein clearance Chinese hamster ovary host cell protein clearance

Sample Host cell protein, ng/mg Sample DNA, ng/mg

Control 32.9 Control 0.596

SNS 28.8 SNS 0.431

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74 Pharmaceutical Technology sseptember 2011 PharmTech .com

This case study on facility biocontainment and

inactivation is the third of eight in a series put

together by the Product Quality Research Institute

Manufacturing Technical Committee (PQRI-

MTC) risk-management working group. The series is

meant to advance the understanding and application

of the International Conference on Harmonization

(ICH) Q9 Quality Risk Management guideline by

providing actual examples of risk-management

assessments used by the bio/pharmceutical

industry. The introductory article and first case

study, on defining design space, appeared in the July

2011 issue of Pharmaceutical Technology (1).

Ted Frank is with Merck & Co; Stephen Brooks, Kristin

Murray,* and Steve Reich are with Pfizer; Ed Sanchez

is with Johnson & Johnson; Brian Hasselbalch is with

the FDA Center for Drug Evaluation and Research;

Kwame Obeng is with Bristol Myers Squibb; and

Richard Creekmore is with AstraZeneca.

*To whom all correspondence should be addressed,

at [email protected]

PQRI Case Study

When a manufacturer produces two or more drug substances in the same manufacturing facility, the facility is considered to be multiproduct. The facility designs, operations, and controls related to

the use for multiple products should provide for appropriate measures to prevent cross-contamination between products. These controls include the containment procedures used to prevent the release of hazardous agents within the facility.

There are numerous facility design and operational at-tributes that may significantly affect the quality of products being manufactured. These attributes include, but are not limited to, area classifications, open versus closed process-ing, utility-system design, cleaning validation/clean-in-place systems, rules regarding equipment sharing, and critical f lows throughout the facility. Facility designs and opera-tions should provide for appropriate segregation of products to prevent cross-contamination. For facilities with multiple products or processes, the impact of potential process or product failures on the other operations in the same facility should be evaluated.

The following case study on facility biocontainment and inactivation is the third of eight in a series put together by the Product Quality Research Institute Manufacturing Tech-nical Committee (PQRI–MTC) risk-management working group. The series is meant to advance the understanding and application of the International Conference on Harmo-nization (ICH) Q9 Quality Risk Management guideline by providing actual examples of risk-management assessments used by the bio/pharmceutical industry. The introductory article explaining the history and structure of the series, as well as the first case study on defining design space, ap-peared in the July 2011 issue of Pharmaceutical Technology (1). The second study addressed functional equivalence for equipment replacement (2).

In the current case study, two existing manufacturing suites were proposed to be remodeled to accommodate and contain manufacturing operations involving bacterial fermentation through viable cells of Streptococcus pneumoniae, a pathogenic Biosafety Level 2 (BL2) organism. These suites were separate

Facility Biocontainment and InactivationA Risk-Management Case Study (Part 3)Ted Frank, Stephen Brooks, Kristin Murray, Steve Reich,

Ed Sanchez, Brian Hasselbalch, Kwame Obeng, and Richard Creekmore

Pharmaceutical Technology sseptember 2011 75

manufacturing areas located adjacent to mammalian cell cul-ture manufacturing-processing areas. Regulatory guidance requires BL2-Large Scale (LS) waste and residues to be inacti-vated prior to exiting the manufacturing area (3). An inactiva-tion autoclave was identified during the initial risk assessment as one of the primary means of inactivation of BL2 waste and process equipment prior to exiting the fermentation suite. The risk-review step in the risk-management process identified that there was only one inactivation autoclave in the fermentation suite and that alternative backup inactivation procedures were desired to maintain continuity of manufacturing operations during autoclave preventive- and corrective-maintenance activities.

This case study describes the evaluation of various backup inactivation procedures for operational feasibility and includes a demonstration of an appropriate level of in-activation of the BL2 waste and equipment.

Risk question and risk-assessment methodThe risk question developed for the subject case study is: What are the appropriate backup inactivation methods (i.e., procedures) that are operationally feasible and provide an appropriate level of decontamination capability that can be uti-lized in the fermentation suite to inactivate BL2 waste and equip-ment when the inactivation autoclave is unavailable?

Selection of a backup inactivation procedure is a precise exercise requiring an objective evaluation of the effective-ness of proposed procedures at inactivating the BL2 organ-ism along with demonstration of consistent execution of these procedures each time they are performed.

Hazards analysis and critical control points (HACCP) is a risk-assessment tool that can be proactively used to identify and implement process controls that consistently and ef-fectively prevent hazards from occurring. HACCP involves evaluation of critical procedural limits and determination of how they will be achieved routinely. Because it is essen-tial that the backup inactivation procedures prevent the re-lease of the BL2 organism outside of the fermentation suite, HACCP was selected as the risk-assessment tool to use to determine the appropriate preventative controls.

Risk identification and analysisFor this evaluation, there was only one hazard to consider: the BL2 organism. The HACCP process was significantly streamlined to control for operator safety and the high level of regulatory requirements for pathogenic BL2 organisms. The hazard was always considered to be significant in this case study (see Table I).

As shown in Table I, each proposed inactivation mecha-nism or procedure was deemed crucial because they were proposed as backups for the primary autoclave inactivation method (which was itself deemed crucial). The evaluation of the effectiveness of the procedures including how they would be controlled to achieve consistency among critical parameters is shown in Table II.

Risk controlIn this case study, identifying effective backup inactiva-tion methods to compensate for times when the primary inactivation autoclave is unavailable for use reduces the risk of a breach of containment in the facility. Table II demon-strates that the backup procedures identified are effective and can be consistently controlled. Table II also indicates that additional, more detailed procedural controls and more clearly defined functional-area responsibilities are required to maintain proper containment of the BL2 organism. These additional procedural controls are identified in the “recom-mended actions” column of Table II.

Risk documentation and communicationFor this case study, the outputs of the risk-assessment pro-cess, including recommendations for additional procedural and functional-area controls, were documented in a risk-assessment report. This report became part of the operat-ing history of the manufacturing facility and the associated product. The project team of each functional area affected by the results of the risk assessment reviewed and signed off on the results and recommendations. The project team assumed responsibility for implementing the recommenda-tions that arose from the quality risk-management process.

Table I: Hazard analysis worksheet. Categories of

items

Actual and potential

hazards introduced,

controlled, or

enhanced at this step

Introduced,

controlled

or enhanced

Are any

potential

safety hazards

significant?

Justify

response

What preventative

measures were

applied to prevent the

significant hazard?

Is this a

critical control

point (CCP)?

CCP rationale

(for both

Yes and No)

Mixed trash

Biosafety Level 2

(BL2) host organism—

known infectious

pathogen

Introduced YesBL2 host

organism

Place trash bag into

another trash bag,

seal for transport, and

sanitize bag exterior.

Place bags in a covered

container for transport

to an external autoclave.

Yes

This CPP is the

primary means of

containment until

inactivation.

Controlled Yes BL2 host

organism

Inactivation within an

external autoclave. Yes

This CPP is the

primary means of

inactivation.

76 Pharmaceutical Technology sseptember 2011 PharmTech .com

Risk reviewIn the case study presented, it may be appropriate to review the backup procedures as additional detailed procedures are developed. This activity will ensure that the backup procedures are fully effective and controlled in an effort to contain appropriately the BL2 organism.

References 1. T. Frank et al., Pharm. Technol. 35 (7), pp. 72–79. 2. T. Frank et al., Pharm. Technol. 35 (8), pp. 72-75. 3. NIH, Guidelines for Research Involving Recombinant DNA Mol-

ecules, Appendix K (May 2011). PT

Table II: HACCP plan form for the evaluation of the effectiveness and control of standard operating procedures (SOPs). RTD is resistance temperature detector. EH&S is environmental health and safety.

Critical

control

point

Significant

hazards

Critical

limits

for each

preventive

measure

Monitoring

Verification

Documentation/

Supporting

studies and

records

Recommended

actionsWhat How Frequency Who

Place trash

bag into

another trash

bag, seal for

transport,

and sanitize

bag’s

exterior.

Place bags

in a covered

container for

transport to

an external

autoclave.

Biosafety

Level 2

(BL2) host

organism

Bag closure

via tie-knot Closure Visual

Once–upon

closure

Trained

technician

Bag not

accepted if

not sealed None

SOP for this

activity is

required. Any

bags containing

sharps must be

relabled with

appropriate

external sharps

indicator stickers

to ensure those

bags are routed

for incineration

rather than

autoclave

inactivation.

70% vol/vol

Ethanol

concentration

for wipe-

down

Certificate

of analysis

Once–upon

release

Quality

Control

Release of

ethanol for

GMP use Validation reports

1 min

Ethanol

contact time

for wipe-

down Wall-clock

Once–upon

wipe down

Trained

technician

Placement

of bags into

airlock only

after ethanol

inactivation

performed per

SOP Validation reports

Complete

coverage

Ethanol spray

coverage of

bag

Visual–

ensure

surfaces are

wetted

Once–upon

wipe down

Trained

technician

Placement

of bags into

airlock only

after ethanol

inactivation

performed per

SOP Validation reports

Inactivation

within

external auto

clave

BL2 host

organism

12 min

Sterilization

hold time–

set at 90

minutes

Controller

timer

Throughout

cycle

Automated

unit

controller

Cycle tape

reviewed and

retained for at

least 3 years.

Unit is alarmed

if cycle

acceptance

parameters

not achieved.

Autoclave loads are

challenged monthly

with Bacillus

stearothermophilus.

Electronic records

of the verifications

are retained for at

least 3 years.

Flow fot these

materials will

need to be

proceduralized

and training of

all impacted

functional areas

will need to be

determined.

EH&S will need

to ensure thet

autoclaved

gowns are not

disposed and

are returned for

laundering.

121 °C

Sterilization

temperature RTD

Throughout

cycle

Automated

unit

controller

Cycle tape

reviewed and

retained for at

least 3 years.

Unit is alarmed

if cycle

acceptance

parameters

not achieved.

PQRI Case Study

Training ToolsThis PQRI risk-management case study series includes online

training tools, available at PharmTech.com/PQRIstudies. The PDF

trainers include: a HAZOP training guide, a FMEA training guide, a

HACCP training guide, and a Risk Rank Filter training guide.

October 23–27, 2011 Walter E. Washington Convention Center, Washington, DC, USA

www.aapspharmaceutica.com/annualmeeting

2011 AAPS Annual Meeting and Exposition

Mark Your Calendars!


INSIDE ICH

PharmTech.com/ich

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PharmTech.com/ich

The International Conference on Har-monization (ICH) Steering Com-mittee and Expert Working Groups

met in Cincinnati, on July 12–16, 2011. The following provides a summary of the major achievements made during the meeting.

The ICH Quality Implementation Working Group (IWG), composed mainly of members from previous ICH Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System work-ing group members, continued to make excellent progress. The group completed three Points to Consider documents cov-ering the criticality of quality attributes and process parameters, control strat-egy, and the level of documentation in enhanced (i.e., quality-by-design [QbD]) regulatory submissions.

The group was reminded that these documents are not intended to intro-duce new regulatory requirements but are intended to provide clarity for both regulators and industry and to facilitate preparation, assessment, and inspection related to applications filed for marketing authorizations. These documents will serve to provide supplementary informa-tion to the previously completed Q&A’s and training materials for ICH’s quality guidelines Q8, Q9, and Q10.

Three new Points to Consider docu-ments are expected to be finalized at

the November ICH meeting in Sevilla, Spain. These documents will address de-sign space, modeling, and process vali-dation/continuous process verification. The ICH Quality IWG will also organize two additional Q8, Q9, and Q10 training workshops, one in Ottawa, Canada, on

Sept. 26–27, and the other in Seoul, South Korea, on October 4–5. These workshops will be similar to the three that took place in 2010 in Europe, Japan, and the United States. The training material, Q&As, and Points to Consider documents are avail-able on the ICH website.

The ICH M7 Genotoxic Impurities guidelines involves the assessment and control of DNA reactive (i.e., mutagenic) impurities in pharmaceuticals to limit po-tential carcinogenic risk. This guideline is also moving forward. The working group searching for consistency between the Q3D Metal Impurities guideline and the Q11 De-velopment and Manufacture of Drug Sub-stances guideline identified three impor-tant focus areas: scope, methods, and risk mitigation. The final ICH M7 guideline will therefore try to apply these concepts to new and existing products. One issue the group has yet to resolve is whether or not excipients will be included in M7. The guideline is targeted to reach Step 2 (six-party consensus) by November 2012.

Meanwhile, the ICH Q3D expert working group has reviewed safety as-sessments for 27 metals and tentatively agreed to limits. The group had dis-cussed the scope of the guideline and reached agreement that biotechnologi-cal drug products should remain in the guideline’s scope. There remains some concern regarding limits for lead and mercury. The key issue stems from mineral-based excipients (e.g., TiO

2, cal-

cium carbonate) because lead is naturally found at the source of the ore. The levels of lead are dependent on the ore source and can vary drastically over the span of several years.

A coalition created by the Inter-national Pharmaceutical Excipients Council, which includes members from various industry organizations, will be working on data collection dur-ing the next 6–10 months to assist in the finalization of levels for key met-als. Besides the safety aspect, there is an ongoing larger discussion regard-ing control strategy. A section will be added to Q3D to reflect the limited risk associated with inclusion of metal im-purities in biotechnologically derived drug substances. Q3D should reach Step 2 in June 2012.

The ICH Q11 group did not meet in Cincinnati, because the draft guideline reached Step 2 in April 2011. This guide-line describes approaches to developing process and drug-substance understand-ing and provides guidance on what in-formation should be provided in a com-mon technical document. It also clarifies the principles and concepts described in ICH guidelines Q8, Q9, and Q10. PT

A summary of the latest steering committee

and expert working groups’ meeting.

Georges France and Jean-Louis Robert

Quality Implementation and Harmonization Continue

There remains

some concern

regarding limits for

lead and mercury.

Georges France is the EFPIA Topic Leader

for the ICH Quality Implementation Working

Group (Q–IWG). Jean-Louis Robert is the

EU Rapporteur for the Q–IWG and chair of

the EU Committee for Medicinal Products for

Human Use Quality Working Party.

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PharmTech.com/outsource

could the European debt crisis be the event that consolidates the dose CMO industry? That thought

might seem like a stretch, but the fi-nancial turmoil roiling Europe could definitely have a big impact on the CMO industry.

Much of the media coverage of Eu-rope’s debt crisis has focused on the ability of governments in the so-called PIIGS countries—Portugal, Ireland, Italy, Greece, and Spain—to repay or refinance their national debt. It is much more than that, however.

The European debt crisis is poten-tially a banking crisis as well because the banks hold much of the sovereign debt. If the PIIGS were to default, the banks would be forced to write down the value of their bond holdings, and the result-ing losses would reduce their equity and the capital ratios that they must main-tain under international and national regulations. That scenario would force the banks to raise more capital and/or reduce their lending to bring assets back in line with their capital. The reduced lending would be felt throughout Eu-rope because the affected institutions, especially the big trans-European banks, such as Deutsche Bank, are major lend-ers throughout the Euro zone.

Another concern is that government austerity programs, combined with reduced bank lending, will severely

weaken the already fragile economies of the PIIGS countries. Those economies are already a mess, plagued with low de-mand, high unemployment, and low tax revenues. Lower government spending, tighter private-sector credit, and higher interest rates will further suppress over-all economic activity and household in-comes in the coming years.

In fact, the bank pullback already is under way. Recent reports in the finan-cial press (as of the writing of this article in early August) indicate that the Euro-pean banks are reducing their private-sector lending in the PIIGS countries in an effort to reduce their exposure to the weakening economies.

implications for cMosThe deteriorating European financial situation will play out to the detriment of European CMOs in two principal ways: undermining their operating performance and affecting the avail-ability and cost of debt needed to fi-nance their businesses.

operating performance. The deteriora-tion of the operating performance al-ready is occurring because expenditures on drugs are falling sharply through re-duced volumes and lower prices. These lower volumes and prices are especially apparent in countries where the national healthcare systems are primary buyers

and distributor of drugs and therefore affected more by reduced government revenues and spending. The deteriorat-ing economies also will impact privately financed spending on drugs.

CMOs are feeling the affect of re-duced spending on drugs through lower production and demand from clients for lower prices. Furthermore, many European CMOs also are generic-drug manufacturers that use their excess ca-pacity for contract manufacturing. The reduced spending also is taking a toll on their generic-drug business.

Even before the financial crisis, many European CMOs and generic-drug com-panies were plagued by low utilization and narrow profit margins. Further de-terioration of operating profitability has a range of deleterious implications for the CMOs, ranging from deferred main-tenance and capital investment, all the way to receivership. Any sustained de-terioration in operating profitability will reduce the credit worthiness of CMOs and threaten their access to bank credit.

Availability of financing. The availability and cost of bank credit could impact a number of CMOs, including those that are owned by private-equity companies. Private-equity firms typically use the debt capacity of the companies they own to reduce the amount of equity they have invested in the companies and even as a means of generating cash that they pay to themselves as a dividend. In the case of European CMOs, even though the owners in most cases didn’t pay much or anything for their facilities, the owners could have borrowed against their assets and they could be highly leveraged. Even where companies don’t depend on debt for financing assets, any deterioration of operating performance could affect

the Eu Debt crisis and cMos

The EU debt crisis portends of possible negative

repercussions for the dose CMO industry.

The financial crisis is

hitting the European

CMO sector at a time

when it is already

weak.

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,

[email protected],

www.pharmsource.com.

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CMOs’ ability to get lines of credit for basic operating needs.

The financial crisis will hurt the CMO industry by making it more difficult for their clients to get exter-nal financing. Financial crises always make investors more risk averse, and investing in new drug development is inherently risky. Europe has always been a difficult place for early-stage companies to raise venture capital, and the deteriorating economic situation is likely to make it worse.

consolidating cMo industry?The financial crisis is hitting the Euro-pean CMO sector at a time when it is already weak. According to the Pharm-Source ADVANTAGE database, Europe has nearly twice as many contract dose manufacturers as North America, in-cluding 100 solid dose CMOs and 70 in-jectables CMOs. Only about one-third of these CMOs are FDA-registered, meaning most of them are limited to competing for business to supply European or emerg-

ing markets. As a result, competition for the available business already is intense, thereby pushing pricing and operating margins to barely sustainable levels.

The overcapacity problem has come about because it is so difficult to close redundant manufacturing facilities in Europe. Faced with huge severance costs and negative publicity if they close a facility, global bio/pharmaceutical companies have preferred to give away facilities to management teams and private-equity firms that are willing to run them as CMOs. That approach gets rid of the headache for the pharmaceuti-cal company, but it has created an unsus-tainable situation for the CMO industry.

Under these dire circumstances, we believe that a number of CMOs face significant risk of insolvency in the near term. While most of them are pri-vately held companies that don’t publish their financial statements, the situations where we can see the financial results show very poor operating margins and minimal debt capacity. The precarious

state of the European financial system and the implications of that weakness may be enough to push some of those companies over the edge.

challenges aheadBio/pharmaceutical companies that de-pend on European CMOs face a major due-diligence challenge. They need to monitor their European CMOs closely, gain a thorough understanding of their balance sheets and cash flows, and be aware of their exposure to negative de-velopments in the credit environment. For CMOs owned by larger entities, the oversight should extend to the corporate parents as well. There are some major CMOs whose corporate parents have extensive interests in sectors outside pharmaceuticals that are heavily ex-posed to the financial crisis, such as re-tailing and property development. Bio/pharmaceutical companies also will need to have alternate sourcing plans in place in the event that financial devel-opments interrupt product supply. PT

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Xcelience Expands Its Headquarters in TampaXcelience is expanding its ex-

isting 24,000-ft2 headquarters

in Tampa, Florida, with the

addition of nine rooms (i.e.,

1000 ft2). The company also is

adding another new 24,000-ft2

facility close to the existing

facility to accommodate 45

new employees. Xcelience

plans to double its staff over

the next three years and is

currently seeking chemists

and managers for preformula-

tion and formulation. Open

positions can be found on the

Xcelience website.

“We have weathered the

economic crisis and feel hon-

ored by the confidence our

long-term clients have shown

in us throughout. Now, as our

business experiences a strong

rebound, we are poised to en-

sure that we have the capac-

ity and staff to maintain the

highest level of quality for our

rapidly expanding customer

base,” said Xcelience CEO and

President Derek Hennecke in

a press release.

The job creation has made

the company eligible for a

Florida Qualified Targeted

Industry Tax Refund incen-

tive award of $135,000. “It

demonstrates the successful

outcomes we’re achieving to-

ward job creation,” said Gray

Swoope, president of Enter-

prise Florida, in an Xcelience

press release.

Sensient Launches New WebsiteSensient Pharmaceutical

Coating Systems, a subsidiary

of Sensient Technologies,

launched a new website,

www.sensientpharma.com.

The new website is designed

to be a resource for compre-

hensive product information.

It is intended to be easy for

customers to use and to pro-

vide technical support for

clients as well.

Catalent Announces Cold-Chain ExpansionsCatalent Pharma Solutions’s

Clinical Supply Services divi-

sion has expanded its global

cold-chain supply operations

in the United States, United

Kingdom, and Germany, to

meet increasing demands for

global supply. The expansions

will be implemented in all

major areas of Catalent’s cold-

chain storage and distribution,

including 2 to 8 ∘C and −80 ∘C

capabilities. In some instances,

the expansion will more than

triple existing capacity for stor-

age and distribution. Catalent

expects that the cold-chain

expansion at its European sites

in Bolton, UK, and Schorndorf,

Germany, will be completed

by the end of 2011.

Tris Names Vice-President of QualityTris Pharma has appointed

Dominick DiPaolo as vice-pres-

ident of quality. DiPaolo served

as senior manager of global

corporate quality at Pfizer from

2002 to 2005. From 2005 to

2011, he led quality operations,

mostly in remedial situations,

at Barr (formerly Pliva), Wock-

hardt Pharmaceuticals (Morton

Grove), and, most recently,

G&W Laboratories.

“Now with multiple

branded and generic regu-

latory filings under FDA

review, it was imperative to

strengthen our investment in

quality, creating a new posi-

tion of vice-president of qual-

ity,” said Ketan Mehta, presi-

dent and CEO of Tris Pharma,

in a press release.

John Plachetka, chair,

president, and CEO of POZEN

PharmTech:What is the biggest industry

challenge you’re now facing?

Plachetka:The biggest challenge that

POZEN sees in the healthcare

industry is bringing novel

therapies to market in a way

that is efficient and affordable

to customers, yet also meets

FDA’s development guidelines.

The traditional Big Pharma model has become obsolete. It

has stifled innovation and led to a decline in the approval

of novel drugs and the continued rise of healthcare costs.

POZEN’s business model is designed to avoid some of the

pitfalls of traditional drug development and commercializa-

tion. The company works under compressed timetables,

compared with larger pharmaceutical companies, and uses

an in-source model that employs a small expert team that

leads the drug-development and commercial strategies,

while working closely with strategic partners.

PharmTech:Do you see a new industry trend emerging?

Plachetka:One current trend that we see in the industry is in the devel-

opment of novel combination therapies. POZEN has been

researching how to best integrate existing medicines to

achieve superior outcomes since I founded the company in

1996. We believe that the benefits of many gold-standard

medicines today are not fully realized because of toler-

ability, safety, or efficacy concerns for certain patient types.

Recently, FDA and the industry have begun to recognize

the potential of integrated therapies, and FDA is evaluating

how to update development guidance. POZEN is currently

developing a family of products to maximize the benefits of

aspirin by reducing its associated gastrointestinal damage.

PharmTech:How do you stay abreast of new developments in the industry?

Plachetka:We hold close, strategic relationships both in and outside of

the pharmaceutical industry and frequently participate in con-

ferences and seminars. We regularly read medical journals and

industry trade publications. To remain in touch with the de-

mands of our customers, we actively conduct market research.

INDUSTRY PIPELINE

Pharmaceutical Technology SEPTEMBER 2011 85

MANUFACTURING EQUIPMENT & SUPPLIES

MANUFACTURING EQUIPMENT & SUPPLIES

MANUFACTURING

EQUIPMENT & SUPPLIES OUTSOURCING & CONSULTING SERVICES

Filter-

integrity tester Thirty years of

design refinements

have resulted in

the Sartocheck

4 plus advanced

filter-integrity tester. The unit incorporates

productivity-enhancing features and is built

to be durable. The device also was designed

for the operator’s ease of use. Sartorius Stedim

North America, Bohemia, NY • www.sartorius.

com • tel. 631.254.4249

Tablet pressSpecialty Mea-

surement offers

the MiniTab

press, which

is designed

to manufacture tablets ranging from 0.5 to

4 mm in diameter. The introduction model

can produce < 300,000 tablets/h; larger

models will be capable of making > 2 million

tablets/h. The compact size of the machine,

less than 250 × 500 × 500 mm, makes it ideal

for glove-box applications. SMI, Lebanon, NJ •

www.smitmc.com • tel. 908.534.1546

Radar transmitterThe Magnetrol Eclipse

Model 705 Guided Wave

radar transmitter meets the

requirements for wetted and

nonwetted materials, process

connections, and surface

finishes for the hygienic

industries. The Eclipse was

designed to meet level-

measurement-instrument

needs for companies in the

food and beverage, biophar-

maceutical, and pharmaceutical industries.

Magnetrol Hygienic Measurement Solutions,

Downers Grove, IL • www.magnetrol.com •

tel. 800.624.8765

Syringe filtersMeissner offers a choice of

STyLUX polyethersulfone

or SteriLUX polyvinylidene

difluoride 25-mm syringe

filters for laboratory and

R&D applications. The

syringe filters are suitable

for scale-up evaluation of membrane filters,

capsules, cartridge filters, UltraCap, and Ul-

traCap H.D. high-capacity capsule filters. The

25-mm syringe filters are offered in sterile

and nonsterile versions with absolute reten-

tion ratings of 0.2 μm and

0.4 μm. Meissner Filtration Products, Camarillo,

CA • www.meissner.com • tel. 805.388.9911

High-shear

mixer systemThe Ross Solids–Liq-

uid Injection Mani-

fold is a high-shear

mixer system de-

signed to prevent the

formation of agglom-

erates and fish eyes in thickened solutions.

It uses a specially engineered rotor–stator

assembly that generates a powerful vacuum

for drawing solids into the mix chamber. The

liquid stream enters the mixer and immedi-

ately encounters the powder addition under

intense shear conditions. Ross, Charles & Son

Company, Hauppauge, NY • www.mixers.com •

tel. 800.243.ROSS

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 choices and also repairs bags.

Kavon Filter Products, Wall Township, NJ •

www.kavonfilter.com • tel. 732.938.3135

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

Compliance

servicesMicrobix Biosystems

helps clients who are

developing products that

must comply with several

pharmacopeias. The

company provides multicompendial water

for injection that meets the specifications

of the US, European, and Japanese pharma-

copeias. The company also provides USP

purified water and offers custom solutions,

buffers, and media packed under

GMP conditions.

Microbix Biosystems, Mississauga, Canada •

www.microbix.com • tel. 610.325.9814

Drug-

delivery

systemsVetter offers

a portfolio of

drug-delivery

systems. Its

commercial

manufacturing division aseptically fills sy-

ringes, cartridges, and vials according to high

quality and safety standards. The company

also offers patient-friendly injection systems,

such as the Vetter Lyo-Ject dual-chamber

syringe and the dual-chamber cartridge V-LK.

Vetter Pharma International, Ravensburg,

Germany • www.vetter-pharma.com •

tel. +49 751 3700 0

INDUSTRY PIPELINE


OUTSOURCING & CONSULTING SERVICES

OUTSOURCING & CONSULTING SERVICES

CLEANROOM EQUIPMENT & SUPPLIES PACKAGING EQUIPMENT & SUPPLIES

Ionizing

blow-off gunTerra Universal’s IonGun

Ionizing Blow-Off Gun is

designed to simplify safe

cleaning and packag-

ing of delicate medical

devices. Squeezing the

trigger releases a balanced stream of positive

and negative ions to neutralize static surface

charges. Simultaneously, a burst of clean air

or nitrogen dislodges and removes particles

held by static attraction. Terra Universal,

Fullerton, CA • www.terrauniversal.com •

714.578.6000

Drug-

development

servicesCovance provides

drug-develop-

ment services to

clients in the biotechnology and pharmaceuti-

cal industries. The company has a portfolio of

drug-discovery; preclinical; clinical; chemistry,

manufacturing, and controls; and commercial-

ization services. Covance’s global capabilities

are geared toward meeting customers’ needs

through its processes and client services. Co-

vance, Princeton, NJ • www.covance.com •

tel. 888.COVANCE

Outsourced servicesCoating Place is a leader in services from

Wurster fluid-bed formulation development

to commercial manufacturing. The company

performs bead layering, extrusion–

spheronization, roller compaction, and

capsule filling and tableting. Coating Place

processes both solvent and aqueous formula-

tions. Its facilities are registered with the US

Food and Drug Administration.

Coating Place, Verona, WI • www.encap.com •

tel. 608.845.9521

Contract services Mikart has provided contract development,

manufacturing, and packaging services to

the pharmaceutical industry since 1975. The

company’s capabilities include formulation

development; analytical services; solid- and

liquid-dose manufacturing; packaging in

bottles, blisters, and multilaminate pouches;

project management; and regulatory ser-

vices. Mikart, Atlanta, GA • www.mikart.com •

tel. 888.4 MIKART

Contract

servicesPatheon is a leading

provider of contract

development and

manufacturing ser-

vices 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 ensures

that customers’ products can be launched

anywhere in the world. Patheon, Research Tri-

angle Park, NC • www.patheon.com •

tel. 905.821.4001

Containment

capabilitiesLyophilization

Technology has

on-site contain-

ment capabili-

ties for highly potent compounds, oncology

therapeutics, and biologicals. The company’s

qualified facility features negative-pressure

isolators for primary containment within an

ISO 7 room and ISO 5 processing areas. The

company seeks to safeguard products’ integ-

rity and provide high quality.

Lyophilization Technology, Ivyland, PA •

www.lyotechnology.com • tel. 215.396.8373

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

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 sterile with lot-specific

documentation. Veltek, Malvern, PA •

www.sterile.com • tel. 610.644.8335

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

INDUSTRY PIPELINE


PACKAGING EQUIPMENT & SUPPLIES LABORATORY EQUIPMENT & SUPPLIES

CHEMICALS, RAW MATERIALS, INTERMEDIATES, & EXCIPIENTS

CHEMICALS, RAW MATERIALS, INTERMEDIATES, & EXCIPIENTS

On-line TOC

analysisTo help phar-

maceutical

companies

improve quality

and reduce costs, GE Analytical Instruments

offers a science- and risk-based program for

achieving real-time release of pharmaceutical

water. The program streamlines a complex

process and helps companies move total

organic carbon testing from the laboratory to

the production floor in approximately

six months.

GE Analytical Instruments, Boulder, CO •

www.geinstruments.com • tel. 800.255.6964

Transfer

packaging for

prefillable syringesBD TSCF packaging en-

sures the secure transfer

of sterile prefillable syringe components into

the pharmaceutical filling environment. The

packaging is compatible with IDC Biosafe

doors for aseptic filling machines within isola-

tor or barrier systems. This packaging is part

of the BD SCF global offer, which features

expertise in sterile processing of preserva-

tive-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

Filtration systemEMD Millipore’s

Samplicity filtration

system is designed

to provide a high-

throughput alterna-

tive to syringe filters

when preparing

samples for ultra-

high- and high-purity liquid chromatography

analysis. This vacuum-driven system enables

the simultaneous filtration of eight samples

in seconds, including samples with high vis-

cosity or high particulate levels. The system

is available with EMD Millipore’s Millex filter

materials. EMD Millipore, Billerica, MA • www.

millipore.com • tel. 978.715.4321

Pharmaceutical

polymersEUDRAGIT acrylic

polymers are

designed for enteric,

sustained-release,

and immediate-

release drug-delivery

formulations of solid

oral dosage forms.

Evonik’s portfolio of development services

ranges from formulation support to indi-

vidually designed drug-delivery technolo-

gies. Evonik Degussa Corp., Pharma Polymers,

Piscataway, NJ •

www.eudragit.com • tel. 732.981.5383

Alpha-lactose-

monohydrate

FlowLac 90 is a spray-

dried alpha-lactose-

monohydrate that

helps enable virtually

dust-free production.

The excipient has

outstanding compac-

tion properties and

a fast disintegration

profile. Its spherical particles and porous

surface provide excellent flowability and high

content uniformity. FlowLac 90 is appropriate

for low- and high-dosage direct-compression

formulations. MEGGLE Group Wasserburg, Was-

serburg, Germany • www.meggle-pharma.

com • tel. +49 0 80 71 73 4 76

Polyethylene glycolCarbowax Sentry low-aldehyde polyethylene

glycol (PEG) excipient grades 300, 400, and 600

are suited for gelatin capsules or liquid formula-

tions in which aldehyde impurities decrease sta-

bility. Clear, viscous grades resist rancidity and

microbial growth and carry a low specification

limit for ethylene glycol, which helps high-dose

products comply with US Pharmacopeia <467>

standards. Dow also offers Carbowax Sentry PEG

excipient grades 3350, 4000, and 8000 in hard,

waxy form. The Dow Chemical Company, Midland,

MI • www.dow.com • tel. 800.447.4369

WebsiteRoquette has

launched a

website for its

pharmaceuti-

cal division.

The site

grants access to the company’s excipient and

active product lines and offers information

about services. A formulation tool provides

assistance to formulators from the product-

development cycle through to launch.

The special services and support sections

describe Roquette’s application expertise.

Roquette, Keokuk, IA •

www.roquette-pharma.com • tel. 319.524.5757

ExcipientsBiddle Sawyer’s

low-viscosity Phar-

macoat grades are

film formers and

granulation bind-

ing aids. The com-

pany’s Metolose

and Metolose SR excipients are designed for

thickening liquids and formulating sustained-

release matrices. Biddle Sawyer also offers hy-

droxy propyl methyl cellulose phthalate and

its Aqoat product for enteric coatings. Biddle

Sawyer, New York, NY •

www.biddlesawyer.com • tel. 212.736.1580

Chemicals and

intermediates

catalogSpectrum’s

2012–2013 Bulk Fine

Chemicals and In-

termediates Catalog

contains more than

3300 products for scale-up and production,

including a comprehensive selection of com-

pendial grade chemicals available from a sin-

gle source. Custom synthesis and manufac-

turing capabilities for active ingredients and

controlled substances are also highlighted

in Spectrum’s reference handbook. Spectrum

Chemical Manufacturing, Gardena, CA • www.

spectrumchemical.com • tel. 800.901.5516

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broader scaling capabilities for chemistries not suitable to batch scale-up.

This scalability feature of CFRs is appealing for circumventing nonscaling

problematic chemistries in a timely fashion. It is not uncommon for there to

be one or more steps in an initial discovery synthesis that is not amenable

to batch processing. When this occurs, significant time, effort, and money

have to be invested in process research and/or development to resolve the

chemistry or retool the synthesis. CFR technology, on the other hand, offers

the potential to scale the existing problematic chemistry to overcome the

bottleneck. For example, Johnson and Johnson (New Brunswick, NJ) dem-

onstrated the utility of CFR technology for rapidly scaling gram to kilogram

quantities of early-stage clinical trial API where batch processing was a

concern (4). Several classes of reactions that presented safety or hazardous

concerns for batch manufacturing were shown to scale efficiently, safely,

and with shorter process research times. The reaction classes reported by

the Johnson and Johnson group included exothermic reactions, reactions

at elevated temperatures, reactions with unstable intermediates, and reac-

tions involving hazardous reagents (4). Implementing CFR technology in an

otherwise batch process to resolve early scalable issues provides an attrac-

tive strategy for expediting early-stage process development. Under this

mixed “batch-CFR” paradigm, the problematic step(s) can be optimized to a

CFR early on in the process allowing the chemistry to be readily scaled from

grams to kilograms. Manufacturers of continuous CFRs such as Corning

(Corning, NY) make smaller scale reactors that can be used for optimiz-

ing the continuous-flow chemistry on a small scale and employing the

smaller reactor to make the desired product on a scale of grams to about a

kilogram. When larger-scale production is required, the chemistry is readily

transferred to an identical larger reactor simplifying the technology transfer

process from laboratory scale to plant scale. Consequently, the “Batch-CFR”

approach has the potential to be more expedient and cost effective as it

takes advantage of CFR technology’s ability to scale existing chemistry that

is not suitable or safe for larger-scale batch processing. CFR technology may

also allow the CMO to scale reactions beyond the capacity of their fixed

reactors as an alternative to doing a technology transfer to another facility

with larger fixed reactors.The contract manufacturer will still likely use fixed equipment to process

the continuous-flow reaction maelstrom. Although significant gains have

been made in in-process monitoring and continuous crystallization, at the

present time, it is more expedient for early-stage continuous flow reactions

to be worked-up using traditional methodology such as filtration, extraction,

solvent removal, and crystallization in fixed equipment. If the project moves

to commercialization, particularly in the hands of a large pharmaceutical

company, the process is more likely to become a fully optimized continu-

ous process from start to finish. With a “Batch-CFR” process, this transition

should be facilitated since the more challenging chemistry has already been

adapted to CFR technology.The decision by a CMO to implement CFR technology to resolve a

process scale-up issue is a critical risk decision requiring buy-in from the

sponsor client. The technology holds significant promise for efficient and

cost-effective development of early-stage cGMP processes. The “Batch-CFR”

approach provides a much greater probability for scaling the initial discov-

ery synthesis directly, thereby requiring significantly less process research

and development work. CFR technology, however, requires different strate-

gic thinking and technical expertise compared with classical batch manu-

facturing. Because most drug-development professionals are classically

trained, there is likely to be some natural resistance to implementing CFR

technology in early-drug development. This mindset has been referred to

as “batch mentality (5). However, with FDA and the pharmaceutical industry

encouraging the shift to CFR technology, contract manufacturers are likely

to follow suit. Sources

1. A. Pellek and P. Van Arnum, Pharm. Technol. 9 (32),

52–58 (2008). 2. B. Trout and W. Bisson, “Continuous Manufacturing

of Small Molecule Pharmaceuticals: The Ultra-Lean Way

of Manufacturing,” 2009 MIT Global Operations

Conference, Dec. 2, 2009, http://ilp-www.mit.edu/

images/conferencemedia/trout.pdf, accessed

Aug. 16, 2010. 3. “Chemisty in Flow Systems” in Beilstein J. Org. Chem.

Thematic Series 4, 5 (15), A. Kirschning, Guest Ed.,

Apr. 29, 2009, www.beilstein-journals.org/bjoc/

browse/singleSeries.htm?sn=4, accessed Aug. 16, 2010.

4. X. Zhang, S. Stefanick, and Frank J. Villani, Org. Proc. Res.

Dev. 8 (3), 455–460 (2004). 5. P. Thomas, Pharm. Manuf., www. pharmamanufacturing.

com/articles/2010/088.html, accessed Aug. 16, 2010.

James Hamby, PhD, is vice-president of business development at Ash

Stevens, 18655 Krause Street, Riverview, MI 48193, tel. 734. 282.3370 Ext.

1144, [email protected] with permission from the September 2010 Supplement to Pharmaceutical Technology. Copyright ©2010, an Advanstar publication. All rights reserved.

www.pharmtech.com

#1-28051222 Reprinted by The YGS Group, 717.505.9701. For more information visit www.theYGSgroup.com/reprints.

CliniCal-Trial MaTerials

September 2010

Volume 34

Number 9

pharmtech.com

The Industry’s Authoritative Source

The current trend in the pharmaceutical industry for the manufacture of

small-molecule therapeutic agents is moving toward continuous flow pro-

cesses. In 2007, the Novartis–MIT Center for Continuous Manufacturing was

established with $65 million in funding from the drug company. The center

is proposing a “Blue Sky” concept where there is a continuous process from

the start of a chemical synthesis through final pharmaceutical dosage form

(1, 2). The Blue Sky program is an ambitious goal but is gaining ground rap-

idly among thought leaders in the pharmaceutical industry and US Food

and Drug Administration. Consequently, the momentum for this concept is

likely to have a trickle-down effect for contract manufacturers (CMOs) that

design and develop early-stage manufacturing processes for clients devel-

oping innovator small-molecule drugs.

Continuous-flow technology

Continuous-flow technology involves the continuous introduction of a

stream of chemical reactants into a flow or microreactor to yield a desired

reaction product on a continuous basis. The versatility and usefulness of

continuous-flow reactor (CFR) technology is expanding rapidly with an

ever broadening scope of applicable chemistries and the development

of new flow technologies (3). Champions of continuous-flow technology

cite a wide range of potential advantages compared with traditional batch

manufacturing of pharmaceuticals. In general, the greater optimization

and control achievable with CFR technology can translate to significant sav-

ings in time and costs and can have a favorable safety and environmental

impact. Furthermore, the small-reaction volume, broad operating pressure

and temperature ranges, and mixing efficiencies of flow reactors extends

the repertoire of chemistries beyond that of the safety and technical limita-

tions of batch reactors. The capital investment for CFR technology is also

substantially less, as is the footprint required in the plant than a similar

capacity batch-reactor system. However, even though the potential advan-

tages of CFR technology can be significant, the technology is currently not

applicable or practical in all situations.

Early-stage development

Adapting CFR technology to early-stage development projects has sig-

nificant merit, but also significant challenges. CMOs work with numerous

sponsor clients, diverse chemistries, and projects in all stages of develop-

ment. Many of the projects CMOs encounter are very early stage with the

development candidate being licensed out of an academic laboratory

or coming directly from the sponsor company’s discovery laboratories.

These early-stage projects more often than not require various degrees

of process research and/or process development to make the discovery

synthesis amenable to current good manufacturing practice (cGMP) scale-

up. Also, to receive additional funding or secure a development partner,

the sponsor company has a strong sense of urgency to enter the clinic and

achieve proof-of-concept as soon as possible. This puts pressure on the

CMO to rapidly develop a scalable process to meet the near-term active

pharmaceutical ingredient (API) goals of the sponsor company and at the

same time enable the process to further scale-up to meet later stage API

demands.

Small-molecule drug development processes are typically in the

range of six to eight synthetic steps. Given the time constraints and level

of technical challenge, the design of an initial six to eight step totally

continuous-flow process for an early-stage drug development project is

generally not practical and is typically reserved for established commercial

processes. CFR technology, however, does offer the distinct advantage of

Contract Manufacturing and Continuous Flow

Reactor Technology for Early-Stage Drug Development

James Hamby

Have you been featured in Pharmaceutical Technology? For instant credibility, put a reprint into your prospect’s hands.

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Susan J. Schniepp

the United States Pharmacopeia (USP) is the oldest continuously revised compendium in the world. Estab-

lished in 1820, this independent organi-zation has been setting US standards for medicines and pharmaceuticals for more than 185 years. Although FDA recognizes USP standards, the US Pharmacopeial Convention organization was created to be independent from the government, mak-ing it the only nongovernmental compen-dium in the world. The original USP was a collection of recipes to aid pharmacists in formulating medicines for patients. The mission was to produce a book that would allow pharmacists to be able to offer reliable products with consistent names to patients in the United States.

At the time the first USP debuted, the pharmaceutical industry did not exist and pharmacists used the information in USP to deliver uniform products to the approx-imately 7 million residents residing in the 22 states that comprised the US at that time. The original publication contained monograph instructions for 621 items and was updated at approximately 10-year intervals.

the evolution of USpToday, USP is updated annually and con-tains more than 4000 monographs in ad-dition to a myriad of general-test and infor-

mation chapters. USP has more than 550 full-time employees and uses more than 1000 volunteers to set current compendial standards. In a few short years (9 to be exact) USP will celebrate its 200th birthday. USP has much to be proud of.

However, during the past decade, the organization seems to have decided that the patients and pharmaceutical industry of the US are not a big enough arena for its standard-setting activities. USP has changed its mission statement to indicate that it wishes to “improve the health of people around the world through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods” (1). Its current vi-sion is “…to be a leader in promoting the public health by creating a unique knowledge base—consisting of quality standards and information on proper use—for medicines and related products and practices. USP will ensure that people throughout the world have access to this knowledge base” (1).

USP purchased the Food Chemicals Codex and opened offices in Switzerland, India, China, and Brazil. In its October 2008 mid-cycle convention report, USP in-dicates that the report is intended to inform “…USP’s volunteers—members of the USP Convention; Board of Trustees; Council of

Experts, Expert Committees, and Advi-sory Panels; and Stakeholder Forums and Project Teams—of the strides made to date in the 2005–2010 cycle. It offers a snapshot of significant achievements, milestones, and progress toward the goals articulated at the 2005 USP Convention. And perhaps most importantly, it provides a glimpse of where USP is going in the future…” (1).

In addition, at the USP 2010 Conven-tion, the organization passed Resolution 4, which deals with supporting and advanc-ing global public-health initiatives.” The resolution states, “Working in consultation and collaboration with national, regional and global stakeholders, USP resolves to assess the feasibility and advisability of advancing global public health initiatives. Where advisable and feasible, USP should seek to expand its resources for these ini-tiatives, building on identified needs and existing opportunities, in order to support its international activities while preserving and fulfilling its role under US law” (1). On USP’s website, there is an update regard-ing this resolution which indicates that USP is expanding its role in India and China as well as exploring relationships with the Association of Southeast Na-tions and Middle East and North Afri-can nations.

taking on too much responsibilityAlthough these initiatives are altruistic, this author wonders whether USP is reaching a little too far from home in its pursuit of global pharmacopeial dominance. Perhaps some of these international resources could be redirected to continue and speed up the harmonization of monographs and testing requirements with the European and Japa-nese Pharmacopeias, a goal that has been

After a series of structural changes, new global approaches, and compendial

mistakes, the author wonders whether USP is undergoing an identity crisis.

where in the world is the US pharmacopeia?

Susan J. Schniepp is

vice-president of

quality at OSO

Biopharmaceuticals,

susan.schniepp@

osobio.com.

Could some of

USP’s international

efforts be redirected

at monograph

harmonization?

Viewpoint


on USP’s plate for some time. Or better yet, the true altruistic action for this standard-setting body would be to provide the other pharmacopeias assistance, staff, and fund-ing to enhance their national compendia, or to work in a more collaborative man-ner with the World Health Organization to develop additional monographs for the International Pharmacopoeia.

Disrespecting industry inputOne philosophy that has not seemed to change is USP’s reluctance to accept that the USP–National Formulary (NF) is a compilation of the hard work and intel-lectual input of regulatory filings of US proprietary and generic pharmaceutical companies. Representatives from these companies belong to trade organiza-tions. These trade organizations make up the members of USP’s Prescription/Nonprescription Stakeholders Forum (PNP–SF). In the May 19, 2011 PNP–SF meeting, USP announced to the attendees that they were re-evaluating the need and purpose of these meetings. USP proposed reducing its interaction with the industry trade organizations that make up the PNP to a once-a-year webinar instead of the cur-

rent two face-to-face meetings. In addition, USP opened the planning committee for these meetings by posting a call for inter-ested parties on its website and asking these volunteers to nominate a chair person.

If all that wasn’t enough, USP sum-marily dismissed the current PNP–SF industry member’s suggestions to form new project teams in an effort to help USP achieve some of its 2010 resolutions and to avoid such issues as the recall of USP 33–NF 28, the monograph redesign project, the confusing implementation of residual-solvents testing, the number of er-rors in the Pharmacopeial Forum and the potential confusing implementation of the revised USP <231> Heavy Metals General Chapter. These situations have left indus-try with a sense that USP is losing touch of its responsibility to the US pharmaceu-tical and medical communities. The only project team that USP intends to keep is the Compendial Process Improvement Team, whose charter is to address how USP can streamline and speed up its process for getting monographs and making informa-tion available. What USP fails to recognize is that the majority of the people who are representing the industry at the PNP–SF

meetings have scientific backgrounds and can offer constructive and valuable insight regarding technical issues facing the USP.

ConclusionIn summary, there are two issues that are of concern to this author: the apparent glo-balization of USP without sufficient har-monization and the dichotomous position of wanting the US industry to provide its technical information for monographs but discouraging input when it comes to assisting in improving the scientific in-formation contained in USP. It seems that USP is trying to find a new identity that focuses beyond US borders, an approach that conflicts with what should be USP’s main focus: providing current and accurate monographs for use by the US pharmaceu-tical industry. Let’s hope the pharmacopeia can figure out its true identity before it ends up with no identity at all.

Reference 1. USP website, www.usp.org. PT

The author served on the PNP–SF and on a USP

expert committee from 2000 to 2005. She chaired

a USP expert committee from 2005 to 2010.

To fulfill its role as developer of official standards for medicines quality in the United States, the US Pharmacopeial Convention (USP) has looked past US borders, as have manufacturers and FDA. Globalization of the pharmaceuti-cal industry has altered the ways industry, regulators, and pharmacopeias interact, and USP is engaging the industry as it exists today. Concerns have been raised about USP’s global operations and pos-sible effects on efforts to harmonize and modernize monographs in the US Phar-macopeia–National Formulary (USP–NF).Additionally, there are concerns about USP’s engagement with the USP Prescrip-tion/Nonprescription Stakeholder Forum (PNP–SF). I will touch on these in order.

Globalization and harmonizationMost of USP’s energies and resources go to its US compendia, particularly to USP–NF.

Investments during the past several years have been to advance our laboratories, moving from less-than-adequate space and equipment to state-of-the-art facilities and equipment in our Maryland headquarters, India (where a large new building has just opened), China (expansion under consider-ation), and Brazil. All of these laboratories support the work of the Council of Experts, USP’s standards-setting body, specifically to make available public reference materi-als that are critically needed for procedures in USP–NF monographs. USP has devoted considerable energies to better understand-ing basic measurement science (metrology) imperatives so that all parties—particularly FDA—have access to modern monographs and reference materials.

Given the global nature of pharmaceuti-cal commerce, pharmacopeial harmoniza-tion is indeed important. Yet the outputs of the Pharmacopeial Discussion Group

(PDG) have not met expectations. (PDG represents the pharmacopeias of Europe, Japan, and the US, and aims to achieve compendial harmonization.) PDG has focused on a narrow slice of standards: excipient monographs and the Interna-tional Conference on Harmonization (ICH) Q6A-based General Chapters Q6A on test procedures and acceptance criteria for new drug substances and new drug products. After more than 20 years, only 63 excipient monographs of more than 300 in NF, and about 20 General Chapters have been harmonized. NF is missing 137 monographs and many of the remaining ones require updating, including those that have moved through PDG harmonization. Of approximately 1200 excipients in global

USP’s Response: USP in a Global EraRoger L. Williams

Roger L. Williams, MD, is the chief

executive officer of the

US Pharmacopeia.

Viewpoint


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commerce, most have no public standards. PDG excludes major countries and regions, notably China and India, Latin America/Caribbean, and Middle East/North Africa.

Other initiatives are needed, and USP is taking a first step, we hope with other pharmacopeias. We are working with the World Health Organization (WHO) and national and regional pharmacopeias to conduct summits around the world. China has embraced the concept, and will host its second Global Pharmacopeial Summit in Beijing in mid-November. USP hopes a late-2012 culminating meeting, con-vened by WHO, will pave the way for new thinking on pharmacopeial harmoniza-tion. Additionally, USP’s new Medicines Compendium may model a path to more flexible pharmacopeial monographs using performance-based approaches.

MonographsUSP has worked with industry for more than a century to include monographs in USP–NF that mirror FDA approvals. USP greatly appreciates these donations of time, information, and materials from our industry colleagues. We believe every drug needs a public monograph and reference material the moment it enters the mar-ket, allowing FDA and other regulatory authorities to check for adulterated, coun-terfeit, or substandard medicines and their ingredients. USP wishes to work with all manufacturers to gain needed information

and materials to support public standards. But we cannot overlook the numbers:

monographs in USP–NF number more than 4000, yet it is missing nearly 1900. Many need updating. Deficiencies in USP’s heparin monographs provided an exam-ple of why public health is best served by modern monographs—and USP worked carefully with FDA and industry to update these critically needed standards. FDA has identified monographs in USP–NF need-ing improvement; we welcome this input. We have recently received good support from the Consumer Healthcare Products Association, and welcome similar support from other associations.

pnp Stakeholder ForumUSP values the talented representatives from pharmaceutical manufacturers who have worked to advance topics through the PNP–SF since 2000. This has proved an important venue where issues have been discussed and many resolved. In re-cent years, opportunities for stakeholder input into USP standards have increased significantly, including new expert panel rules allowing experts to fully participate in deliberations without having to abstain due to conflict. A new “design phase” ap-proach—which emanated directly from the PNP–SF—uses workshops, webinars, etc., for stakeholders to provide early input into USP standards.

USP spoke about ways to expand the fo-

rum’s reach at the May 2011 meeting. We focused on two principles: USP will con-duct its standards-setting activities in an open, transparent manner that allows par-ticipation by all constituencies; and because USP text and publications may have legal implications in the US and elsewhere, their language must stand on its own and not be interpreted to a few, thereby disadvan-taging parties without that interpretation. All stakeholders should have same oppor-tunity to participate in USP’s stakeholder activities, so that a select group does not have disproportionate voice. Thus, we are exploring conducting the PNP–SF in a for-mat that can be open to more stakeholders: web meetings. But at the PNP stakeholders’ request, we may continue to conduct face-to-face meetings while enabling web access. We hope to provide enhanced ability for others to participate, including shaping agendas and participating in project teams.

As noted, there are crucial issues for consideration. These include the role of the pharmacopeia in a modern, democratic society as a means of advancing modern public standards; the challenge of keep-ing USP–NF monographs up-to-date and USP’s reliance on industry support for this; and the need for pharmacopeias to come together so that patients and practitioners everywhere have access to good quality medicines. If industry, FDA, and USP ad-dress these issues adequately and together, they can be resolved. PT

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PharmTech Sept 2011

Documents

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