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PharmTech.com

December 2011

Volume 35

Number 12

Results from Annual Employment Survey

Contract API Manufacturing

Jim Miller’s Outsourcing Outlook: Biopharmaceutical R&D

PEER-REVIEWED

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Views from

Pharma LeadersA year in review and a look forward

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James P. Agalloco

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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

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Rory Budihandojo

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Boehringer-Ingelheim Shanghai

Pharmaceuticals Co. (China)

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Jim Miller

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PharmSource Information

Services Bio/Pharmaceutical

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Finnbrit Consulting

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Pharmaceutical Consultant,

Schniepp & Associates, LLC

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Director of Global Regulatory

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President,

Sheinin and Associates

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CEO, Emerson Resources, Inc.

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 PharmTech.comDecember 2011 Volume 35 Number 12


Cover story

29 Views from Pharma LeadersAn industry roundtable

moderated by Patricia Van Arnum

Drug shortages, supply-chain security, generic-

drug incursion, and flexible manufacturing mod-

els are some of the issues shaping the industry.

Illustration by Dan Ward. Images: Don Farrall/Getty Images

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

expert analyses for scientists, engineers, and managers engaged in process devel-

opment, manufacturing, formulation and drug delivery, API synthesis, analytical

technology and testing, packaging, IT, outsourcing, and regulatory compliance in the

pharmaceutical and biotechnology industries.

Features

annual surVeY

32 The Employment Outlook Brightens

Rich Whitworth and Amy Ritter

Readers react to the ecomomic

turmoil of the past year and look

forward to 2012.

pharma inGredients

36 Contract API Manufactur-ing: The Year in Review

Patricia Van Arnum

Expansion activity was limited as fine-

chemical producers and CMOs grap-

pled with changing fundamentals.p

pQri case studY

46 Packing Line GMP Optimization

Ted Frank, Stephen Brooks, Kristin Murray,

Steve Reich, Ed Sanchez, Brian Hasselbalch,

Kwame Obeng, and Richard Creekmore

A risk-management case

study from the Product Quality

Research Institute.

Peer-reviewed research

sustained release

41 The Development of a Floating Drug-Delivery System for Metronidazole

Shamsuddin Sultan Khan

and Mesbah Uddin Talukder

The authors developed a met-

ronidazole-based floating drug-

delivery system to investigate the

effect of rate-controlling polymers

on release pattern and duration of

buoyancy in matrix tablets.

Departments/Products

14 In the Field

21 In the Spotlight

56 Pharma Capsules

57 Industry Pipeline

61 Showcase/Markeplace

66 Ad Index

Issue extras➲ The final case studies in the

Product Quality Reseach Institute

risk-management series appear

on PharmTech.com/PQRIstudies. They

focus on internal GMP audits and

pack-out remedies to minimize

contamination and exposure.

Online exclusive➲ USP’s Todd Cecil reviews

Cost-Contained Regulatory

Compliance (Wiley, 2011)

Free eNewsletters Visit PharmTech.com/enews for:

• ePT : Weekly eNewsletter keeps

you current with industry news

and business notes.

• Sourcing and Management:

A monthly eNewsletter to

help you maintain a healthy

supply chain.

• Equipment & Processing Report:

Monthly reports on cutting-edge

techniques and technologies.

Most popular articles

• Pfizer Outlines Its Supply Strategy

PharmTech.com/pfizerstrategy

• Is Three Still the Magic

Number for Process Validation?

PharmTech.com/validationthree

• FDA Approves 35 Novel

Medicines in Fiscal Year 2011

PharmTech.com/2011NMEs

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Pharmaceutical Technology December 2011 7

Columns

Guest editorial

8 Suporting Innovation Requires Consistency and Long-term Vision

John Castellani, PhRMA

Political leaders need to consider

the impact of the biopharmaceutical

industry on the economy.

pharmtech talk

10 Reinventing Invention

Patricia Van Arnum

As 2011 comes to a close, a new

paradigm of product development

is ever more important.

aGent-in-place

12 Buzz Off the Product

Control, a senior compliance officer

Cleanliness is crucial, even if zapping

and trapping is necessary to reduce

product contamination.

Pharmaceutical Technology is selec-

tively abstracted or indexed in:

- Biological Sciences Database

(Cambridge Scientific Abstracts)

- Biotechnology and Bioengineer-

ing Database (Cambridge Scientific

Abstracts)

- Business and Management Practices

(RDSI)

-Chemical Abstracts (CAS)

-Current Packaging Abstracts

-DECHEMA

- Derwent Biotechnology Abstracts

(Derwent Information, Ltd.)

-Excerpta Medica (Elsevier)

-International Pharmaceutical Ab-

stracts (ASHP)

-Science Citation Index (Thomson)

Pharmaceutical Technology is proud to

be a member of DCAT, IPEC, and PDA.

washinGton report

22 FDA Revamps to Meet New Challenges

Jill Wechsler

Added responsbilities and pressures

prompt FDA’s structural overhaul.

bioforum

27 Creating Innovation Nodes to Meet Unmet Medical Needs

Kenneth I. Kaitin

Pharma companies must balance demand for

new drugs while facing reduced R&D spending.

statistical solutions

28 Out-of-Specification Sample-Size Confusion

Lynn D. Torbeck

Precedents set in the recent Barr case lead

to further conflict over sample-size criteria.

inside ipec federation

49 IPEC Tackles Monographs, Impurities, Particles, MorePatricia Rafidison

As the excipient supply chain be-

comes more complex, industry must

comply with new standards.

insider solutions

51 Auditing by the NumbersSusan J. Schniepp

Contract organizations must have

highly organized teams and plans to

accomodate today’s audits.

outsourcinG outlook

52 Troublesome Signs for Bio/Pharmaceutical R&DJim Miller

A dearth of late-stage candidates

could hurt the pharmaceutical

services market in the future.

Viewpoint

64 Developing and Sustaining a Quality CultureIan Uydess and Chet Meyers

Employee training is crucial for mov-

ing forward with a successful risk- and

quality-based manufaturing strategy.

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8 Pharmaceutical Technology DECEMBER 2011 PharmTech .com

GUEST EDITORIAL

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American policymakers of all stripes are talking a lot about the importance of innovation to jumpstarting job

growth and regaining economic momen-tum. In September, for example, President Obama signed a new patent reform bill into law, saying: “If we’re going to create jobs now and into the future, we’re going to have to out-build, out-educate and out-innovate every country on earth.”

Many of Obama’s political opponents also talk about the importance of inno-vation and entrepreneurship as a key to short-term economic recovery and long-term economic health. As a result, a sort of broad bipartisan agreement about the importance of innovation to our future has emerged. It is time to embrace this common ground and find actionable, meaningful, and consistent ways to sup-port innovation.

The Administration and policymakers need to focus on stimulating and growing existing innovative American industries. Look no further than America’s biophar-maceutical research sector to find a dy-namic, technology-driven industry. A re-cent report on employment in the sector by the Battelle Technology Partnership Prac-tice postulated that an “ideal” industry for stimulating US economic growth would: have the ability to grow and increase out-

put in tough economic times; provide high-wage, good quality jobs; be innovative and deploy the latest technology to generate competitive advantages for US compa-nies; generate significant exports; create a strong supply-chain that drives further economic growth; encourage capital flow with sustained growth; and be profitable and provide funds for reinvestment into the R&D cycle.

Battelle concluded that the biophar-maceutical research sector has all of these characteristics, “and more.” In fact, the sector already makes an enormous con-tribution to the national, state, and local economies. According to Battelle, biophar-maceutical research companies supported more than four million jobs nationwide as of 2009, including nearly 675,000 direct in-dustry jobs. The report showed that each direct sector job supported nearly five ad-ditional indirect and induced jobs nation-wide. The jobs created were broad-based and touched a wide variety of businesses and skill levels.

Based on this sector’s performance, it is both perplexing and frustrating to hear President Obama and others from across the political spectrum talk glowingly about innovation and innovative industries. The problem is that there has been little follow-up or a horizontal and long-term strat-egy designed to support their stated goal. When talking about deficit reduction and efforts to control spiraling healthcare costs, President Obama and some in Congress have pushed for policies that could actu-ally discourage biopharmaceutical R&D and innovation.

Consistency and perspective are lack-ing. Too many policymakers often see the

cost of medicines, in particular, as part of the equation for solving immediate fiscal challenges. But they fail to recognize the long-term value of innovative medicines as a means of helping to control health-care costs over the long term. As a result, they often pursue policies that undermine needed incentives for doing innovative medical R&D. Policies, in other words, that may be detrimental to both patients and for our economy in the short- and long-term.

For much of the past 50 years, America has been at the heart of a biopharmaceu-tical revolution. Our companies continue to lead the world both in investing in new medical R&D as well as in developing new drugs. The resulting life-saving medicines and innovative healthcare technologies have contributed enormously to the fight against disease as well as efforts to promote health and extend life.

The value of medical innovation for patients and our economy is increasingly well documented. How to fully realize the promise of innovative medicines—to improve healthcare outcomes and quality and control healthcare costs—remains a fundamental challenge.

Today, America’s biopharmaceutical re-search companies grapple with more com-plex science, an evolving business model, and an often unpredictable regulatory environment. To continue thriving, it is essential for policymakers to take a larger, more integrated view of the role that inno-vative medicines play in securing quality and affordable healthcare for patients. A consistent, horizontal fabric of policies that foster medical innovation will go far to-wards securing a healthier as well as more economically competitive America. PT

Supporting Innovation Requires Consistency and Long-term Vision

Political leaders need to consider the impact of the

biopharmaceutical industry on the economy.

John Castellani

John Castellani

is president and CEO

of the Pharmaceutical

Research and

Manufacturers of

America (PhRMA).

PharmTech.com/forum

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PHARMTECH TALK

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Reinventing InventionPatricia Van Arnum

The end of a year is a time for reflec-tion and in reviewing 2011, what were the issues of greatest impor-

tance to pharmaceutical manufacturers?

We posed that question to executives in the pharmaceutical industry (see “Views from Pharma Leaders” on page 29) and several important themes emerged: a

move away from the industry’s traditional blockbuster drug-development model to smaller volume, specialty products; increased generic-drug incursion; and a resulting need for more flexible internal and external manufacturing approaches in an effort to keep product supply in line with demand. At the same time, the pharmaceutical industry continues to see potential in emerging markets, greater complexity in the global pharmaceutical supply chain, and the attendant need for supply-chain integrity and security measures that maintain product quality amidst that globalization.

As the pharmaceutical industry faces these challenges, it also faces an even more daunting task: improving its product-development model. Earlier this year, John C. Lechleiter, chairman, president and CEO of Eli Lilly, spoke to this chal-lenge. “Ironically, the crisis in our innova-tion model comes at a time when we have vastly more scientific knowledge and data than ever before,” he said in a speech on Mar. 9, 2011, before the US/Japan Busi-ness Council. “But unless we change the way we do research, we won’t translate this knowledge into advances for patients. In the face of diminishing results, we can’t simply perform the same old ritu-als and hope for a different outcome. We must truly ‘reinvent invention.’”

In the end, the ability of the pharmaceu-tical industry to collectively and as individ-ual companies to “reinvent invention” will be the underlying measure of its success in 2012 and beyond. PT.

As 2011 comes to a close, a new paradigm of

product development is evermore important.

Patricia Van Arnum

is a senior editor of

Pharmaceutical Technology.

»Read Patricia’s blogs at

blog.PharmTech.com.

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Cautionary Tales from the Files of “Control,”

a Senior Compliance Officer

Misdirected“We sent two batches of the same product to our contracted third party logistics (3PL) provider,” sighed our GMP Agent-In-Place. “Both had Eng-lish labeling, but one was labeled es-pecially for Burma and the other for the US Virgin Islands. The 3PL sent the Burma material to the Virgin Islands. The customer there, a wholesaler, put the product into inventory and started distribution—even though the product had no National Drug Code number and had the wrong lot number. Two days later, the 3PL realized the mistake when preparing the Burma product for sale—there was no product.

“It turns out that the person who picked the product for the Virgin Is-lands was also the ‘checker’ for the shipment, and they knew they did it right,” said our Agent resignedly. “In the end, we retrieved the incorrect product from the Virgin Islands and sent the correct batch. We also filed a report with FDA regarding the issue.”

Buggy audit“I like to inspect bug electrocutors during audits,” our GMP Agent-In-Place grins. “I always ask about their choice of installation height. I’ve never received a good answer. If the light is especially high, I ask whether there are any low-f lying or crawling bugs that the device could miss. One au-ditee asked for my advice concerning low-f lying bugs. I told them that the trap should be high enough that the

auditor can’t see into the catch basin below the electrocutor and take notice that it hasn’t been cleaned recently.”

Memory lapse“It was in the late 1970s and the toxi-cology laboratory statistician wanted to automate some LD50 calculations,” wrote our GMP Agent-In-Place. “There was an existing programmable calcula-tor on site that he wanted to use. It was about the size of a desktop computer today. The statistician struggled to input the program. It was a week later, after failing repeatedly, that he called the calculator manufacturer and de-termined that the machine had only 1 KB of memory. The program needed more memory, and for that machine, it would cost thousands of dollars. Today, this problem is hard to imagine given that we can purchase 64 GB for a couple of hundred dollars!”

check your pipettes“We buy a product from another company,” our GMP Agent-In-Place started. “We received a report from them that the sterile, single-use labo-ratory pipette tips they used on an pipetter were found to be 1.2% too large. The pipettes were used in one of those funky biological assays, and the assay result was used for an in-process potency adjustment. This resulted in an over potency of 26% (assay is a nonlinear interpolative type). They recalled the product, and so did we.”

Alarming“Our FDA inspector was reviewing our preventive maintenance (PM) system,” noted our GMP Agent-In-Place. “For coolers, she wanted us to ensure that the alarms worked properly during the PM by leaving the cooler door open. In response, we argued that this would be a de-viation, and we’d need resolution as it could possibly be an adverse ex-posure of our products. We further noted (oops) that we had 400 alarms per year, so we knew that the alarm system worked. She thought that was too many, and asked for a sum-mary of the alarms from the Build-ing Management System (BMS). The summary noted 6000 alarms. What a mess! In response to the written finding, we agreed to define some alarms as critical and to check these during PM by changing the electri-cal signal to the BMS without leaving the door open.” PT

Cleanliness is crucial, even if zapping and trapping

is necessary to reduce product contamination.

Buzz Off the Product

Pharmaceutical Technology’s month-

ly “Agent-in-Place” column distills

true-life cautionary tales from the

files of Control, a senior compli-

ance officer. If you have a story to

share, please email it to Control at

[email protected]. We

won’t use any names, but if we do

use your experience in the column,

you’ll receive a Pharmaceutical

Technology t-shirt.

Key Learning Objectives:

■ ■ Learn of the latest advances in topical drug

formulations and how they may be applied in

your project work

■ ■ Learn of the latest regulatory/pharmacopoeial

requirements in product quality and product

performance for topical drug products

■ ■ Learn how to optimize your manufacturing

processes and consistently meet CMC

(chemistry, manufacturing, and controls)

requirements for topical drug products

Who Should Attend:

■ ■ Quality control and quality assurance

directors, group leaders, and technical sta�

■ ■ Senior management (CEO, COO, and

president)

■ ■ Director of development

■ ■ Formulation R&D managers, directors, and

group leaders

■ ■ Formulation scientists

■ ■ Project managers

■ ■ Production directors, managers,

and technical sta�

■ ■ Consultants

LIVE WEBCAST: Wednesday, December 7, 2011 at 2:00 PM EST

Register free at http://pharmtech.com/optimizing

Vinod Shah, PhD,Chair of the Special Interest Group, Regulatory Science, International Pharmaceutical Federation (FIP), and Distinguished Pharmaceutical Scientist and Consultant, US Pharmacopeia

Michael LowenborgR&D Manager, Formulation and Process Development, DPT Laboratories

Majella Lane, PhD, Senior Lecturer in Pharmaceutics, School of Pharmacy, University of London

EVENT OVERVIEW:

Semisolid formulations, such as topical drug formulations, play

an important role in drug delivery and development. Topical for-

mulations can be used to treat local and systematic indications,

o� er ease of delivery, facilitate patient compliance, and avoid the

problem of � rst-pass metabolism. Successfully developing a top-

ical formulation requires an understanding of the physiochemi-

cal properties, such as release characteristics, composition of

the drug-delivery system, and the nature of the drug-delivery

vehicle. Manufacturing a semisolid dosage form requires imple-

menting a CMC (chemistry, manufacturing, and controls) strat-

egy to ensure stability, photosafety, avoidance of product deg-

radation, and minimization of process impurities. This 60-minute

webcast will provide insight from leading industry experts on

recent advances in topical drug formulations, the latest regula-

tory/pharmacopoeial requirements in product quality and prod-

uct performance, and strategies to optimize manufacturing for

topical drug products.

Presented by

Sponsored by

For questions, contact Jamie Carpenter at [email protected]

OPTIMIZING

TOPICAL DRUG DEVELOPMENT & MANUFACTURING

OPTIMIZING

TOPICAL DRUG DEVELOPMENT & MANUFACTURING

Presenters

Moderator:

Patricia Van Arnum, Senior Editor, Pharmaceutical Technology

ON-DEMAND WEBCAST

14 Pharmaceutical Technology mONTH 2011 PharmTech .com14 Pharmaceutical Technology December 2011 PharmTech .com

In the Field

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14 .....Market Report from Asia

18 .....Global Healthcare

on the Ground: USAID

20 .....NME Approvals

20 .....Corporate Sustainability

Packaging is indeed headed to be a lead sector in the Asian pharmaceutical environment, but certain challenges must first be overcome.

pppRepo :Repo :R AAAAsiAsiA

Asia is a key driving force of the current global pharmaceutical industry. In recent years, healthcare demands among the region’s populations have increased and its low operating costs continue to attract pharmaceutical companies. The pharmaceutical packaging sector, in particular, has grown and matured in line with the emergence of China and India as pharmaceutical manufacturing leaders, according to Warwick Bedwell, president of pharmaceutical packaging systems (Asia–Pacific) at West Pharmaceutical Services. Packaging is indeed headed to be a leading sector in the Asian pharmaceutical environment, but certain challenges must first be overcome. contin. on page 16

Jane Wan

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IN THE FIELD

contin. from p. 14For starters, trends and developments within the region vary

from one market to another. Joerg Doescher, sales director Asia of SCHOTT Pharmaceutical Packaging explains: “Emerging markets such as China and India show strong growth and are moving towards a trend of higher quality requirements. Mature markets such as Japan experience slower growth rates that are driven mainly by developments in the field of biotech solutions.”

Interestingly, a fragmented Asian market opens doors for di-versified business opportunities and approaches whether they are through alliances, joint ventures, or acquisitions. But before a company can expect to be successful throughout the Asian re-gion, it has to establish a local presence. Unlike the European and US markets, centralized production is necessary to learn directly from customers and to address local market needs.

Companies “have to be clear about their product roadmap and product life-cycle management in order to be prepared for the market launch of packaging solutions that address future cus-tomer demands. Excellent customer relationships are essential to gain insights to local trends and developments to offer suitable products in time,” says Doescher.

This strategy explains why SCHOTT, based in Elmsford, New York, built a production site within an existing one in Suzhou to promote faster production of their glass products and to gain authority in the high-end Chinese market. The company’s joint venture with Kaisha Manufacturers in Mumbai, India, allowed it to enter the Indian market and provided an opportunity to foster close proximity with customers, opinion leaders, and sharehold-ers. Another example is West Pharmaceutical Services, which is building a second manufacturing facility in Qingpu, China, to prepare for meeting the needs of the Chinese and Indian markets when production begins in 2013.

Counterfeiting Based on a BMI 2011 report, it is alleged that India accounts for one-third of the counterfeit drugs in the region. The World Health Organization (WHO) indicates that 30% of pharmaceuticals are counterfeits in developing regions such as Asia and Latin America compared with 1% in developed countries. As a result, pharma-ceutical packaging players working within the Asian market are rushing to apply new and unique security features to their pack-aging systems to help prevent counterfeiting and to expand their level of support to pharmaceutical industry customers, says Bill Martineau, a senior healthcare consultant at the Freedonia Group.

For example, MeadWestvaco (Richmond, VA) incorporates radiofrequency identification (RFID) tags into pharmaceutical folding cartons so that products can be identified and verified at various points in the supply chain. West Pharmaceutical Services has introduced seals whereby drug manufacturers can incorpo-rate multiple layers of protection to their drug products to en-hance patient safety, combat drug counterfeiting, and safeguard their supply chain.

Implementing such systems, however, is not easy. “Few phar-

macies in China and other countries have the equipment to au-thenticate drug packages. Moreover, governments have been slow to strengthen anticounterfeiting requirements due to resistance from local drug makers who depend upon high-volume, low-cost generics for sales and profits,” says Martineau,

Krithika Tyagarajan, director for chemicals, materials, and food Asia–Pacific at Frost & Sullivan, highlights that major pack-aging companies have to consider various requirements to imple-ment an effective track-and-trace technology into their systems. For example, the design has to be protected. It should be foolproof and difficult to copy, and must be consistent throughout the ap-plication. Companies such as Dr. Reddy’s, based in Hyderabad, India, are working with packaging manufacturers and track-and-trace technology providers to supply consistent and cost effective applications. Bilcare, of Pune, India, has introduced a patented, nonclonable track-and-trace authentication-enabling technology that allows the product to be traced from origin to consumer.

Aging populationAsia’s aging population is also changing the way packaging is developed for products in the region. Several Asian governments have increased health insurance and reimbursement plans, thereby giving a much higher percentage of the population ac-cess to medicines. “The elderly prefer recognizable and straight-forward opening methods. So, the challenge is to design one that is highly visible [and] easily identifiable,” explains Tyagarajan. Products need to be both senior-friendly and child-resistant. In addition, he points out that “companies need to consider factors including product package compatibility, safety and security, sus-tainability, regulations and compliance, delivery format, waste management of disposables, and track-and-trace capability.” AstraZeneca has incorporated all of these factors into the design of their products. Rexam, also based in the United Kingdom, has come up with a design for cap closures that is senior friendly.

Another consideration with the aging population is the num-ber of intravenous infusions delivered each year throughout the region, currently about 6.5 billion. That number is expected to grow, placing the need for prefillable syringes and cartridges in high demand, says Bedwell.

Future outlookLooking forward, Asia’s pharmaceutical packaging industry looks promising. Currently, the region accounts for 26% of the global pharmaceutical packaging market, but that percentage is expected to increase to 34% by 2015. China alone is expected to grow from a 5% share to 15% in 2015, and India from 2% to 4%.

Packaging-sector growth and success will differ among countries within Asia, and those that grab hold of it are likely to win big. “Packaging is used as a differentiator and brand builder. With time, packaging will take on different forms in the healthcare sector and will not [be limited] to security or safety aspects,” adds Tyagarajan.

Jane Wan is a freelance writer based in Singapore

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IN THE FIELD

Global Healthcare on the GroundUSAID Works to Carry out President

Obama’s Global Health Initiative

President Obama launched the Global Health Initiative in May 2009 to introduce an integrated approach to the government’s investments in global health. The initia-tive involves programs of the US Agency for International Development (USAID), the Department of Health and Human Services (HHS), PEPFAR, and the Peace Corps, among other agencies. Innovation and development are key components of the initiative’s and the administration’s goals. Pharmaceutical Technology spoke with Amie Batson, appointed by Obama to lead USAID’s role in the initiative, about progress thus far and plans forward.

PharmTech: Why are innovation and development such a big push now now compared with past years?

Batson: At USAID, we realize the ben-efits of investing in innovation for global health go well beyond improvements in health. Some of the greatest advances in development have come from extending the reach of innovative breakthroughs to those who lack access health facili-ties. We are looking to build stronger partnerships with the development and scientific communities to support the creative thinkers who are developing the next generation of health technolo-gies capable of reaching more people at reduced costs to maximize impact.

USAID Administrator Dr. Rajiv Shah has stated on several occasions that the largest opportunities to improve human health and the human condition do not lie in optimizing services to the 10–20 % of people in the developing world who have access to world-class health facili-ties. They lie in extending our reach to the 80-90% of people who do not.

PharmTech: USAID Administrator Shah has spoken about how the agency is trying to improve its relationship with the private industry to make communication easier and less bureaucratic. What is USAID looking to do in this regard? What types of new partnerships is the agency forming?

Batson: Cultivating a productive invest-ment environment will require partner-ships with a range of stakeholders in donor and host countries, including the private sector, civil society organizations, research institutions, foundations, and emerging and traditional donors. Our partner-ships should reflect new models such as South–South and trilateral cooperation, and include meaningful roles for civil so-ciety and the private sector.

Leveraging the collective resources of partners through public-private partner-ships allows the development community to capitalize on opportunities to extend the reach and depth of our programs. USAID’s Global Development Alliance (GDA) is a premiere model for public-pri-vate partnerships, helping to significantly expand and deepen the impact of develop-ment assistance by linking US foreign as-sistance with the resources, expertise, and creativity of private sector partners. Since 2001, USAID has formed more than 900 alliances with over 1,700 distinct partners to leverage more than $9 billion in com-bined public and private resources. Across industry and sectors, USAID is working in partnership with both global and local corporations to increase our reach and the effectiveness of development projects.

PharmTech: What can industry expect going forward in terms of working with USAID to get its new products or vac-

cines to developing nations? What type of assistance may be provided and what are the timeframes?

Cultivating

a productive

investment

environment will

require partnerships

with a range of

stakeholders.

Batson: USAID is going to continue to focus on what we do best. That is we will continue to work with our partners at global, regional, and country levels to provide varying support. We work with WHO and UNICEF, as well as our other donor partners, GAVI, the Gates Foundation, and most importantly, countries themselves. USAID is not the only partner to industry with regard to getting programmatically suitable vac-cines developed and used in developing countries. Together, the US government makes tremendous investments in vac-cines from basic research and develop-ment to field level strengthening of im-munization programs.

PharmTech: Can you talk about the large commitment the US recently made to GAVI and what this will achieve? Does USAID have any other financing pro-grams in the pipeline?

Batson: To reiterate, one of the most transformative technologies at our dis-posal is vaccines. The United States’ coordinated support for GAVI comple-ments the efforts of the National Insti-tutes of Health, the Centers for Disease Control and Prevention, and USAID in the research, development and sustained use of vaccines in robust, country owned immunization programs.

contin. on p.20

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IN THE FIELD

contin. from p. 18The US commitment leverages the

billions of dollars that other donors have committed to GAVI, multiplying the impact of our funding more than eight-fold, and allowed GAVI to negoti-ate a price reduction of 67% on rotavirus vaccines so more of the world’s most vul-nerable people will be protected against preventable diseases.

Combined with other donors, our funding will enable the Alliance to pro-vide countries with sufficient amounts of programmatically suitable vaccines to immunize an additional 243 million children in the poorest countries with vaccines against pneumococcal disease, rotavirus, Haemophilus influenzae type b (Hib), hepatitis B, meningitis A, and yellow fever, and ensure the complete rollout of pentavalent vaccine. Experi-ence delivering vaccines to expanded target populations could also serve to strengthen immunization programs to put the world in a position to save more lives with potential future vaccines against malaria, tuberculosis, and HIV.

PharmTech: Once a new drug or vaccine is introduced a developing-nation mar-ket, what are USAID’s goals for ensuring that the country can sustain the admin-istration, purchase, and distribution of that product?

Bastson: We strongly support the GAVI co-financing strategy that requires all countries to make a co-payment for every dose of vaccine provided to that country through GAVI procurement. The relatively recent revisions to the GA-VI’s co-financing policy requires a larger payment for countries closer to ‘gradua-tion.’ We want countries to be mindful of their financial obligations but we want to continue working with our partners on the expansion of the evidence base for decision making so that when countries have to make hard decisions about how to spend their money, they will realize the tremendous health impact vaccines have.

An expanded version of this interview is

available at PharmTech.com/Batson.

Zone in on: Regulation FDA Approves 35 Novel Medicines in Fiscal Year 2011

Erik Greb

At a press conference held Nov. 10, 2011, FDA Commissioner Margaret Hamburg said the agen-

cy had approved 35 novel medicines in fiscal year 2011. Among the approved products were

two drugs for late-stage metastatic melanoma and the first drug to treat Hodgkins lymphoma

in 30 years. Other approvals included drugs to treat late-stage prostate cancer, thyroid cancer,

metastatic breast cancer, and late-stage lung cancer.

Hamburg highlighted the agency’s efforts to bring new drugs to market quickly and effi-

ciently while maintaining high standards for drug safety and effectiveness. “FDA approved

nearly 70% of these 35 new drugs before any other regulatory agency in the world,” she

said. Of the 23 cancer drugs approved between 2003 and 2010 by FDA and the European

Medicines Agency, all 23 were approved first in the US, said Hamburg, citing a study pub-

lished in Health Affairs.

FDA has expanded its drug-approval pathways to include Fast Track, Accelerated Approval,

Priority Review, and Expanded Access programs, which are designed to speed the testing, avail-

ability, and approval of drugs in various ways. Almost half of the 35 new drugs approved in FY

2011 were approved under priority review, said Hamburg. Under this program, FDA aims to

complete its review of safety and effectiveness in six months.

The agency also has shown flexibility regarding clinical trials. Clinical requirements for many

of the newly approved drugs were streamlined to permit smaller, shorter, or fewer studies than

previous studies. FDA approved several drugs on the basis of single-arm studies or studies with

extremely small patient populations, Hamburg said.

FDA’s efforts to modernize its regulatory pathways depend on its initiatives to strengthen

regulatory science, said Hamburg. The agency’s Advancing Regulatory Science Initiative current-

ly seeks to identify opportunities to invest in regulatory science. Last year, FDA and the National

Institutes of Health launched a Regulatory Science Initiative to encourage research in this field.

The agency also established several Centers of Excellence in Regulatory Science, including sites

at Georgetown University and at the University of Maryland.

CSR and sustainability forum

Pharmaceutical Technology’s Sourcing and Management eNewsletter provides specialized

coverage of the bio/pharmaceutical industry’s activities in corporate social responsibility (CSR) and

sustainability as well as developments from other business sectors, government organizations,

professional, trade, and scientific associations, and NGOs. In the December issue (available at www.

PharmTech.com/PTSM):

• An ecofriendly approach for the regioselective synthesis of rufinamide

• Sustainable manufacturing design and operations at Pfizer’s Freiburg, Germany, facility

• 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]

Pharmaceutical Technology DECEMBER 2011 21

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

Cation exchanger offers direct capture of recombinant proteinsEMD Millipore’s Eshmuno chroma-tography resins are ion exchangers designed for fast and efficient purifica-tion of antibodies. The new multimode cation exchanger Eshmuno HCX media was specifically designed for the direct capture of recombinant proteins at high salt concentrations. Eshmuno’s tentacle technology creates a multi-point interaction with the biopharma-ceutical, thus resulting in increased binding capacities. The hydrophilic polyvinyl ether base allows for high flow rates and expedited processing.

PharmPrep P sorbent, part of the company’s portfolio of chromatog-raphy media, features particles that have a perfect spherical shape. These particles are designed to pack columns more efficiently and with more stable results than sorbents with irregular materials. The two sizes (i.e., 10 and 20 μm) of the PharmPrep P sorbent enable the user to change to larger particles to increase productivity by operating preparative columns at increased flow rates. The sorbent has a pore diameter of 100 Å (10 nm) and can fit easily into the polishing step of small peptides and other biopharma-ceutical and pharmaceutical APIs.

Single-use mixing systems for large volumesSartorius Stedim Biotech has expanded its standard range of Flexel magnetic mixers. The mixers, previ-ously ranging in capacity from 50 to 1000 L, are now available in volumes of 1500 and 2000 L. The single-use system is designed for aseptic mixing in process-development and manufacturing applications. It is appropriate for biopharmaceutical processes that re-quire powerful mixing torque, such as buffer prepa-ration, media preparation, product resuspension, and homogenization applications. A stainless-steel cross mount on a pulley system enables the single-use bag to be unfolded for easy filling and optimal drainage. Its mixing is based on a bottom-mounted, magneti-cally driven impeller capable of providing high-torque mixing in large liquid volumes.

EMD Millipore

Eshmuno HCX resin

www.millipore.com

Sartorius Stedim Biotech

Flexel for magnetic mixers

www.sartorius-stedim.com

Biopharmaceuticals, such as vaccines, have become an important part of the drug indus-try’s product portfolios. Several drugmakers will rely on these therapies to help soften the blow of coming patent expirations. In various ways, this month’s products are intended to help the industry produce biopharmaceuticals efficiently, at large scales, and under the appropriate conditions. Sartorius now offers magnetic mixers in larger sizes than before. Compounding cleanrooms from Terra Universal help drugmakers meet US Pharmacopeial

standards for sterility. Chromatography resins from EMD Millipore are intended to help companies purify antibodies quickly and efficiently.

Compounding cleanrooms comply with USP <797>Terra Universal’s compounding cleanrooms are suitable for compounding sterile injectables and other preparations in accordance with US

Pharmacopeia <797> standards. An ISO 5 (Class 100) primary processing area with three high-efficiency particulate air filter–fan units provides a total of 1950 cfm (3315 m³/h) of 99.99% particle-free air (measured at 0.3 µm diameter).

The cleanrooms’ fan–filter units exceed USP <797> particle-count and air-change requirements between the buffer room and the antechamber room. Users have a choice of polycarbonate and static-dissipative polyvinyl chloride panels. A powder-coated steel support frame creates a rigid, durable structure that requires no external bracing or ceiling support. The unit’s sliding vinyl curtain creates a separate antechamber that offers another level of protection to the buffer room from the ambient environment. The antechamber is also under positive pressure, and personnel can don garb or prepare materials, thus leaving the buffer room strictly for needed equipment.

Terra Universal

Compounding cleanroom

www.terrauniversal.com

Editors’ Picks of PharmaceuticalScience & Technology Innovations


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Pressure to spur development of new medical products, deal with an increasingly global pharma-

ceutical supply chain, and accomplish more tasks with tighter budgets is prompting visible changes at FDA. Commissioner Margaret Hamburg took a broad look at the agency’s long-established administrative structure following the departure of Deputy Commissioner Joshua Sharfstein at the beginning of the year, with an eye to meeting expanded regulatory as-signments.

In recent years, Congress has called on the agency to regulate food quality more closely and to monitor tobacco marketing, while continuing to en-sure the safety, quality, and efficacy of medical products. The result is a top-level reorganization that shifts daily management and decision-making to others, permitting the commissioner to focus more on crucial scientific and policy issues.

Top deputies Most notable is the designation of a cadre of top deputies to oversee impor-tant agency functions (see Figure 1). Of particular importance to pharma-ceutical and biotech manufacturers, a

new deputy commissioner for medical products and tobacco, Stephen Spiel-berg, now coordinates the activities of FDA centers for drugs, biologics, medical devices, and tobacco products. Spielberg also will oversee a cluster of programs that affect all medical units, including offices for orphan drugs, pediatric therapeutics, combination products, and good clinical practices.

Another new deputy commissioner for global regulatory operations and policy, Deborah Autor, will manage FDA’s Office of International Pro-grams and the Office of Regulatory Affairs, which runs the agency’s far-f lung field force. This force includes FDA foreign offices, which have been established around the world to sup-port oversight of an expanding volume of food and medical products imported into the United States. Autor is quite familiar with supply-chain vulnerabili-ties and difficulties related to surging imports. She previously headed the Office of Compliance (OC) within the Center for Drug Evaluation and Re-search (CDER), which also has been overhauled.

The explosion in foreign production of FDA-regulated products requires

more collaboration and information exchange with established regulatory counterparts, according to Autor. “We can never get enough resources to cover all those facilities,” she told the PDA–FDA Joint Regulatory Confer-ence in September 2011. Autor also seeks to level the playing field between US-based and foreign manufacturers by gaining authority to block drugs from US markets if their producers limit or refuse FDA inspection or fail to comply with US quality standards. Autor anticipates further assessment of these approaches in a consensus study by the Institute of Medicine (IOM) on the global public health risks from substandard, falsified, and counterfeit medical products.

These two new deputies join the head of FDA’s Office of Foods, Mi-chael Taylor, who oversees the Center for Food Safety and Applied Nutrition and the Center for Veterinary Medi-cine. An FDA veteran, Taylor has the daunting task of implementing recent

WASHINGTON REPORT

Jill Wechsler

is Pharmaceutical

Technology’s Washington

editor, 7715 rocton ave.,

chevy chase, Md 20815,

tel. 301.656.4634,

jwechsler@advanstar.

com.

Added responsibilities and outside

concerns prompt overhaul of agency’s structure.

Jill Wechsler

FDA Revamps to Meet New Challenges

These changes aim

to address various

criticisms of FDA’s

regulatory posture.

In Washington this month

• New deputies and super

offices aim to better manage

FDA programs.

• FDA, Congress, and industry

weigh potential changes to

PDUFA and the pending generic-

drug user-fee program (GDUFA).

• Growth of imports and supply-

chain complexity continue to

refocus agency efforts.

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food safety legislation without the re-sources and personnel necessary to inspect more food facilities and to ex-pand oversight as required.

And Chief Scientist Jesse Goodman continues to lead important regulatory science initiatives. Goodman’s office oversees the National Center for Toxi-cological Research, counterterrorism and threats, and professional develop-ment and integrity for FDA profession-als. Special offices for women’s health and for minority health fall under Goodman’s purview, but also report to Hamburg.

Counselor to the Commissioner John Taylor, who served as Hamburg’s temporary deputy commissioner for much of this past year, returns to his advisory role, but with specific staff responsibilities. He will manage pol-icy and planning functions, legislative

relations, and external affairs, which includes FDA’s press office and liaison with the healthcare community.

Hamburg also is establishing a high-level office of operations with a chief operating officer to head the agency’s increasingly complex administrative functions. These functions include in-formation technology, finance, facility management, and budget formulation.

The aim of these organizational changes, Hamburg explained in a July 2011 announcement, is to establish a more effective management structure for an agency that now has 12,000 em-ployees (1600 of which reside in the Commissioner’s office) and is respon-sible for regulating more than 20% of US consumer products. The new struc-ture reduces the number of officials re-porting directly to the commissioner, while emphasizing the importance of

innovation and science and the effect of globalization on FDA and regulated entities.

These changes also aim to address various criticisms of FDA’s regulatory posture. Manufacturers claim that an overly-cautious approach to potential safety issues generates unreasonable requirements that keep innovative and effective products from patients, explained consultant Steve Grossman at the October FDA Inspections Sum-mit sponsored by FDA Week. Patient and disease groups, particularly those involved with rare conditions, echo these concerns and are pushing for FDA to revise risk calculations so that promising therapies can reach the mar-ket without delay.

Yet, consumer representatives and some members of Congress continue to voice concerns about product safety.

Figure 1: FDA organizational chart after recent restructuring by Commissioner Hamburg, as of November 2011.

OFFICE OF THE COUNSELORTO THE COMMISSIONER

COUNSELOR TO THE COMMISSIONER

John M. Taylor III, J.D.

OFFICE OF LEGISLATIONASSOCIATE COMMISSIONER FOR

LEGISLATIONJeanne C. Ireland

OFFICE OF WOMEN’SHEALTH

DIRECTORMarsha Henderson, M.C.R.P.

(Acting)

OFFICE OF MINORITYHEALTH

DIRECTORMichelle Yeboah, DrPH (Acting)

OFFICE OF THE CHIEF SCIENTIST

CHIEF SCIENTISTJesse Goodman, M D., M.P.H.

OFFICE OF THE CHIEFCOUNSEL

CHIEF COUNSELElizabeth Dickinson, J.D.

(Acting)

Main Tele: 301-796-5000Fax: 301-847-3531WO Bldg 1 Rm. 221710903 New Hampshire AvenueSilver Spring, MD 20993-0002

OFFICE OF THE COMMISSIONER

COMMISSIONER OF FOOD AND DRUGSMargaret A. Hamburg, M.D.

OFFICE OF POLICY AND PLANNINGASSOCIATE COMMISSIONER FOR

POLICY AND PLANNINGDavid Dorsey, J.D (Acting)

OFFICE OF OPERATIONS

CHIEF OPERATING OFFICERVacant

ASSOCIATE COMMISSIONERCaroline Lewis

OFFICE OF GLOBALREGULATORY OPERATIONS AND

POLICY

DEPUTY COMMISSIONERDeborah M. Aulor, Esq. (Acting)

OFFICE OF SPECIALMEDICAL PROGRAMS

DIRECTORJill H. Wamer, J.D. (Acting)

CENTER FORVETERINARY

MEDICINE

DIRECTORBemadette M. Dunham,

D V M., Pd. D.

CENTER FOR FOODSAFETY AND APPLIED

NUTRITION

DIRECTORMichael M. landa, J.D.

(Acting)

CENTER FOR DEVICESAND RADIOLOGICAL

HEALTH

DIRECTORJeffrey Shuren, M D., J.D.

CENTER FOR BIOLOGICS

EVALUATION ANDRESEARCH

DIRECTORKaren Midihun, M D.

CENTER FOR DRUGEVALUATION AND

RESEARCH

DIRECTORJanel Wiidcock, M D.

CENTER FOR TOBACCOPRODUCTS

DIRECTORLawrence R. Deylon,

M D, M.S.P.H.

OFFICE OFREGULATORY

AFFAIRS

ASSOCIATECOMMISSIONER

Dara Conigan, J.D.

NATIONAL CENTERFOR TOXICOLOGICAL

RESEARCH

DIRECTORWilliam Slikker, Ph. D.

OFFICE OFINTERNATIONAL

PROGRAMS

ASSOCIATECOMMISSIONERMary Lou Valdez

OFFICE OF EXTERNAL AFFAIRSASSOCIATE COMMISSIONER

Virgina Cox

Approved by the FDA Reorganization Coordinator and Principal DelegationControl Officer

OFFICE OF MEDICAL PRODUCTSAND TOBACCO

DEPUTY COMMISSIONERStephen P. Spielberg, M D, Ph.D.

OFFICE OF FOODS

DEPUTY COMMISSIONERMichael R. Taylor, J.D.

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Demands for more extensive testing of new drugs both prior to approval and after coming to market led to provi-sions in the 2007 FDA Amendments Act (FDAAA) that added greatly to FDA’s oversight responsibilities for new drugs and biologics. Now, some legis-lators want to modify certain FDAAA requirements, particularly those for Risk Evaluation and Mitigation Strat-egies (REMs) and conflict-of-interest rules.

Spielberg up frontThe challenge for Spielberg, a lead-ing pediatrician and pharmacologist, is to coordinate responses to these is-sues. His elevated position makes him a ready spokesman for FDA medical-product regulators and gives him au-thority to make timely policy deci-sions that otherwise would wait for Hamburg to weigh in. He also will facilitate the development of products that involve multiple agency centers, including combination products, or-phan drugs, and pediatric therapies.

Spielberg comes to FDA with 30 years experience in academia and in-dustry. He has served on FDA advisory committees and got to know Hamburg as a member of the advisory Science Board. Before coming to FDA, Spiel-berg was director of the Center for Per-sonalized Medicine and Therapeutic Innovation at Children’s Mercy Hos-pital in Kansas City, Missouri. Previ-ously, he was dean of Dartmouth Med-ical School, and prior to that, he held senior research positions at Johnson & Johnson and Merck. While in industry, he chaired a Pharmaceutical Research and Manufacturers of America pedi-atric task force and was instrumental in promoting the Best Pharmaceuticals for Children Act, which was enacted in 2002 to provide incentives for develop-ing pediatric therapies.

An initial task for Spielberg is to or-chestrate reauthorization of the Pre-scription Drug User Fee Act (PDUFA), along with new fees for generic drugs and biosimilars, by September 2012. Although industry and FDA gener-ally agree on a new five-year PDUFA

program, they fear that the legislators will add numerous pet policies to this must-pass legislation.

A related challenge for Spielberg is to help resolve serious disagreements between the medical-device industry and the Center for Devices and Radio-logical Health (CDRH) over proposals to revise the device-approval process. Safety issues and notable product re-calls have prompted efforts to stiffen FDA regulatory and testing require-ments, particularly for those products approved under the 510k regulatory procedure. After a lengthy evaluation process, which included public meet-ings and an IOM report, CDRH offi-

cials have proposed changes likely to require additional clinical testing of some devices. Manufacturers are pro-testing vehemently and urging Con-gress to support innovation by block-ing such action.

“Super” changes at CDERParallel to the restructuring of FDA’s top management, CDER Director Janet Woodcock has engineered op-erational changes that also seek to deal with globalization and overcome obstacles to new drug development. Growth in responsibilities and in staff has prompted the elevation of nearly all of CDER’s main operating units into

Figure 3: New structure of the Office of Manufacturing & Product Quality within FDA’s

Center for Drug Evaluation and Research, as of November 2011.

Figure 2: New structure for the Office of Compliance within FDA’s Center for Drug

Evaluation and Research, as of November 2011.

Office Director

Deputy Director

Assoc. Dir. for Program Mgmt. &

Org. Strategy

Assoc. Dir. for Risk Sci., Intelligence &

Prioritization

Assoc. Dir. for Policy &

Communication

Assoc. Dir. for Regulatory Sciences

Senior Advisor

Division of International Drug Quality

Division of Domestic Drug Quality

Sr. Regulatory Counsel

Assoc. Dir. for Drug Quality Assurance

Division of Good Manufacturing Practice

Assessment

Division of Policy, Collaboration & Data

Operations

Office of Unapproved Drugs and Labeling

Compliance

Office of Drug Security, Integrity

and Recalls

Office of Manufacturing and Product

Quality

Office of Scientific

Investigations

Office of Compliance


Washington Report

“super offices” with broader manage-ment structures better able to monitor diverse operations.

In May 2011, Woodcock added the Office of Surveillance and Epidemiol-ogy (OSE) to the super-office list, join-ing the Office of New Drugs, Office of

Pharmaceutical Science, and Office of Translational Sciences. OSE Director Gerald Dal Pan gained more support staff for his immediate office, plus for two subordinate offices: the Office of Medication Error Prevention and Risk Management and the Office of Phar-macovigilance and Epidemiology. The

various divisions of these larger op-erators manage CDER’s adverse-event reporting system, oversee sponsors’ observational studies, prevent medi-cal errors caused by product names, and orchestrate risk-management pro-grams. The move aims to highlight the

importance of drug-safety issues and hopefully quiet those who want to shift drug safety out of CDER and into an independent entity.

Next, Woodcock unveiled a new structure for CDER’s Office of Com-pliance, making it another super office with multiple suboffices and divisions

(see Figure 2). Ilisa Bernstein has been OC acting director since Autor left last summer. While many OC functions remain fairly constant, a new Office of Drug Security, Integrity & Recalls was created to address the challenges of globalization and growing drug counterfeiting and diversion (see the August 2011 Washington Report col-umn, “FDA Maps Strategy to Counter Supply-Chain Threats”). The Office of Manufacturing and Product Quality oversees field inspections and compli-ance with GMPs (see Figure 3). An in-creasingly visible function is to prevent and mitigate drug shortages related to manufacturing and compliance issues. A larger Office of Scientific Investiga-tions now monitors pharmacovigilance and REMS programs, in addition to the conduct of clinical trials and human subject protection.

More recently, CDER’s Office of Medical Policy (OMP) also became a super office. Led by Rachel Sherman, OMP consists of the Office of Pre-scription Drug Promotion (formerly the Division of Drug Marketing, Ad-vertising, and Communications) and the new Office of Medical Policy Initia-tives. This last entity will oversee FDA’s Sentinel Initiative for modernizing drug surveillance and adverse event detection; the Clinical Trials Trans-formation Initiative to modernize trial conduct and oversight; and the Patient Medication Information project which seeks to update FDA policies for com-municating risk information to the public. A key task is to support health reform initiatives related to biosimilars and other policy issues.

All the new acronyms are confusing, and critics are skeptical about so many “super” offices within CDER. Wood-cock sees these changes as leading to “a high-functioning, policy-driven, risk-based organization” that can “evolve and grow.” And with any luck, CDER’s new management structure will pro-vide more time for Woodcock to exam-ine drug regulatory operations more broadly and explain its actions and policies to its many constituents. PT

In a fitting keynote address for the 25th

annual meeting of the American Association of

Pharmaceutical Scientists (AAPS) in Washington

in October 2011, FDA Center for Drug Evaluation

and Research Director Janet Woodcock recalled

her nearly 25 years at FDA and speculated

about what the next 25 years might hold for

biomedical research and drug development.

When AAPS was founded in 1986, the “drug lag”

crisis was the main concern for regulators and

manufacturers, Woodcock recalled, generating

complaints about US patients waiting longer

than Europeans to access important new

medicines. At the same time, the AIDS epidemic

created “an incredible sense of urgency” to speed

new treatments to market. Frustration about

drug lag prompted FDA, manufacturers, and

Congress to launch the drug user-fee program in

1992, providing additional funds that accelerated

CDER and CBER approval processes, and brought

many changes to FDA.

Woodcock saw the pendulum shift over the next

decade, as concerns about drug safety prompted

calls for broader assessment of new therapies and

more extensive oversight of new drugs. The rise

in drug advertising to consumers in the late 1990s

also “caused quite an uproar,” Woodcock noted, a

development that she feels harmed the industry’s

reputation. Those concerns culminated in the 2007

FDA Amendments Act, which authorized PDUFA

IV and required FDA to pay more attention to

ensuring the safe use of medicines on the market.

In looking ahead, Woodcock worries that

the worldwide economic crisis will have a

profound effect on industry’s productivity and

FDA operations. She expects to see decreased

staffing for the agency, which will increase its

reliance on user fees. Manufacturers, in turn, are

looking more to emerging markets for products,

clinical research and sales, thus highlighting

the need for international standards and more

collaboration among regulators.

More optimistically, Woodcock anticipates that

important discoveries in molecular medicine

and greater understanding of disease will drive

new drug discovery. Scientific advances also

will make today’s production practices obsolete,

encouraging a shift to continuous manufacturing

processes and quality-by-design approaches.

These developments, she predicted, will provide

for a leaner, more effective, more globalized

drug regulatory process.

Woodcock looks forward and back

The move aims to highlight the

importance of drug-safety issues and

hopefully quiet those who want to shift

drug safety out of CDER and into an

independent entity.


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FDA approved 35 new drug applications (NDAs) for new molecular entities in fiscal year (FY) 2011, the second

highest approval total in a decade. (Thirty-seven NDAs were approved in FY 2009). The FY 2011 approvals include seven products to treat cancers, two products for hepatitis C, and the first new drug to treat Lupus in more than 50 years. For an indus-try stressed by patent expirations on many top-selling products, severe reimburse-ment pressures, increasing regulatory demands, intense market competition, political scrutiny, and the relentless rise in new drug-development costs, the large number of approvals is welcome news for companies and patients alike.

Public demand to treat an expanding array of diseases and conditions is grow-ing. There is an urgent need for newer and better medicines to treat a host of neuro-psychiatric disorders, such as depression and schizophrenia, and neurodegenera-tive diseases, such as Parkinson’s disease, Alzheimer’s disease, and age-related de-mentias, a particularly crucial need in light of the aging population in many Western nations. Demand for new medicines is also high in pain management, infection (especially those caused by resistant bac-terial strains), Type 2 diabetes, and many cancers. Add to that the host of neglected diseases of the developing world, and it is clear that much work still needs to be done.

The challenge of drug developmentBringing a new medicine to market is time-

consuming, risky, and expensive. Research by the Tufts Center for the Study of Drug Development pegs the cost at $1.3 billion for each new drug approved. Meanwhile, attrition rates, a major contributor to these alarming R&D costs, remain stubbornly high. Success rates for compounds entering human studies average a dismal 15% across all therapeutic areas, and drop to a stagger-ing 8.2% for neuropsychiatric drugs.

The result of high-cost, low-success drug development is that R&D spending by many of the large pharmaceutical firms, especially over the last decade, has skyrock-eted. In 2010, eight companies exceeded $5 billion in R&D spending, with Pfizer leading the pack at $9.4 billion. These high levels of spending are not sustainable in light of the relatively small number of ap-provals by each firm annually. As a result, several firms, most notably Pfizer, Sanofi, and GlaxoSmithkline, have announced significant reductions in R&D spending.

New r&D models How can large pharma’s decision to re-duce R&D spending be reconciled with its goal of boosting productivity? More importantly, how will the public demand for new drugs to treat unmet medical needs be met? The answer lies in new R&D models that leverage the expertise and capabilities of various stakeholders, and, importantly, spread the enormous risk of drug development.

Open innovation, academic–industry partnerships, and the transformation from FIPCos (fully integrated pharmaceutical companies that take drug candidates from laboratory bench to market) to FIPNets (fully integrated pharmaceutical networks

that encompasses all the major stakehold-ers in drug development, including large and small pharmaceutical firms, academic research centers [ARCs], patient groups, public–private-partnerships, and CROs), represent the new face of pharmaceutical R&D. In the new model, all stakeholders have a place at the table and share in the risks and the rewards of innovation.

The emergence of innovation nodesUltimately, industry R&D will align along “innovation nodes,” referring to disease-, therapeutic area-, or technology-focused collaboratives that will leverage the col-lective capabilities of various public and private entities. A current model of an in-novation node is the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Recog-nizing the enormous challenge of develop-ing medicines for this disease, 12 compa-nies got together in June 2010 and agreed to pool clinical data to identify new preclini-cal screens. The goal was to enable compa-nies to make better decisions about which compounds to bring into human testing. Today, ADNI has more than 20 companies involved and has attracted the interest of patient groups, ARCs, and CROs, which provide access to patients and expertise crucial to developing new products.

In time, innovation nodes will be cre-ated to address other vexing medical needs, including, Parkinson’s disease, rheumatoid arthritis, certain cancers, and various pedi-atric indications. One might say that the era of solely private sector-based innovation is over. In the new era, the public sector, through ARCs, public–private partner-ships, and patient groups will play a crucial and indispensable role. PT

Kenneth I. Kaitin, PhD, is director and

professor at the Tufts Center for the Study

of Drug Development at the Tufts University

School of medicine.

Pharma companies must balance demand for

news drugs while facing reduced R&D spending.

Kenneth I. Kaitin

Creating innovation Nodes to meet unmet medical Needs


StatiStical SolutionS

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PharmTech.com/statsPharmTech.com/stats

the sample size needed to investigate an out-of-specification (OOS) result continues to be a point of conten-

tion within the pharmaceutical industry. The following quotes from the US vs. Barr Laboratories case, which covered OOS issues, provide good background to the discussion (1):

“... the number of retests per-

formed before a firm concludes that

an unexplained out of specification

result is invalid or that a product is

unacceptable is a matter of scientific

judgment.”

“Nevertheless, retesting cannot

continue ad infinitum. Because

such a practice is not scientifically

valid ...”

“Such a conclusion cannot be

based on 3 of 4 or 5 of 6 passing re-

sults, but possibly 7 of 8.”

“ ... retesting determinations will

vary on a case by case basis, a nec-

essary corollary of which is that an

inflexible retesting rule, designed to

be applied in every circumstance, is

inappropriate.”

The specific question here is: “How big should the sample be?” and it is the most commonly asked question of a profes-sional statistician. The truth is that there is no simple answer because it depends

on the information available. There are at least four possible approaches:•Scientific estimate•Seven out of eight as in the Barr case•Statistical formula with historical

estimates•Statistical formula with sample.

Scientific estimateOne approach to determine the sample size would be to ask a trained analyst with industry experience to use his or her best scientific judgment to determine what would be an adequate sample size to se-lect. Prior to the Barr case this was (and still is in some places) the standard oper-ating procedure. Although this has scien-tific basis in the fact that the best person available uses all information to estimate a size, the fact that different people would not get the same number is not scientific. However, the Barr case quotes would seem to support this approach.

Seven out of eight As in the Barr case, the seven out of eight rule is used by some companies in the ab-sence of any other available information. However, so far there is little statistical justification for seven versus any other value. Some companies choose nine only so they can say they have improved upon the Barr criteria.

Statistical formula with historical estimatesAs I tell my clients, the statistical answer to the sample-size question is: “We first need a prior estimate of the inherent variability, the variance under exactly the same conditions to be used, an estimate of the alpha risk level, the beta risk level, and

the size of the difference to be detected.” The formula for the sample size for a

difference from a mean is:

n = (tα + t

β)2 S2 / d2 (Eq. 1)

where tα and t

β are the one sided t distri-

bution values for the given α and β risk levels selected and S2 is the variance of the total product, process or method and d is the difference to be detected.

Four values are needed to calculate the sample size. The alpha and beta errors are standardized for most scientific and indus-trial applications to α = 0.05, β = 0.05 or 0.10. Thus, the t values are taken from the standard t table for α and β and a given number of degrees of freedom of the data used to estimate the variance. The other two values are more difficult to obtain.

According to FDA, “The number may vary depending upon the variability of the particular test ...” (2). This prior esti-mate of the variance of the method for a given product may be difficult to obtain. If the product, process or method has been changed, the data must be limited to that last change to be representative. Also, some products are made only a few times a year. There may be only three or four batches and thus three or four values. This amount is not enough to get a good estimate of the variance. If sufficient data does exist, from historical records, then perhaps the esti-mate can be made. A sample size of 30 or more is preferred to obtain a reasonable estimate of the standard deviation.

The size of the difference to be detected is difficult to determine in advance because one does not know in advance how far out of specification any future OOS result may be.

contin. on p. 54

Precedents set in the historic Barr case continue to

raise questions over suitable sample-size criteria.

Lynn D. Torbeck

out-of-Specification Sample-Size confusion

Lynn D. Torbeck

is a statistician at

PharmStat Consulting,

2000 Dempster,

Evanston, IL 60202,

tel. 847.424.1314,

[email protected],

www.PharmStat.com.


Simply put, 2011 was a year of transi-tion for bio/pharmaceutical compa-nies, contract manufacturers, and

suppliers. Financial pressures caused by generic-drug incursion, the pressing need to augment R&D productivity and control costs, and an increasingly global and complex supply chain are some of the key issues cited by executives par-ticipating in Pharmaceutical Technology’s industry roundtable. We asked execu-tives to share their views of the leading issues shaping the bio/pharmaceutical industry overall and manufacturing and supply specifically. Participating in the roundtable were: Jeffrey Lee Craig, global director of marketing and business devel-opment at ATMI, a provider of single-use bioprocessing systems; Karen Zak, vice-president of marketing, pharmaceuticals, at the excipient and performance ma-terials company Avantor Performance Materials; Guy Villax, CEO of the CMO Hovione ; Michael Kleinrock, research di-rector at the IMS Institute for Healthcare Informatics; and John Kelly, vice-pres-ident of strategy and transitioning sites for Pfizer Global Supply (see Figure 1).

Overall industry trendsPharmTech: Reviewing 2011, what would you identify as the most significant issues shaping the bio/pharmaceutical industry?

Kelly (Pfizer): Key products continued to lose patent exclusivity. Research pipe-lines have become more robust as new medicines to treat unmet medical needs are developed and approved. Emerging-market demand continued to redefine geographic boundaries and increased the complexity of global supply chains. These significant factors will continue to inform the industry’s transition away from the blockbuster model and toward develop-ing smaller volume, specialty products.

Kleinrock (IMS): One of the most significant issues, by far, is the policy-driven actions that imposed additional costs to manufacturers or cut prices on medicines. These were largely motivated by fiscal and debt issues and impacted markets across the world.

Second is the unprecedented num-ber of patent expirations that took place in 2011, which are driving the growth

Views from Pharma Leaders

A year in review and a look forward.

An Industry

Roundtable moderated

by Patricia Van Arnum

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Cover Story: 2011 Review and 2012 Outlook

Drug shortages, supply-chain security, generic-drug incursion, and f lexible manufacturing models are some of the issues shaping the bio/pharma industry.


Cover Story: 2011 Review and 2012 Outlook

of generic drugs. We [IMS Institute for Healthcare Informatics] expect to see fu-ture spending on generic drugs coming from increased competition and incen-tives as patents on innovative products expire. The US will see the largest expan-sion of generic-drug spending compared with other global developed markets. US generic-drug spending is anticipated to be 7–8% through 2015.

Villax (Hovione): The increased speed and severity of regulatory activity reached a crescendo in 2011—Warning Letters, import alerts, recalls, and consent decrees. Some of it was clear evidence of global medicine agencies acting to recover con-trol over the generic-drug industry whose lightning-speed development and global-ization has caught regulators off guard. Take for example, an EU inspectorate report leading to a FDA Warning Letter.

The intensity of outsourcing by innovator-drug companies also is a significant trend, and here the most notable stories are in line with regula-tory actions: a string of Warning Let-ters hitting Big Pharma because of their Indian-based supply chains. As one in-dustry executive noted at a recent con-ference, ‘A firm can have all the SOPs [standard operating procedures], sys-tems, and controls required, but without [a] quality culture, product quality and business continuity are not assured.’ Expect customers to be looking for evi-dence of a true quality culture across the organization and at every level.

Zak (Avantor): During 2011, the phar-maceutical industry has shown a renewed

emphasis on all aspects of security and overall quality throughout an increas-ingly more complex supply chain. Global supply-chain security initiatives are critical tools to prevent what has become an abun-dance of counterfeit pharmaceutical raw materials and therapeutics found in both developed and emerging markets. They also play an important part in addressing concerns about potential adulteration for economic gain, contamination, theft, and lack of appropriate regulatory compli-ance. With patient safety as the public’s fundamental expectation of the industry, pharmaceutical companies have made supply-chain security a primary responsi-bility that applies across the organizational boundaries of procurement, manufactur-ing, packaging, and regulatory compli-ance. Collaboration within the industry across suppliers and manufacturers al-lows for the determination, sharing, and implementation of best practices that will continue to enhance supply-chain security and build patient confidence.

Craig (ATMI): In 2011, we noticed a continued push toward gains in manu-facturing efficiency. In recent years, manufacturers have qualified and vali-dated single-use technologies to acceler-ate milestones and address productivity demands. Currently, we are focused on scaling manufacturing processes and optimizing supply-chain infrastructure. Right now, single-use technologies are in the early stages of industrialization. The cycle of innovation is ongoing even as single-use products and systems are being integrated for more efficient manu-

facturing platforms. Many positive steps were made in 2011 to help solve efficiency challenges. Ultimately, a new approach to manufacturing will be realized through these new technologies.

Manufacturing and supply trendsPharmTech: Looking back at 2011, what would you identify as the most signifi-cant issues shaping the direction of bio/ pharmaceutical manufacturing from a supply perspective, technical perspective, and/or regulatory perspective?

Kelly (Pfizer): Issues shaping the di-rection of pharmaceutical manufacturing include: continuing to align capacity with future anticipated demand, ensuring the security of the supply chain, and meeting shifting global market requirements.

Kleinrock (IMS): The current drug-shortages issue in the United States is of in-creasing concern to patients, clinicians, and policymakers. The issue is reflective of the challenges associated with complex sterile injectables and the supply chain; they were the genesis of a recent report by the IMS Institute where we identified several new trends and found significant volatility in the suppliers of drugs, but not always in the total volume of medicines. These issues will not get any easier as we approach 2012.

Zak (Avantor): The most significant fact is that pharmaceutical manufactur-ers are operating in a time of continuous change. They are facing an extraordinary range of challenges, from handling risk-management initiatives while maximiz-ing their manufacturing, outsourcing, and quality capabilities, to balancing the need

Figure 1: From left, Jeffrey Lee Craig, global director of marketing and business development at ATMI; Karen Zak, vice-president of

marketing, pharmaceuticals, at Avantor Performance Materials; Guy Villax, CEO of Hovione; Michael Kleinrock, research director at the

IMS Institute for Healthcare Informatics; and John Kelly, vice-president of strategy and transitioning sites for Pfizer Global Supply.


for speed in technical problem resolution, all with the emphasis placed on supply-chain security. They are facing these chal-lenges while dealing with the intricacies associated with the development of new products and their components, along with the responsibility to provide an unin-terrupted supply of safe and secure phar-maceuticals to the global patient popula-tion. In response to these challenges, cost management and operational excellence projects abound, including the develop-ment of enhanced collaborations internally between R&D and manufacturing as well as the use of external partnerships to meet strategic goals.

Craig (ATMI): The direction of the in-dustry is being shaped by the drive to meet tomorrow’s manufacturing demands effi-ciently. Even as single-use vessels, mixers, bioreactors, and manifolds have become reliable, GMP manufacturing standards, innovation, adoption, and continuous improvement of disposable platforms are ongoing. Today, the focus is shifting from evaluation and integration to other con-siderations, including assurance of supply-chain security, the evolution of single-use standards and continuous technology, and efficiency improvement.

A look to 2012

PharmTech: Looking ahead to 2012, what factors, conditions, or other de-velopments do you think will play an important role in determining the per-formance and direction of the pharma-ceutical industry overall and manufac-turing specifically?

Kelly (Pfizer): Pharmaceutical manu-facturers will need to ensure that their in-ternal and external manufacturing capa-bilities are aligned for the expected needs of the emerging new-product pipeline. They must have the strategic flexibility and agility to respond to a more dynamic market environment and increasingly volatile product demand. In the emerging markets, manufacturers will need to look to partnership relations as opportunities for capturing competitive advantage.

Kleinrock (IMS): The performance of the drug pipeline, both in the approval of new entities and in the commercial success of those medicines, will be critical for the

long-term health of the sector and for the patients these medicines treat. For generic-drug makers, an unprecedented bubble in new molecular opportunities comes also with an unprecedented race to the bottom and the margin pressures that await.

Villax (Hovione): Looking ahead to 2012 and onward, I see regulators add-

ing new legislative powers to enable them to effectively control the new global in-dustry landscape and establish effective oversight process. As the Generic Drug User Fee Act (GDUFA) passes into law in the US, and the Falsified Medicines Direc-tive into national laws in 27 EU member states, we should expect shock waves to the supply chains of APIs in the generic-drug industry. We will witness a push toward higher standards and increased compliance. If there is increased demand from the few reliably compliant sources, this may trigger shortages, which may lead to API price increases although this is unlikely to translate into pharmacy-level price increases. The key dates are July 2013 for Europe and 2017 in the US, by which time, we shall have parity be-tween foreign and domestic inspections in two of the major global regions. Japan may be less in the news, but Japan’s Phar-maceuticals and Medical Devices Agency (PDMA) does expect the Japanese Drug Master File (J-DMF ) to mirror in detail the reality of what goes on in the plant and for the inspectors to verify compli-ance in the field against the Japanese version of the document; in fact, this is the only document they consider valid. Expect surprises.

Zak (Avantor): The following chal-lenges faced in 2011 within the phar-maceutical industry will continue as we move into 2012: •The need for flexibility and adapt-

ability within the manufacturing environment will continue, driven by the emphasis on cost containment and efficiencies. •The use of external resources and

locally situated partnerships will grow as a means to enhance presence in global/emerging markets. •The ability to participate in these

emerging markets will depend on the capability to have small, batch operations that can cost-effectively produce finished products locally.

•There is a growing need for an ongoing comprehensive ap-proach to resolving supply-chain security issues as they evolve around the globe. •Uncertainty surrounding the sub-

optimal performance of the global economy will continue to influence business decisions. •Manufacturers will continue to

contend with an environment of intense regulatory scrutiny, which will tighten on all aspects of the very complex supply chain.

Craig (ATMI): Our view of the bio-pharmaceutical industry is shaped by early development and ongoing growth in the single-use manufacturing tech-nology space. We are beyond trial and validation of these technologies. Once the question was: ‘Will these tools work?’ Now, the expectation is to deliver on the efficiency and performance promises of lower operating costs, faster build of manufacturing capacity, and product life-cycle flexibility. These expectations have hit stride in the recombinant pro-tein and vaccine arenas and are expand-ing into the fast-emerging stem-cell and cell-therapy markets. In 2012, the speed at which pharmaceutical and biophar-maceutical organizations achieve stra-tegic clinical milestones and maintain economically viable business models will be differentiators. Suppliers of single-use technologies will be measured by their ability to excel in commercialization and industrialization and their cycle of technology innovation, supply-chain security, and continued improvement of process efficiency. PT

The US is expected to see the largest

expansion of generic-drug spending

compared with other developed markets.


The economic and financial cri-sis that thundered through the world economy in 2008 still

rumbles on today. The downgrade of the US debt rating in August 2011, along with the economic chaos that has taken over the European Union in recent months, have done little to lend confidence to the bio/phar-maceutical market. When analyzing data from Pharmaceutical Technology’s 2011 annual employment survey, readers’ outlooks are positive with regard to job security and business growth for 2012. Approximately 64% of respondents feel that their jobs will be secure in 2012, while 82% believe 2012 will bring improved business conditions or, at the very least, not decline.

In last year’s survey, everyone was riding the employment roller coaster—11.3% of respondents lost their jobs but salary rises were given to those lucky or smart enough to remain in employment. This year,

7.2% left jobs involuntarily following restructuring, but many other indi-cators remain relatively unchanged, with 59.4% experiencing a salary in-crease. The median salary of all re-spondents rose from $102,500 in 2010 to a median of $103,100 for 2011.

At the end of 2010, the majority of survey respondents thought that busi-ness within the bio/pharmaceutical industry would improve in 2011, but given the enormity of global economic worries, it’s no surprise that a recov-ery has been somewhat delayed.

More secure even in troubled timesGiven the tone of mass media this past year, most respondents have probably had cause to consider just how secure they are in their current roles. But the results from the 2011 survey are positive. As noted, 64% of respondents “agree strongly” or “agree somewhat” that they are se-cure in their current job (see Figure 1). To put this into context, insecu-

rity ran high at 53% in 2010—US respondents were above the aver-age at 55.3%—so there is a marked improvement. It is interesting then that, when asked to compare job se-curity to last year, 40.9% claim they feel less secure today than in 2010 (men somewhat less secure at 44.8% than women at 33.3%). Nevertheless, 33.6% of you would consider moving to another position based solely on improved job security, with another 52.9% considering it an important criterion, making it clear that secu-rity is still an issue of concern.

Breaking the data down by organi-zation type, contract manufacturers and service providers offer slightly more security (68.9% agreed their job was secure) than generic or tra-ditional bio/pharmaceutical compa-nies (64% and 63.8%, respectively) in a pattern that ref lects last year’s sur-vey, although groupings are closer for 2011. The pattern is somewhat reversed when respondents discuss whether they were likely to leave their job involuntarily in the com-ing year; 28% of respondents work-ing for generic-drug firms agreed, as compared with 21.5% in traditional pharma companies and 25% in con-tract organizations. Geographically, things get a little more interesting; Europe (East and West) trails in job security with 58.7% of respondents feeling safe, US and Canada match the total figure at 64.5%, but for the rest of the world (of which 54.5% is made up of India) job security sits at a very high 84% (see sidebar, “Emerging economies,” for more de-tails about India’s bio/pharmaceuti-cal employment sector).

Only 21.6% of a l l respondents agreed that leaving their job invol-untarily was likely, but what about moving on to new pastures volun-tarily? A hefty 66.5% of respondents “disagree strongly” or “disagree somewhat” that they will leave vol-untarily (33.5% were in agreement), so many are either satisfied at work, or mindful that the job market has seen better days. Once again, lo-

The Employment Outlook Brightens

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Employment Survey

Readers react to the economic turmoil of the past year and look longingly forward to 2012.

Rich Whitworth and Amy Ritter


cation plays an important role in this opinion. In North America, the figures follow the general trend (because of the survey weighting), with 30.5% of respondents agreeing that they are likely to leave their job voluntarily. In Europe however, the figure ramps up to 38%, and for the rest of the world, almost half “agree strongly” or “agree somewhat” with the statement. Given that these fig-ures are at odds with job security, there must be signif icantly more powerful drivers for job satisfaction.

Rating satisfaction According to this year’s responses, salary is surprisingly not a pillar of job satisfaction but is important. Only 34.3% of respondents feel they are paid fairly for their level of expertise, despite 59.4% of respon-dents receiving salary increases in 2011. Rather, the majority (46%) feel that they are paid at the low end of the scale but within market value or simply not paid the going rate (19%)(see Figure 2). Location also seems to have little part to play with salary satisfaction, with similar responses given across the world.

When it comes to salary increases, Europe seems to have the least gener-ous employers, with only 50% of re-spondents seeing an increase in 2011 and a relatively high 12% witnessing

decreases in salary. Compare these percentages with North America’s 61.7% of respondents who had an in-crease and 7% of which had a decrease this past year, and the rest of the world which had 69% of respondents indi-cating a salary increase (and only 6.9% experiencing decreases).

Although respondents may not get paid what they believe they deserve,

they do feel respected and needed by their employers. Three quarters of respondents agree (either strongly or somewhat) that their work is fully valued by their employer, up from 64.6% in 2010 (see Figure 1). This feeling is particularly strong in traditional bio/pharmaceutical companies (80.8%) compared with generic-drug firms (64.7%) and con-

Figure 1: Respondents indicate to what extent they agree with statements about their current position and company.

47.7%

57.5%

15.3%

30.3%

23.1%

19.5%

25.1%

30.5%

28.2%

28.8%

42.7%

31.7%

44.9%

50.3%

16.4%

7.8%

33.2%

22.3%

29.4%

19.7%

18.7%

5.5%

6.5%

22.8%

4.7%

15.8%

15.8%

6.0%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

My work is fully valued by my employer.

My job is secure.

I would like to leave my job, given the opportunity.

In my current position, I use my skills and training to their fullest extent.

There is opportunity for career advancement in my current position.

My gender is not a factor in determaining or limiting my professional advancement at my current company.

I experience no discrimination for any reason at my current company.

Agree strongly

Agree somewhat

Disagree somewhat

Strongly disagree

This survey was deployed for the period October–

November 2011, and reflects the answers of 461

people. On average they are male (66.8%), aged

44.7, with 19.3 years experience. The highest level

of education completed by most is a bachelor’s

degree (38.9%), followed by a master’s degree

(34.1%), and 21.7% have a PhD. In terms of

location, the US accounts for the majority of

respondents at 63.7%, a figure that is slightly

reduced this year because of increased responses

from Canada and India, both of which saw a two

fold increase to 5.9 and 3.9% respectively. Europe

accounted for much of the remainder at 23.7%.

The majority of survey respondents (58.9%)

are employed at a traditional (44.9%) or

generic (14%) bio/pharmaceutical company,

followed by contract manufacturing, research,

and service organizations (15.6%). Companies

supplying technology, equipment, or raw

materials to support the bio/pharmaceutical

industry account for 5.2% of respondents,

while academic institutions account for to

4.3%, and consulting companies 4.6%. Three

percent of respondents work in government or

regulatory organizations, and the remaining

8.5% of respondents represent a range of niche

organizations, including medical-device, in-

vitro diagnostics, and environmental testing.

Of all organizations, the majority (47.6%) are

publicly traded companies, followed closely by

privately held companies at 41.4%. Nonprofit

organizations account for much of the remainder

at 6.8%. Almost one-third of respondents work

for large organizations with more than 20,000

global staff, which is unsurprising considering

the number of mergers seen in recent years.

In terms of job focus, the largest group of

survey respondents (16.4%) work in quality

control and assurance (QC/QA), with researchers

(including preclinical, clinical, and drug

discovery) occupying the second slot with a

healthy 11.5%. Production operations and

management (8.3%), process development

(7.3%), regulatory compliance (7.1%), and

pharmaceutical analytical development (5.8%)

represent other major functions.

About the survey respondents


Employment Survey

tract organizations (70.5%); it seems some headway has been made for contract organizations, which were struggling at the bottom of the pile last year with only 58.4% of respon-dents feeling valued. It could be that ever-stronger relationships between CMOs or CROs and partner com-panies have helped foster a sense of value among all employees working on projects together. Following the trend from last year, men feel slightly more valued than women (at 76.1 and 73.3%, respectively).

So, aside from feeling valued, what other factors help bio/pharmaceuti-cal employees face the early alarm clock every morning? As in 2010, “ intel lectua l st imulat ion” is the number-one driver, with 61.9% of respondents considering it an impor-tant contributor and 27.3% indicat-ing that it is a main source of satis-faction. In fact, this is the top answer regardless of location. The “chance to work on challenging projects” is a close second, with 59.5% citing it as an important factor, and a 28.9% in-dicating that it is their main reason for going to work. Improved work–li fe ba lance, job security, better salary, and benefits fill out the rest of the top of the list in descending order of importance (see Figure 3).

One notable difference this year compared with 2010 is that similar job satisfaction results are produced irrespective of location, type of orga-nization, and gender. This harmony

Figure 3: Resondents indicate the importance of different factors in job satisfaction

(multiple responses were allowed).

Figure 4: Respondents indicate the factors that would entice them to leave their

current position (multiple responses were allowed).

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Intellectual stimulation

Challenging projects

Relationships with colleagues

High salary

Good bene�ts

Good work/life balance

Job security

Supportive management

Adequate resources/infrastructure for required tasks

Adequate time to complete projects

Tolerance and opportunity for all employess

This is the main reason I come to work

This is an important contributor to my satisfaction, but not the only reason I work

This is nice to have, but not all that important a contributor to my satisfaction

This has no impact on my feelings about work at all

I would quit my job because of this factor alone, if I could

27.2

28.8

16.2

15.8

13.9

21.3

20.7

17.4

12.5

10.6

11.9

62.0

59.5

54.9

56.6

61.0

59.5

56.8

53.4

56.3

54.3

48.5

7.1

9.3

23.9

22.9

21.5

13.4

16.4

21.6

24.3

26.1

26.7

36.9%

36.7%

33.4%

32.8%

31.0%

20.8%

18.4%

17.9%

17.0%

10.9%

8.6%

7.6%

49.6%

49.6%

59.5%

51.9%

58.0%

43.9%

55.8%

56.7%

54.0%

47.2%

52.7%

47.2%

10.8%

10.8%

5.8%

12.4%

9.4%

25.5%

18.4%

21.4%

21.0%

33.9%

25.1%

31.8%

2.6%

2.9%

1.3%

2.9%

1.6%

9.7%

7.4%

4.0%

8.0%

8.0%

13.6%

13.4%

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Work/life balance

Professional advancement

Salary

Job security

Intellectual challenge

Scienti�c opportunities

Tolerant work place

Retirement bene�ts

Vacation allotment

Health Insurance

Commuting time

I would change jobs for this alone

This is important, but would not be suf�cient on its own to make me change jobs

This is a consideration, but would not factor heavily into my decision

This would have no impact whatsoever on my decision

Geographic location

Figure 2: Respondents indicate their level of salary satisfaction.

0.0% 5.0%

19.1%

45.7%

34.4%

0.7%

10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 40.0% 45.0% 50.0%

I am paid below market value, considering my level of expertise and responsibility.

I am paid within market value for my job function, but at the low end of the range, considering my level of expertise and responsibility.

I am paid fairly for my level of expertise and responsibility.

I am paid excessively for my level of expertise and responsibility.


is also the case when considering the factors that weigh in the deci-sion to change jobs. Thirty-seven percent of all respondents say they would change jobs for an improved work–life balance alone; similarly, professional advancement (36.6%), salary (33.2%), job security (32.6%), and intellectual challenge (31.3%) are all strong deciding factors (see Fig-ure 4). Changing tact slightly, when asked which sole factors would make respondents quit, 38% cite low pay. Discrimination also ranks highly as a reason to leave a job (34.4%). However, the latter response may be hypothetical considering that 78% of respondents say they have not experienced discrimination in their current job. Surprisingly, 41% of all respondents say that restructuring or the threat of a restructure has no impact on feelings about work. Per-haps this is because, of the 59.7% of you who have been through a merger, acquisition, downsizing or restruc-turing, 42% saw no significant effect and 39.8% saw only a change in job responsibilities. Therefore, just 18.2% left jobs voluntarily or otherwise.

The future is brightIn conclusion, respondents want to be paid more in better jobs with more benefits, while enjoying a re-duced workload and suffering from less stress—no real surprises there. Looking forward to 2012, a very positive 50.9% of respondents think that their company’s business will improve in 2012 (only 17.9% expect a decline). As for the general outlook of the bio/pharmaceutical industry, once again, the results are positive with 72.6% predicting that business will improve. However, 24.2% believe growth will only occur overseas in 2012. Only 11.3% expect no signifi-cant change, leaving 16.1% of respon-dents lying awake at night worrying about decline.

As bot t les a re u ncorked a nd glasses raised on December 31, toasts should be made to a prosperous, healthy and bright 2012.

When asked what effect gender had on

determining or limiting respondents’

professional advancement at their current place

of employment, 85.9% agreed that gender

was not a factor. However, break that figure

down for male and female respondents and a

different story is told. Whereas 91.6% of men

said it was not a factor (67% agreeing strongly),

the percentage drops substantially to 72.5% for

women (only 35% strongly agreeing).

Median salaries of respondents are lower for

women at $93,300 than men ($109,600), despite

male and female respondents being of a similar

average age (44.9 years old for men, 43.7 for

women). However, this could be a reflection of

the number of years’ experience in the industry

(on average 20 for men and 17.7 for women),

or educational background: 24.9% of men

have a doctorate versus only 15.4% of women.

Additionally, 60.8% of women disagree that

there is opportunity for advancement in their

current position. The only sign of reparation

is that 61.3% of women experienced salary

increases in 2011 compared with 58.6% of men.

Unequal opportunity

The law of averages exerts full force in most surveys,

but respondents from emerging nations bucked the

trends in the 2011 Employment Survey. Although

they represented a small number of respondents,

19 from India and 3 from Asian countries other

than China, Japan or India (“Other Asia”), their

demographics were sufficiently different from the

rest of the respondents to warrant a mention. For

example, 55.6% of this population work in a generic-

drug firm compared with only 13.9% of all survey

respondents. Respondents in

India or “Other Asia” are on

average younger at 30.8 (44.7

was the median age for all

respondents), consequently less

experienced (at 7.5 years in the

industry, compared with 19.2

years for respondents overall),

but with a more homogenous

academic background—94.7%

of Indian or “Other Asian”

respondents have a master’s

degree and the remaining 5.3%

have a doctorate (see Figure 5).

Other telling figures are that

none of these respondents

left work involuntarily in

2011, nor did they witness a

salary decrease, with a high

76.5% receiving increased pay.

85.7% of respondents from

India feel secure in their role

compared with only 64.3% of all

respondents. Indicators of job

satisfaction do follow the global

trends though, and despite

the positivity, more than 70%

of respondents from India or

“Other Asia” say they are likely

to leave their jobs voluntarily in

the coming year.

Emerging economies

Median age of respondents

45.0%

All respondents

India/other Asia

40.0%

35.0%

30.0%

25.0%

20.0%

15.0%

10.0%

5.0%

20-2

5

26-3

0

31-3

5

36-4

0

41-4

5

46-5

0

51-5

5

56-6

0

61-6

5

over 6

5

0.0%

Education of respondents

100.0%

All respondents

India/other Asia

90.0%

80.0%

70.0%

60.0%

50.0%

40.0%

30.0%

20.0%

10.0%

0.0%

Associates Bachelors Masters Doctorate

Figure 5: Median age (top panel) and highest degree

attained (bottom panel) by all survey respondents (blue)

compared with those from India and ”Other Asia” (red).


The year 2011 was another year of tran-sition for fine-chemical producers and contract manufacturers of APIs and intermediates. As the pharmaceutical industry as a whole deals with slowing growth, increased generic-drug incur-sion, reduced R&D productivity, and the financing pinch for smaller and emerging bio/pharmaceutical companies, so do its suppliers. Expansion activity among fine-chemical producers and contract API manufacturers was limited although cer-tain areas, such as high-potency manu-facturing, continue to attract investment as do biopharmaceutical manufacturing and related services.

Expansion activityOne of the noteworthy expansions in 2011 was the opening of Almac’s new North American headquarters in Soud-erton, Pennsylvania, in May 2011. The completion of the two-year construction project and $120-million investment provides the company with parallel ser-vice offerings in the United States and in Europe through the company’s Craiga-von, Northern Ireland, site. The new 240,000-ft2 North American headquar-ters houses more than 800 employees.

The new Souderton site integrates the company’s clinical technologies and clinical services activities into one location after being housed in separate locations in Audubon and Yardley, Pennsylvania. Almac consists of five major units: Almac Clinical Services, Almac Clinical Technologies, Almac Sciences, Almac Pharma Sciences, and Almac Diagnostics. Almac Clini-cal Services provides clinical-supply services, such as comparator sourc- IM

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Expansion activity was limited as fine-chemical producers and CMOs of API and intermediates grapple with changing industry fundamentals.

Contract API Manufacturing: The Year in ReviewPatricia Van Arnum

Pharma Ingredients: APIs & Excipients

Patricia Van Arnum

is a senior editor at

Pharmaceutical Technology,

485 Route One South,

Bldg F, First Floor,

Iselin, NJ 08830

tel. 732.346.3072,

[email protected].

ing, blinding and overencapsulation, packaging and labeling of clinical-trial supplies, and distribution and depot activities. Clinical Technologies provides interactive voice and web-response systems and other similar support services. Almac Sciences pro-vides custom-synthesis services and technology. Key functions include: API development and manufacturing, biocatalysis screening and selection, route selection, process development, solid-state chemistry services, and de-velopment and manufacture of custom peptides, oligonucletides, and proteins. Almac Pharma Services provides phar-maceutical development and drug-product manufacture for all phases of clinical trial supply (Phases 0–IV) and commercialization. Almac Diagnos-tics provides biomarkers for discovery and validation, bioinformatics, and genomic services.

In October 2011, Almac announced that it is expanding its manufactur-ing capacity to over 30 m3 at its Euro-pean headquarters in Craigavon. The upgraded facility will include reactor vessels, cleanroom product isolation, and drying equipment for highly po-tent API manufacturing up to 600-kg batch sizes. The company expects the facility to be built, commissioned and validated within the next two years. The company also is expanding its pharmaceutical development services capabilities with a new non-GMP formulation-development facility for the development and scale-up of solid oral dose products, including for high-potency compounds.

In 2011, other companies reported expansions in high-potency manufac-turing. Piramal Healthcare announced that it is performing commercial-scale antibody–drug conjugate (ADC) man-ufacturing at its Grangemouth, Scot-land, facility. The company is currently evaluating plans to build out additional manufacturing suites to accommodate kilogram batch sizes. Several ADC-based therapies are in late-phase clini-cal trials, approximately one dozen are in Phase I development, and more than 20 are in preclinical development. Earlier this year, Piramal opened a new $400,000-quality-control laboratory

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suite at its facilities in Grangemouth to support its ADC portfolio.

Sigma-Aldrich’s custom manu-facturing and services business unit, SAFC, recently completed an assess-ment by SafeBridge Consultants and has been granted SafeBridge cer-tification for its commercial-scale high-potency API facility in Verona, Wisconsin. Constructed at a cost of $30 million and officially opened in April 2010, the Verona site was built specifically to support manufacturing for Phase III and commercial scales up to Category IV compounds. The SafeBridge assessment also included a successful recertification of SAFC’s nearby Madison, Wisconsin, high-potency facility.

Also in 2010, SAFC completed an expansion of its Jerusalem, Israel facil-ity, which increased SAFC’s contract manufacturing capabilities in large-molecule recombinant proteins and small-molecule APIs through fermen-tation, including high-potent APIs and secondary metabolites. The expansion focused on niche fermentation of APIs and bulk drugs, secondary metabolites, cytotoxins, and large-molecule proteins.

In October 2011, Saltigo reported that it will build new production capacities for potent APIs at its facility in Red-mond, Washington. The company will expand its production to produce and handle Category III substances. Capac-ity up to the kilogram range will be-

come available at the beginning of 2012.Aescia recently invested in a new

high-containment facility in Queen-borough, United Kingdom. Separately, the company also purchased three manufacturing sites in Germany and Italy from the biopharmaceutical com-pany UCB as announced in late 2010. Aesica acquired sites in Monheim and Zwickau, Germany, as well as UCB’s Pianezza, Italy site.

In September 2011, Alphora com-pleted the expansion of a cytotoxics R&D laboratory as part of an ongoing $4-million capital program for 2011. The 2011 capital program also includes other additions to R&D, GMP operations, ana-lytical services and staffing. The new labo-ratory is designed to handle high-potency APIs and Class IV compounds. Other parts of the capital plan include the con-struction of a fourth cGMP kilo laboratory, a 10,000-ft2 GMP warehouse, and a new enterprise resource planning system, all of which are expected to be completed in the fourth quarter of this year. Expansion of a second pilot plant is planned for 2012.

Lonza is investing CHF 24 million ($26.2 million) to expand cytotoxic manufacturing capabilities at its fine-chemicals facilities in Visp, Switzer-land. The investment will add multi-kilogram-scale cytotoxic capacity for clinical and commercial production. Lonza currently operates high potency GMP laboratory suites on a gram scale. The expansion is expected to be com-pleted in the second quarter of 2012.

Lonza also is investing CHF 10 mil-lion ($10.9 million) to expand its bio-pharmaceutical development services platform in Singapore. The expansion includes the addition of 1858 m2 of laboratory space and associated equip-ment and will support cell-line con-struction, upstream and downstream process development, and analytical services. The facility is expected to come on line in the first half of 2012.

I n M a r c h 2 011, L o n z a a n -nounced it was investing £16 million ($25.3 million) to further develop the flexibility and capability of its Slough, UK biopharmaceutical manufacturing facility with the construction of a new 60,000-ft2 building adjacent to existing buildings to create a Slough campus. The investment includes a new fermen-tation suite, new purification suites, new process-development laboratories, and a new GMP warehouse. The proj-ect is scheduled for completion by the end of 2012.

In May 2011, Lonza announced an

Outlook for global contract pharmaceutical manufacturing, research, and packaging

As 2011 comes to an end, some analysts point to overall positive fundamentals

for contract pharmaceutical manufacturing and packaging. An increasingly cost-

competitive environment, precipitated in part by greater generic-drug incursion

and reduced drug R&D productivity, are some of the factors driving market

growth, according to a recent analysis by BCC Research.

Global pharmaceutical contracting revenues totaled nearly $218 billion in 2011 and

are expected to reach nearly $361 billion in 2016, representing a compound annual

growth rate (CAGR) of 10.6%, according to BCC Research. BCC segments the global

market for pharmaceutical contracting into four segments: contract manufacture of

over-the-counter (OTC) drugs and nutraceuticals, contract manufacture of bulk and

dosage-form drugs, contract research, and contract packaging.

The OTC drug and nutraceutical segment accounted for nearly $128 billion in

2011 and is expected to grow at a CAGR of 10.9% to reach nearly $215 billion in

2016, according to BCC. The bulk and dosage-form drug segment was valued

at $53.4 billion in 2011 and is expected to increase at a CAGR of 10.1% to reach

$86.3 billion in 2016.The contract research segment was estimated at

$30.2 billion in 2011 and is expected to increase at a CAGR of 10.8% to reach

$50.5 billion in 2016 . The contract packaging segment, which was valued at

$6.4 billion in 2011, is expected to increase to $9.3 billion in 2016, representing a

CAGR of 7.8%, according to BCC.

The rise in contract activities is occurring as growth in the global generic-drug

market inceases and cost compettition rises. The global generic-drug market was

estimated at $225 billion in 2011 with a CAGR of 9.7% projected through 2016

when the market will reach $358 billion. The combined markets in the United

States and Canada were valued at $73 billion in 2011, are increasing at a CAGR of

7.9%, and are projected to reach $107 billion by 2016. The combined generic-drug

market in France, Germany, Italy, Spain, and the United Kingdom was $42 billion

in 2011 and is expected to increase at a CAGR of 8.4% to reach $63 billion in 2016.


High-potency

manufacturing

continues to be

an active area of

investment.


expansion of its viral-based therapeu-tics business with the construction of a new, cGMP cleanroom located ad-jacent to its existing Houston, Texas, operations. The expansion provides for large-scale capacity to support late-stage viral vaccine and gene ther-apy projects. Lonza announced enter-ing the viral manufacturing business through the acquisition of Vivante GMP Solutions in August 2010.

Other firms are making select invest-ments. Hikal has started construction of a new, multipurpose, multiproduct API manufacturing facility, which is sched-uled to be operational by June 2012. The plant will consist of two parallel streams and will accommodate 32 reactors with capacities ranging from 6 m3 to 10 m3 for a total reactor volume of approxi-mately 300 m3 . The custom manufac-turing arm of Dr. Reddy’s Laboratories expanded its Chirotech Technology Center at Cambridge Science Park, UK. In April 2011, the company opened a new 33,000-ft2

facility for laboratories

and offices. The facility will support the company’s capabilities in biocatalysis and chemocatalysis, activated mPEGs, and peptides.

A changing landscapeThis year also saw some merger and acquisition (M&A) activity, primarily bolt-on acquisitions by select provid-ers, some acquisitions by private-eq-uity investors, reorganizations by other companies, and the emergence of new names in contract biopharmaceutical manufacturing.

Evonik Industries reorganized by combining its business in custom manufacturing of APIs (exclusive syn-thesis), pharmaceutical amino acids (the Rexim product line), and pharma-ceutical polymers in a new healthcare business line, effective Sept. 1, 2011. The newly formed business line is part of the Health and Nutrition Busi-ness Unit. Earlier this year, Evonik increased its capacity by 50% to make pharmaceutical-grade glycine at its plant in Nanning, China.

Earlier this year, Johnson Mat-they completed the integration of the

biocatalyst offerings from X-Zyme, which the company acquired in July 2010. Johnson Matthey expanded the biocatalyst offerings into product and service offerings into its catalysis and chiral technologies business. The port-folio from X-Zyme includes enzymatic catalysts for scalable production of highly pure chiral amines and alcohols. The biocatalysts and related technol-ogy complement the chemocatalytic technology and related expertise of Johnson Matthey.

Granules India, a pharmaceuti-cal manufacturer, and Ajinomoto OmniChem, a producer of f ine chemicals, formed a joint-venture, Granules–OmniChem, to provide APIs and intermediates. Granules OmniChem is constructing a new facility in Vishakhapatnam (Vizag), Andhra Pradesh, India. The construc-tion of the facility was scheduled to begin by November 2011 and is ex-pected to be completed by late 2012 with production beginning by Janu-ary 2013. The company will initially focus on high-value, low-volume APIs and intermediates for existing custom-ers and will custom manufacture new chemical entities in the future.

CABB, a f ine- and specia lt y- chemicals company, acquired the fine-chemicals company KemFine Group Oy through its Swiss subsidiary, for an undisclosed sum. In October 2011, Bar-clays Private Equity agreed to acquire CU Chemie Uetikon , a fine-chemical producer based in Lahr, Germany.

Carbogen Amcis restructured its Swiss operations in Bubendorf, Aarau, and Hunzenschwil. Under the restruc-turing plan, the Aarau site will focus more strongly on development and the Hunzenschwil site on the pilot production of early-phase projects. Large-volume production and the

manufacturing of highly active agents will continue at the Bubendorf site. The company planned to reduce head-count by 60 employees.

On the biopharmaceutical front, earlier this year, Genzyme completed the sale of its pharmaceutical interme-diates business to International Chemi-cal Investors Group (ICIG). ICIG purchased substantially all of the phar-maceutical intermediates business, ex-cluding the drug-delivery technologies portion. The acquired business was renamed Corden Pharma Switzerland and operates as part of ICIG’s pharma-ceutical business within the Corden Pharma group platform of companies. In September 2011, ICIG also acquired the former Boulder, Colorado, opera-tions of Roche, which manufactures APIs, peptides, and small molecules. The operations are now named Corden Pharma Colorado.

Fujifilm Diosynth Biotechnologies, the former Merck Biomanufacturing Network, began operations under its new name following the completion of the acquisition of the Merck Bio-manufacturing Network by Fujifilm in April 2011. Fujifilm Diosynth Biotech-nologies provides contract biologics development and manufacturing ser-vices. The acquisition included facili-ties in Research Triangle Park, North Carolina, and Billingham, UK, manu-facturing contracts, business-support operations, and a workforce.

In June 2011, Fujifilm and Mitsubi-shi formed a partnership for contract manufacturing for biopharmaceuticals. Under the partnership, the companies signed an agreement to transfer the ownership of 20% equity interests in Fujifilm’s wholly owned biopharmaceu-tical contract manufacturing subsidiar-ies, Fujifilm Diosynth Biotechnologies U.S.A. and Fujifilm Diosynth Biotech-nologies UK to Mitsubishi.

Also, in 2011, Johnson & Johnson acquired the biopharmaceutical and biomanufacturing firm, Crucell. Fol-lowing the acquisition, Crucell oper-ates as the center for vaccines within the Johnson & Johnson pharmaceuti-cals group. PT


Several new

players entered the

market for contract

biomanufacturing.


The authors developed a metronidazole-based

floating drug-delivery system to investigate the

effect of rate-controlling polymers on release

pattern and duration of buoyancy in matrix

tablets. Sustained-release floating tablets were

formulated systematically using cellulose ether,

hydroxypropylcellulose, and carbomer 934P

according to a 32 full factorial design.

Shamsuddin Sultan Khan* is a research associate, and

Mesbah Uddin Talukder is an assistant professor of

pharmacy, both at the University of Asia Pacific, House-

73, Rd. 5A, Dhanmondi R/A, Dhaka-1209, Bangladesh,

[email protected].

*To whom all correspondence should be addressed.

Submitted: Aug. 16, 2011. Accepted: Oct. 11, 2011.

Sustained Release

Sustained-release dosage forms enable prolonged action of a drug in the body. Much research has focused on overcoming the short residence times and unpredict-able gastric emptying times of drugs in sustained-release

oral drug-delivery systems (1). A floating drug-delivery system floats in the gastric juice without affecting the gastric empty-ing rate. It forms a cohesive gel barrier that serves as a reservoir and releases the drug over the desired period of time. This technique helps increase a drug’s gastric residence time and reduces the variability in bioavailability (2, 3).

Metronidazole is used as an antibiotic, amebicide, and antiprotozoal, and as a gel preparation for dermatological conditions (4–8). The drug has a wide therapeutic index for sustained-release administration (5). For example, a sustained-release oral dosage form of metronidazole is an effective anti-biotic because it is locally active in the gastric mucosa (9). The prolonged effect of locally active metronidazole increases its clinical efficacy at eradicating Helicobacter pylori (10). Oral, sustained-release metronidazole has several advantages for treating H. pylori locally through systemic absorption (11).

Metronidazole was chosen as a model drug to develop a sustained-release floating matrix tablet because it has a half life of 6–8 h. Methocel K15M CR (hydroxypropyl methylcel-lulose, Dow Chemical) is beneficial in controlling drug re-lease in a floating formulation, but Carbomer 934P (carboxy polymethylene–prop-2-enoic acid, ChemIndustry) enables more floating time than Methocel K15M CR and hydroxy-propyl cellulose (HPC) (12).

MaterialsMetronidazole BP was obtained from Aarti Drugs. Methocel K15M CR with a molecular weight of 10–1,500 kDa, HPC, and Carbomer 934P were obtained from Eskayef Pharma-ceuticals. ChemIndustry provided 1-ethenylpyrrolidin-2-one (povidone). Sodium bicarbonate, citric acid, lactose, and magnesium stearate were provided by Wiechers and Helm.

MethodsPreparation of standard curve. A standard curve of metronida-zole hydrochloride was constructed by serially diluting an

The Development of a Floating Drug-Delivery System for MetronidazoleShamsuddin Sultan Khan and Mesbah Uddin Talukder

cO

lO

Rc

On


Sustained Release

aqueous solution of the drug to obtain the concentration in the range of 1–20 µg/mL using simulated gastric fluid with-out enzymes and phosphate buffer as the diluents. The spec-trophotometric analysis was performed using a Shimadzu spectrophotometer at the absorbance of 278 nm against a blank for each solution. The measured absorbance, plotted against the respective concentration of the standard solu-tions, appeared as a straight line.

Preparation of tablets. Metronidazole tablets were prepared using rate-controlling polymers and other gas-generating ex-cipients. Each formulation contained 400 mg of metronida-zole, 100 mg of sodium bicarbonate as a gas-generating agent, 30 mg of citric acid, 70 mg of povidone, and 160 mg of lactose.

Polymers and excipients with various concentrations (see Table I) were mixed together by pestle carefully for 20 min. Next, 1.5% (w/w) of magnesium stearate was rubbed with the punch and die as lubricant. Each tablet was 50% (w/w) metronidazole powder. Tablets were prepared by direct compression using a 13-mm die and flat-faced punch (KBR Press). Sufficient compression load was applied to produce tablets with a hardness of 6–17 kg.

A 32 randomized full-factorial design was used to design the formulations. Three factors were evaluated in this study at three levels and tested in nine possible formulations. The amounts of polymers were determined as independent vari-ables, and percentage release as a dependent variable.

Physical testing of the tablet. The tablets’ thickness and di-ameter were measured with digital vernier calipers. Tablet hardness was determined at room temperature by diamet-ric compression using a hardness tester (Veego Scientific Devices). The percentage friability of the tablets was deter-mined using a tablet-friability apparatus (Veego Scientific Devices) operated at 25 rpm for 4 min. Tablets were weighed accurately, placed in the chamber and, rotated for 4 minutes (100 rotations). At the end of the run, the dust on the tab-let was removed carefully, tablets were weighed accurately again, and the percent friability (f) was computed from the weight of the tablets before and after the test according to the following equation:

w

f = (1− –––) × 100 [Eq. 1]

w0

where Wo and W are the weights of tablets before and after

the test, respectively.The bulk density of the powder, normally expressed as g/mL,

was determined by dividing the weight of the powder by the volume it occupies. Tap density was determined by subjecting the powder in a graduated cylinder to 500 taps by the stan-dardized US Pharmacopiea II tapping procedure (with VTAP MATIC-II, Veego) and using following equation:

mass of powder

tapped density = –––––––––––––––––– [Eq. 2]

tapped volume

The Hausner’s ratio was determined as the ratio of the initial bulk volume to the tapped volume. The Carr’s index was calculated using bulk and tapped densities data through the following equation:

tapped density − bulk density

Carr’s index = ––––––––––––––––––––––––––––––––– × 100% [Eq. 3]

tapped density

Buoyancy of the tablet and floating properties. The tablets were placed in 900 mL of 0.1 N mol L−1 HCl solution, and floating properties were determined using USP dissolution test apparatus II (Electrolab and Veego) at 50 rpm and 37 ± 0.5 ∘C. The time required for the tablet to rise to the surface and float was taken as the floating lag time. The in vitro buoyancy was determined according to floating lag time and duration of floating viscosity.

Water uptake. Water uptake was determined in an acid medium of 0.1 N HCl (pH 1.2) and water at 37 ± 0.5 ∘C. The percentage of water uptake was calculated according to the following equation:

w

t−w0Water uptake (%) = ––––––––– [Eq. 4]

w

0

in which wt is the weight of the swollen tablet at time t, and w

o

is the initial weight of the tablet. The saturation time was ob-tained by determining the point at which no more water was taken up (i.e., 20–30 s). The swelling of the polymer depends

Table I: Properties of tablets containing Methocel K15M CR, hydroxypropyl cellulose (HPC), and Carbomer 934P in a metronidazole-based tablet formulation. Tablet

formulation

Methocel

K15M CR (mg) HPC (mg)

Carbomer 934P

(mg) Lactose (mg)

Buoyancy or floating

lag time (min)

Total floating

time (h)

Water

uptake (%)

F1 40 – – 160 5 4.20 6.33423

F2 60 – – 140 5 3.00 10.7366

F3 80 – – 120 5 1.38 17.6396

F4 – 40 – 160 none – 1.50376

F5 – 60 – 140 none – 4.01003

F6 – 80 – 120 none – 1.00376

F7 – – 40 160 5 7 6.53595

F8 – – 60 140 5 8 11.9326

F9 – – 80 120 5 8 6.17128


on the rate of water penetration into the tablet. The water-penetration measure-ment was primarily used to evaluate polymer-penetration interactions that enable the tablet to dissolve (3).

In vitro drug-release studies. The in vitro release studies of metronidazole tablets were conducted using USP dissolution apparatus II (Electrolab and Veego). The dissolution testing was performed using 900 mL of 0.1 N HCL at 50 rpm and 37 ± 0.5 ∘C. A sample of the solu-tion was withdrawn from the dissolu-tion-testing apparatus every hour for 8 h, and the samples were replaced with fresh dissolution medium. The samples were diluted with 0.1 N HCl 55 times. Absorbance of these solutions was mea-sured at 278 nm using a Shimadzu spectrophotometer.

Kinetic study. The in vitro release mechanism of drug from floating tablets was determined on the basis of theoretical dissolution evaluations including zero order, first order, Hi-guchi kinetic model and Korsmeyer–Peppas kinetic model with goodness-of-fit test.

Statistical analysis. Analysis of variance was applied to F1 through F9 to see whether release characteristics differed significantly (p • 0.05) because of variation in polymer con-centrations. Results showed that polymer-based formula-tions had significantly different release characteristics.

Results and discussionThe weight, diameter, and thickness ranges are shown in Table II. Tablet hardness increased in direct proportion to the amount of pressure applied and in indirect proportion to the concentration of polymers. Hardness also varied accord-ing to the type of polymers included. The percent friability was less than 0.5%. The data obtained are shown in Table II.

The bulk density of the granules was between 0.322 and 0.788 g/cm3, indicating their good packing capacity. The tapped density of the granules was between 0.375 and 0.866 g/cm3,

showing good flow characteristics. The Carr’s index, Hausner’s ratio, and angle of repose of the granules were within range, thus indicating good flowability. Results are shown in Table III.

The 80-mg tablet formulations containing Methocel K15M CR showed significant water penetration (i.e., 17%) that en-abled the tablet to dissolve, whereas formulations containing HPC showed only 1–4% water penetration. The metronida-zole formulation containing Methocel K15M CR and Car-bomer 934P had a floating lag time of less than 300 s. Formu-lations using HPC had no buoyancy after 8 h. Formulations containing Methocel K15M CR had floating time of 4 h, and Carbomer 934P had a floating time of 8 h (see Table I).

Tablets’ f loating capacity depends on the density of the system, the quantity of the gas-generating agents (i.e., NaHCO

3 and citric acid), and the concentration of polymers.

Table I shows the floating lag time of the tablets. The tablets formulated with Methocel K15M CR and Carbomer 934P became buoyant after 5 min of contact with the dissolution medium, but the HPC-containing tablets did not show any buoyancy after 8 h.

The in vitro drug release was best described by the Higuchi kinetic model, and its highest linearity was R2 = 0.903. These results confirmed that the drugs were released by a combina-tion of diffusion and erosion (see Table IV).

Table III: Flow properties of granules.Tablet formulation Compressibility index (%) Hausner ratio Angle of repose (∘)

F1 20.000 1.250 39.8

F2 22.223 1.286 39.8

F3 9.107 1.100 39.8

F4 50.000 2.000 39.8

F5 28.578 1.400 37.56

F6 12.499 1.143 39.8

F7 20.000 1.250 37.56

F8 16.667 1.200 35.53

F9 6.248 1.067 35.53

Table II: Physical characteristics of the metronidazole tablet.Tablet formulation Average weight (mg) Average diameter (mm) Average thickness (mm) Hardness (kg) Friability (%)

F1 788.2 ± 0.0647 13.146 ± 1.3886 4.201 ± 0.0716 13.6 0.2454

F2 800.6 ± 1.3876 13.111 ± 1.5801 4.232 ± 0.0716 10.0 0.1245

F3 793.2 ± 1.5793 13.122 ± 1.6620 4.234 ± 1.3886 9.10 0.1256

F4 801.8 ± 1.6603 13.122 ± 1.6531 4.280 ± 1.5801 11.6 0.3736

F5 799.2 ± 1.6688 13.122 ± 1.6602 4.288 ± 1.6621 8.0 0.3764

F6 791.6 ± 1.6180 13.104 ± 1.6101 4.310 ± 1.6661 6.60 0.5121

F7 770.8 ± 1.4998 13.096 ± 1.4945 4.152 ± 1.6141 13.6 0.1312

F8 774.6 ± 1.3262 13.102 ± 1.3289 4.118 ± 1.4954 13.2 0.1265

F9 781.2 ± 1.0585 13.098 ± 1.0638 4.148 ± 1.3314 17.0 0.0


Sustained Release

The floating behavior and percentage release of the metronidazole tablets also were investigated. F1 tablets had a total f loating time of 4.20 h. F7 tablets had a f loating time of 7 h, and F8 and F9 tablets had a floating time of 8 h. This difference may occur because NaHCO

3

forms gas quickly and citric acid reduces the density of the tablet (i.e., < 1 g/cm3). On the other hand, F4, F5, and F6 tab-lets had no floating ability, perhaps be-cause the system’s density was greater than 1 g/cm3. In addition, HPC may re-tard the release of carbon-dioxide gas to the system. The buoyancy of the tablets formulated with Carbomer 934P lasted for 8 h because this light and porous material helped produce a low-density

system. In vitro drug-release profiles present the cumulative percent release of drug against time (see Figures 1–3). F1 tab-lets released about 70–93% drug. All other tablets had released about 71% drug after 8 h. No drug–drug or drug–excipient interactions were found, hence 100% release of metronidazole may be achieved with further experiments.

All sustained-release formulations have rate-controlling mechanisms, such as swelling, diffusion, and erosion (13). The Higuchi kinetic model best described the drug release from these tablets, which depended on the concentration of polymers. F1 tablets, which contained only 40 mg of Metho-cel K15M CR, had the highest release of drug (i.e., 93.69%). Buoyancy in F1 tablets lasted 4.20 h and was decreased by in-creasing the amount of Methocel K15M CR. Also, the release of drug increased at first, then gradually decreased with time by the diffusion mechanism. F7, F8, and F9 tablets formulated with Carbomer 934P released approximately 71% of the drug. These conditions might have caused rapid hydration of Car-bomer matrices, gel formation, swelling, and diffusion, which increased the release duration of metronidazole.

F2 and F3 tablets released the drug rapidly (i.e., 1 and 2 h, respectively). A possible reason is that Methocel K15M CR increases the surface area to expose the deposited drug to the dissolution medium. The drug-release profile is important in describing bioavailability and in optimizing controlled release. The release of metronidazole from the tablets was based on non-Fickian diffusion and the concentration of the rate-controlling polymers (14). Asnaashari et al. showed that a high amount of rate-controlling polymer provided sufficient floating ability and release in formulations with two or more polymers (15). The au-thors’ experimental results showed that drug release was almost 93.69% using 40 mg of Methocel K15M CR and 70% using Car-bomer 934P. Buoyancy of F1 and F9 tablets lasted 4.20 h and 8 h, respectively, with no combinations of polymers.

ConclusionThese results, in combination with those of previously pub-

Table IV: Kinetic and statistical parameters obtained from drug-release data of metronidazole floating tablets and release profiles.

Formulation Zero-order

Higuchi kinetic

release model Best fitted

modelRelease mechanism

R2 K0

R2 Kh

F1 0.411 2.616 0.853 32.32 Higuchi model Diffusion and erosion


F3 0.475 2 0.903 24.71 Higuchi model Diffusion and erosion







Figure 1: In vitro drug-release profiles of F1, F4, and F7 drug

formulations.


formulations.

0

10

20

30

40

50

60

70

80

90

100

0 0.5 1 1.5 2 2.5 3

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g r

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(%

)

Square root of time (h)

F1

F4

F7

0

10

20

30

40

50

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70

80

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lished reports, justify the use of rate-controlling polymers such as Methocel K15M CR, HPC, and Carbomer 934P to develop metronidazole floating-matrix tablets. The results suggest that a metronidazole-based floating drug-delivery system using a low amount of polymers could reduce the cost of pharmaceutical production and the likelihood of ad-verse effects. Such a formulation may maintain the specific plasma concentration and local action against H. pylori for

peptic ulcer disease, and further studies could improve the formulation’s clinical efficiency.

References 1. A.A. Deshpande et al., Pharm. Res. 14 (6), 815–819 (1997). 2. F. Stops et al., Int. J. Pharm. 308 (1–2), 8–13 (2006). 3. F. Stops et al., Int. J. Pharm. 308 (1–2), 14–24 (2006). 4. S.C. Sweetman, “Biowaiver Monographs for Immediate Release

Solid Oral Dosage Forms: Metronidazole,” in The Complete Drug Reference, C.F. Rediguieri et al., Eds. (Pharmaceutical Press, Lon-don, 36th ed., 2009), pp. 837–841.

5. J.S. Simms-Cendan, J. Infect. Dis. 3 (5), 153–156 (1996). 6. J.W. Tracy and L.T. Webster, Jr., “Drugs Used in the Chemo-

therapy of Protozoal Infections,” in The Pharmacological Basis of Therapeutics, J.G. Hardman, L.E. Limbird, and A.G. Gilman, Eds. (McGraw-Hill, New York, 10th ed., 2001), pp. 1105–1109.

7. K.C. Lamp et al., Clin. Pharmacokinet. 36 (5), 353–373 (1999). 8. E.D. Ralph et al., Antimicrob. Agents Chemother. 6 (6), 691–696

(1974). 9. B.N. Singh and K.H. Kim, J. Control Release 63 (3), 235–259

(2000). 10. S. Burton et al., J. Pharm. Pharmacol. 47 (11), 901–906 (1995). 11. V. Alvisi et al., Drugs Exp. Clin. Res. 22 (1), 29–33 (1996). 12. M. Rahman et al., J. Pharmaceutics Cosmetol. 1 (2), 81–92 (2011). 13. M.D. Chavanpatil et al., Int. J. Pharm. 316 (1–2), 86–92 (2006). 14. T. Higuchi, J. Pharm. Sci. 52 (12), 1145–1149 (1963). 15. S. Asnaashari et al., Pharm. Dev. Technol. 16 (4), 1–8 (2010). PT

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This case study on packaging line GMP

optimization is the sixth 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/

pharmaceutical 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 Evalua-

tion 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

Packaging represents a critical manufacturing opera-tion requiring strong GMPs and quality oversight to ensure sustained and robust compliance. Historically, inadequate packaging practices have been a meaning-

ful ongoing contributor to product recall actions industry-wide. A strong understanding of the compliance risks asso-ciated with product packaging is a necessary and important component of a good quality system.

This case study on packaging line GMP optimization is the sixth of eight in a series put together by the Product Quality Research Institute Manufacturing Technical Com-mittee (PQRI–MTC) risk-management working group. The series is meant to advance the understanding and applica-tion of the International Conference on Harmonization (ICH) Q9 Quality Risk Management guideline by provid-ing actual examples of risk-management assessments used by the bio/pharmaceutical industry.

The introductory article and first case study, on defin-ing design space, appeared in the July 2011 issue of Phar-maceutical Technology (1). Subsequent case studies in the series (8 in total) can be viewed online at PharmTech.com/PQRIstudies.

In this case study, the authoring firm has enjoyed satis-factory compliance performance across their international packaging operations. Nonetheless, recognizing the critical-ity that packaging plays in ongoing quality assurance, the firm engaged in a risk-assessment of a number of established packaging lines at several key packaging sites worldwide. The goal of the assessment was to further enhance the qual-ity assurance of existing packaging operations and practices.

The risk question and risk-assessment methodThe risk question developed for the subject case study is: What processes, procedures, and/or events during the packag-ing of a product create an unacceptable risk, real or perceived, to the quality of that product as received by our customers?

The project team assigned to this initiative sought to find a method that was inductive, systematic, and comprehen-sive, with the understanding that the risk factors for this

Packaging Line GMP OptimizationRisk-Management Case Study (Part 6)Ted Frank, Stephen Brooks, Kristin Murray, Steve Reich,

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


application were generally well de-fined and quantitative. The risk tool selected to perform the analysis was: functional failures and effects analysis (FFEA). This tool represents a hybrid of failure modes and effects analysis, or FMEA, and uses a risk matrix instead of a risk priority number (RPN). FFEA is a systematic, function-based method for examining the effects of functional failures on system performance.

In this case study, a team of subject-matter experts conducted the analysis by identifying and assessing the ef-fects on a system associated with in-dividual functional failures. To apply risk-based, decision-making concepts to the FFEA, the team also identified the frequency of each functional fail-ure and the severity of the potential effect (outcome) and compared each to predetermined risk-acceptance criteria. The team suggested corrective actions when required by the risk-acceptance criteria or when the team identified oppor-tunities for improvement.

The risk analysisThe assessment effort required that potential product de-fects from any given packaging operation be defined and graded for severity, frequency, and on the ability of the op-eration and/or an operator to detect the defect. Tables I and II summarize the definitions and categories applied for se-verity and frequency. Defect detection was categorized and graded on a 0-to-4 scale to reflect a detection capability of “none” (unable to detect) to “always” detect.

A team of packaging subject-matter experts, and local site packaging engineers familiar with the subject packaging lines under assessment, worked to collect relevant data about the packaging line. All operations involved with the line function (e.g., equipment, procedures) were listed and all corresponding potential failures were then listed. For each potential failure, the team worked to understand its poten-tial impact on packaging operations and then worked to as-sign a severity category. Following severity classification, the team reviewed the dominant causes relevant to the defined potential failure and assigned each a frequency category.

For each potential failure, all safeguards (e.g., detection capabilities) were reviewed and a detection capability was assigned. For determinations of severity, frequency, and detection, all relevant data was taken into consideration, to include maintenance and operation logs, batch records, deviation investigations, customer complaint records, and so forth.

In the FFEA model, the calculated frequency (F) is com-bined with the ability to detect (D) and then plotted against severity (S) as follows:

F- D = F (new) S vs. F (new) [Eq. 1]

The resulting work output from this assessment was re-corded in tabular form. Table III shows an excerpt of the resulting work product.

Using the collected tabular information, a risk matrix was assembled (see Figure 1). In Figure 1, items A through D from Table III are noted to reflect their calculated frequency. The risk matrix helps to visually prioritize the results from the risk analysis. In this case study, item “A” would get im-mediate action to eliminate or reduce the risk. Items “B” and “D” would be evaluated and actions would be taken if practical and appropriate to reduce or eliminate risk. No actions would be required for item “C”.

Risk controlIn this case study, risk is reduced by introducing a struc-tured and standardized approach to understand and deter-mine the potential likelihood of system or operator failures and the probability of any resulting defect impacting the final product and end-user. Potential risks which are above a predefined threshold, taking into account severity and frequency of occurrence (the later of which is modified to account for the probability of on-line detection), are consid-ered for elimination or mitigation.

Table II: Sample frequency categories.Frequency Scoring Scale

Remote Very Frequent

Score = 0 1 2 3 4 5 6 7 8

Description

1 event every

1,000 years

1 event every

10 years

10 events

every year

1,000 events

every year

1 event every

100 years

1 event per

year

100 events

per year

10,000 events

every year

Table I: Sample severity categories.Categories Novice

1 Effect is not noticeable

No quality impact; production or financial impact would be insignificant

2 Minor effect

No impact of license or new drug application (NDA); possible quality problem (e.g., scuff

label) and possible production problems (e.g., excessive rejects)

3 Moderate effect

Quality concern (e.g., exceed internal metrics, customer complaint); impacts production

for short period of time (e.g., days)

4 Major effect

Quality impact; exceeds license of NDA limits (e.g., miscount, missing label/circular);

impacts production for extended period of time (e.g., a week or longer leading to

extensive equipment downtime and reworking)

5 Critical effect

Quality problem with potential impact to patient safety (e.g., mislabeled product mix) and

may result in a market action and/or significant production problem (e.g., atypical event

which causes a major loss of production and/or potential impact to product supply).


Risk documentation and communicationThe risk analysis for the subject case was reviewed by an oversight committee to confirm findings and support risk-mitigation activities. Learnings from the assessment were shared with the firm’s other operations that used similar packaging equipment and/or packaging practices. In addi-

tion, learnings from the full set of packaging-line risk assess-ments were captured for consideration in future packaging line design and equipment procurement efforts.

Risk reviewAs part of the firm’s auditing activities, the corporate group responsible for periodic site audits received copies of the risk conclusions and action plans to confirm that corrective ac-tions were deployed effectively. The risk-assessment summa-ries were maintained at the local site packaging departments for use in future troubleshooting exercises involving devia-tion investigations or product complaint evaluations. PT

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.

Table III: Resulting work product (sample).

Item

No.

Potential

failure

Dominant causes Severity

category

Frequency Safeguards Safeguard

type and

category

(detection)

Eliminate or

M,tigate riskEvents/Year

initiating event

after safeguards

Frequency

category

A Incorrect expiry

date printed

on-line

Incorrect setup 5 1–10 4 Engineering/

Administrative

Controls

D = 0 Yes

B Overfill Feeder failure (e.g., pin

breaks, dropping excessive

tablets); floor feeder (i.e.,

no precise control); static

and dust buildup in the

filler tubes

4 100–1000 6 Vision system

with reject

verification

Flap detection for

overfill

D = 4 Evaluate

options and

implement

where

appropriate

C Wrong

shrinkwrap

n/a 1 0.01–0.1 2 n/a n/a None

D Cleaning

residue (left

from cleaning

agents)

Cleaning concentration is

high; human error (e.g.,

improper cleaning, rinsing,

and/or inspection)

3 1–10

1–10

4

4

Line cleaning

inspection

(extended time

allocated for

cleaning and

inspecting due

to equipment

design)

D = 0 Evaluate

options and

implement

where

appropriate

Figure 1: Risk matrix.

1 2 3 4 5

Severity Category, S

*F(New) = Freq-Detection Capability

D A

C B

8

7

6

5

4

3

2

1

0

>10,000

10,000

1000

100

10

1

0.1

0.01

0.001

<.001

Fre

qu

en

cy (

eve

nts

pe

r ye

ar)

Mo

difie

d F

req

ue

ncy

Ca

teg

ory, F

(Ne

w)*

Matrix Key

Very low risk; no action warranted

Some risk; action on case-by-case basis

Unacceptable risk; action required

Al

l F

igu

RE

S A

RE

Co

uR

TE

Sy

oF

Th

E A

uT

ho

RS

SS


Inside IPEC–FEdEratIonInSIdE IPEC–FEdEratIon

PharmTech.com/ipec

alittle over 18 months since it was established, the strategy and work programs of the International Phar-

maceutical Excipients Council (IPEC) Federation have started to take shape. The federation’s overall focus is to provide expertise on excipient regulatory and sci-entific issues, to assist in the harmonization of quality standards, and to promote global supply-chain security.

Originally formed with representatives from the four existing IPECs—IPEC-Americas, IPEC–Europe, IPEC–Japan (JPEC), and IPEC–China—the IPEC Fed-eration is set to add IPEC-India to its mem-bership. The federation also has formed partnerships in Latin America through trade associations in Brazil and Argentina and has a partnership with Mexico in the works. The following section summarizes recent progress made by the organization to date.

Monograph harmonizationOne of the federation’s priorities is the global harmonization of excipient mono-graphs. The organization has been working in partnership with the Pharmacopoeial Discussion Group (PDG), which brings to-gether experts from the US, European, and Japanese pharmacopeias. The two groups met in June 2011, and made progress on several fronts, including the inclusion of additives in pharmacopoeia monographs, where additives are typically present in commercially available materials, as well as standardization of methods for measuring

viscosity of cellulosics. An IPEC working group will continue to consult within an industry coalition and plans to run a global workshop on viscosity of cellulosics to de-velop recommendations for discussion with PDG.

Recognizing that additives can be components in excipients is a major step-forward and work is ongoing to compile a comprehensive list of additives and pro-cessing aids that are typically used in the manufacture of excipients. The goal is to collaborate with regulatory authorities, including FDA, to find a way to “grandfa-ther” the permitted inclusion of such com-ponents in specific excipients where their historical and safe use can be demonstrated and justified.

third-party certificationOne of the biggest projects undertaken since the formation of the IPEC Federa-tion in 2010, is to support the third-party excipient-certification program known as EXCIPACT. The program is designed to complement other third-party schemes such as the ANSI-accredited International Pharmaceutical Excipient Auditing (IPEA) program set up by IPEC–Americas. The auditing program provides certification

that an excipient manufacturer meets IPEC–Pharmaceutical Quality Group (PQG) Excipient GMPs. EXCIPACT will provide an equivalent certification for companies who already may be certified to ISO–9001, the international standard for quality-management systems, but that need their certification expanded to cover the additional requirements for excipient GMPs and good distribution practices (GDPs). The latter standards go beyond ISO–9001 to include requirement for con-tamination control, document traceability, cleaning, training, and so forth.

GMP and GDP legislation for excipients has been proposed in both Europe and the United States. As a result, excipient sup-pliers could be faced with an avalanche of quality audits and related requests to en-sure customers and regulators that their facilities and products meet these new requirements. Excipient users will need to find a way to obtain physical audit in-formation on every supplier they use and that cannot be done with available in-house audit resources.

Industry experts from the European Fine Chemicals Group (EFCG), IPEC–Europe, IPEC–Americas, PQG, and the European Association of Chemicals Dis-tributors (FECC) developed the EXCI-PACT certification scheme to provide in-dustry with an alternative means to obtain independent assessment of manufacturers and suppliers of pharmaceutical excipients. Most suppliers are already ISO-certified, meaning that they meet a defined set of GMP and GDP standards. EXCIPACT and IPEA are two pathways that IPEC will be offering to achieve the same level

As the excipient supply chain becomes more complex, industry

must up the ante to comply with new standards and regulations.

Excipient suppliers

could be faced with

an avalanche of

quality audits and

related requests.

Patricia Rafidison is chair of the IPEC

Federation, and the global regulatory affairs and

compliance manager at Dow Corning.

IPEC tackles Monographs, Impurities, Particles, and MorePatricia Rafidison


Inside IPEC–FEdEratIon

of certification as ISO—one for companies that are already ISO-certified and one for companies that are not ISO-certified and want to go through a full certification to excipient GMPs.

IPEC–Japan recently established Self-imposed Standards for Manufacturing Control and Quality Control of Pharma-ceutical Excipients and its Explanation. The English version of these standards will be published in 2011. IPEC–Japan also began a third-party certification sys-tem in 2005.

These programs demonstrate that ex-cipient suppliers, distributors, and the pharmaceutical industry are fully com-mitted to the use of high quality excipients and ensuring their integrity throughout the supply chain. The use of EXCIPACT and the IPEA certification schemes add a significant contribution to ensuring patient safety and supplier quality, while minimiz-ing overall supply-chain costs.

risk assessment and the supply chain Another IPEC Federation priority has been the development of guidance on risk-assessment principles for excipients, along the lines of the recent European Directive on Falsified Medicines, which was issued earlier this year. The aim is to develop a set of guidelines that can be used by users and suppliers of excipients to determine how GMP principles should be applied for a specific excipient. Excipient risks can come from both the intended uses of an excipient as well as the way the excipient is manufac-tured and distributed.

The federation responded quickly to extraordinary events affecting the excipi-ent supply chain around the world in 2011, notably the earthquake and subsequent nuclear incident in Fukushima, Japan, and adulteration of clouding agents with phthalate plasticizers used in pharmaceu-ticals and foods in Taiwan.

When the earthquake occurred in Fu-kushima in the Tohoku district of Japan in March 2011, followed by a large tsunami, the Fukushima Dai-ichi Nuclear Power Station shut down. There were collapsed houses and a cutoff of transportation networks along the Pacific coast of the district. IPEC–Japan investigated the situ-ation promptly and found that there were

few excipient-manufacturing facilities in the area, and therefore, little influence of the radioactive contamination from the nuclear power station. Consequently, the Federation announced that the pharma-ceutical excipients in Japan were safe and provided regular updates to the public and the industry.

Similarly, the IPEC Federation devel-oped a frequently asked questions (FAQs) document to address the Taiwan phthal-ate contamination situation in Taiwan in order to help companies evaluate any risks related to the two contaminants (DEHP and DINP) involved in the Taiwan inci-dent. In the wake of that incident, IPEC has begun to investigate, along with other trade groups, the possibility that packaging may play a role in contamination of drug products and whether migration of certain phthalates into drug products poses any significant safety risks.

Elemental impuritiesOne of the IPEC Federation’s key roles is to provide input from the industry perspec-tive into global regulatory expectations. To that end, the organization has taken a position on the US Pharmacopeia’s (USP) draft General Chapters on elemental impu-rities (<232>, <233>, and <2232>), which in IPEC’s view, call for unrealistic for imple-mentation timeframes (September 2013). USP’s timeline does not give industry enough time to obtain needed data for impurity levels in the majority excipients, which could lead to a regulatory compli-ance issue.

The International Conference on Harmonization’s (ICH) expert working group on elemental impurities (Q3D) is developing draft guidance on this topic that will provide the impurity limits that are likely to supersede those set in current monographs. The federation is gathering information on elemental-impurity levels in multiple excipients through an industry coalition, with the goal of submitting data to ICH. The IPEC Federation is also considering holding a workshop in 2012 (after the working group finalizes the limits) to begin sharing actual test data, which will need to be developed within the excipient industry.

Visible particles in excipientsA primary cause of drug recalls during the past year has been the presence of visible particles in pharmaceutical products, and the IPEC Federation has responded with the formation of a working group to ex-plore the role that excipients can play in this area. The group plans to develop a guide-line on how to measure and properly as-sess the significance of visible particles that can be found in excipients. The guidance will ideally dispel any confusion around the presence of particles in excipients and clarify that it is not possible to achieve zero visible particles in these materials.

nanotechnologyA relatively new area of the federation’s work is an attempt to monitor nanotechnol-ogy developments with respect to their im-pact on excipient monographs, as well as in the context of draft guidance on nanotech-nology published by FDA in June 2011 (1). A major concern for the excipient indus-try is that excipients not developed for their “nano” properties may fall within particle-size range definitions being discussed for “nano” materials and therefore may be re-quired to comply with potential new safety-assessment requirements.

Particularly, the federation is looking to change the particle-size range expan-sion from less than 100 nm to a range of 100 nm to 1 μg. There is a need for global harmonization of these initiatives within US, Europe, and other countries. IPEC has worked with various trade associations to submit comments regarding these issues to FDA in response to their draft guidance.

Overall, the federation’s 2011 work plan is full, but much remains to be done. Many of the initiatives mentioned here will con-tinue into 2012, as will the organization’s member-expansion program.

acknowledgmentThe author would like to thank David S. Schoneker with IPEC–Americas for his contribution to this article.

reference 1. FDA, Guidance for Industry: Considering

Whether an FDA-Regulated Product Involves the Application of Nanotechnology (FDA,

Rockville, MD, June 2011). PT


Insider Solutions

Auditing by the Numbers

In the pharmaceutical industry, the most frequently audited facilities are without a doubt contract organizations. These or-

ganizations are constantly being audited by prospective clients, existing clients, global and domestic regulatory authorities, and their own staffs. They deal with due dili-gence, regulatory quality systems, routine GMP inspections, preapproval inspections, and internal audits on a monthly, if not weekly basis.

Audits can last anywhere from 1 day to 3 weeks depending on the type of audit being performed. In addition to typical audits, such as yearly GMP assessments by clients and regulatory authorities, contract organi-zations can also be tasked with “for-cause” audits by inspectors due to customer com-plaints or product recalls. Clients might also decide to perform a “for-cause” audit if the contract organization manufactured a number of lots with associated investiga-tions for deviations during the manufac-turing process.

To stay ahead of the audit game, contract organizations must have a system for han-dling audits that is efficient, consistent, and flexible. A great deal of experience among the audit team is necessary because the team must be audit ready all the time while also assuring that the company’s other de-partments maintain an audit-ready pos-ture. The group must have the ability to host more than one audit at a time and be able to address questions and provide doc-

uments—in a timely manner—for as many as three auditors per group. The team must also be prepared to provide some of the same information to more than one group at the same time.

Admittedly, handling two separate audit groups with two to three auditors each is an unusual situation. However, let’s say that a contract organization has 14 clients and each client requires an annual GMP audit. To maximize audit time, each client brings two auditors and plans for a 3-day visit. Considering that each audit requires one day of preparation and one day of follow-up activities for the contract organization, each audit ultimately takes up one week of the organization’s time.

Let’s also assume that the contract orga-nization is trying to attract new business. It has five potential new clients that wish to perform a quality audit before entering into a contractual agreement. In addition, let’s assume that the organization provides sterile injectable products (or a similar product) to the global market, placing it in the high-risk category of manufactur-ing. This classification would result in annual GMP audits from, at a minimum, the regulatory agencies of the US, Europe, and Japan. Agencies typically spend 1 to 2 weeks conducting cGMP audits.

Because contract organizations also must perform internal audits, which typically last one week and occur once a quarter, the numbers above equate to ap-proximately 26 weeks or half of a year de-voted to handling and conducting audits. This amount of time does not take into account preparation of responses to any potential audit observations or necessary follow-up activities.

To successfully accommodate all of these audits, a contract organization must maintain a full-time contingent. Organi-

zations must be aware that the time com-mitment entails more than preparing and hosting audit groups. Each audit could easily take 4 to 5 weeks when consider-ing preparation, hosting functions (both escorting and staging room activities), re-sponses, and followup.

In addition, the organization must have a unique layer of resources to manage in-ternal cGMP audit programs, which are required by regulators to ensure that each facility has a process for meeting compli-ance. Typically, these resources are passed on to customers as part of the cost for a contracted operation.

Given these expectations, there seems to be an opportunity for industry to work with consortiums such as Rx–360 or the International Pharmaceutical Excipients Auditing (IPEA) program to share audits and thereby ease overall costs and time tied to the audits. Moving in the direction of shared audits, however, requires more consistent interpretations and expecta-tions, general acceptance of responses, and perhaps a certification process. Companies using contract services must be willing to share their audit programs and compro-mise on what should be the ideal approach to assessing GMP compliance of contract organizations. They must agree to a set of criterion to be consistently applied for auditing and they must be somewhat con-sistent in their interpretation of the regula-tions. This would allow contract organiza-tions to be able to maintain a robust quality system that is suitable for multiple clients. The use of shared audits has been discussed for quite a while and it seems that Rx–360 and IPEA have started down the road of solving the problem for raw-material sup-pliers. Let’s hope they agree to continue with the process and help out contract organizations in the same manner. PT

Contract organizations must have highly organized

teams and plans to accommodate today’s audits.

Susan J. Schniepp

INSIder SolutIoNS

DO

N B

ISH

OP

/PH

OT

OD

ISC

/GE

TT

Y I

MA

GE

S

PharmTech.com/solutionsPharmTech.com/solutions

Susan J. Schniepp

is vice-president

of quality at OSO

Biopharmaceuticals

and a member of the

Pharmech Editorial

Advisory Board, susan.

[email protected].


outsourcing outlook

JO

NA

TH

AN

EV

AN

S/P

HO

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GE

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Y I

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S

PharmTech.com/outsource

this year has been a good one for development-services providers, especially those that support late

development (i.e., Phase II–III). CMOs and CDMOs report strong demand for late-stage clinical-trial materials and clinical-development services, and our PharmSource surveys indicate that the industry could experience growth of 5–10% this year.

The buoyant conditions for late- development services may not last much longer, however, as there is grow-ing evidence that discovery and early- development activity may be declining. CROs offering preclinical-development services, such as animal toxicology testing, have reported soft market con-ditions and weak revenues throughout the year. CMOs specializing in process development for small-molecule APIs note that demand for process develop-ment and early-stage clinical supplies remains weak even as late-development demand has been strong. This situation is a big concern for late-development services, of course, because a weak early-development pipeline means fewer Phase II and Phase III candidates in coming years.

Much of the blame for this state of affairs can be placed on the highly un-

certain and volatile global financial environment. Investors remain risk-averse and are less likely to embrace investments that require long gestation periods and have a low probability of positive outcomes. Late-stage develop-ment candidates have a greater prob-ability of success than candidates in discovery or early development and are closer to a payoff in the form of li-censing or outright sale to a global bio/pharmaceutical company.

This state of affairs is reflected in venture-capital activity in the bio/ pharmaceutical industry. According to US data provided by the National Ven-ture Capital Association, the number of venture-capital investments in the bio/ pharmaceutical sector is down 15% through the first nine months of 2011 com-pared with venture-capital investments in 2010. The actual dollar value of invest-ments is up, but that is because of some large deals that supported companies with strong late-development prospects, such as the $300 million raised by Reata Pharma-ceuticals from a single investor. Venture-capital support is crucial to early-stage companies, and the decline in funding is a clear warning sign for the industry.

European economic crisis The European financial crisis is another cloud on the bio/pharmaceutical R&D horizon. As part of austerity measures

required to get their sovereign debt sit-uation under control, many European governments are slashing expenditures on drugs. In countries such as Greece and Spain, governments have cut the prices they will pay for drugs by as much as 25% or more and are forcing a con-version to generic drugs from branded drugs. (The southern-tier countries that have the greatest debt problems have lower generic-drug penetration than northern European countries).

According to a report by the invest-ment firm Jefferies and Company, the top-line squeeze is likely to force small and mid-size companies in Europe to cut their R&D expenditures as part of overall cost-cutting measures. A recent article in the Wall Street Journal cites Spain’s Almirall and Greece’s Alapis as mid-size companies that are facing R&D cuts as revenues fall (1).

I f European revenues are se-verely affected, even the global bio/ pharmaceutical companies could end up reducing their R&D spending in Europe. Although those companies try to maintain global R&D networks to tap into the broadest array of oppor-tunities, their R&D activities have typi-cally been matched to the regions with the greatest revenue and profit potential. Over the past 10-plus years, the locus has been in North America, where the high prices and margins in the US market

troublesome signs for Bio/Pharmaceutical r&D

A dearth of late-stage candidates could hurt the

pharmaceutical services market in the future.

As part of austerity measures, European

governments such as Greece and Spain

are slashing expenditures on drugs.

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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DPT is the contract development and manufacturing organization (CDMO) that specializes in sterile

and non-sterile semi-solid and liquid dosage forms. With unmatched technical expertise and fully

integrated drug development and manufacturing services, we can help you successfully develop

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outsourcing outlook

have funded most of the R&D budgets at global bio/pharmaceutical companies. More recently, the focus has been shifting to the high-growth emerging markets. Even though some of the largest global bio/pharmaceutical companies are head-quartered in Europe, continuing sales and profit pressures could force them to move more R&D activity to other locales.

implicationsThe global financial outlook is not likely to improve in the foreseeable future. The outlook in Europe remains highly un-certain, with further cuts in government expenditures likely and the survival of the euro zone at risk. Deep budget cuts are coming in the United States, where the aging population and the need to cut budget deficits will put severe pres-sure on Medicare, the large government-sponsored healthcare program.

These macro environmental chal-lenges and uncertainties compound the

bio/pharmaceutical industry’s internal challenges, most notably the decline in revenues resulting from patent expiries. Under these circumstances, the outlook for bio/pharmaceutical R&D spend-ing would seem to indicate little or no growth in coming years.

The difficult R&D environment will have a mixed impact on the bio/ pharmaceutical services industry. Bio/pharmaceutical company efforts to con-trol R&D costs have helped the contract-services industry, and the penetration of outsourcing is likely to grow, especially in the nonclinical-development seg-ment. However, those benefits will not be equally shared among all industry participants. Thanks largely to the efforts of the global bio/pharmaceutical compa-nies to reduce the number of vendors they work with, a select number of preferred providers is benefiting disproportionately from the outsourcing trend. The clinical-development services segment has already

consolidated into a handful of major CROs with large market shares, and we are seeing evidence of a similar consolida-tion in the nonclinical-development seg-ment although the pace is slower. CROs and CDMOs that don’t achieve preferred-provider status will be left to fight over limited opportunities among small- and mid-size bio/pharmaceutical companies.

The pharmaceutical services industry has traditionally risen and fallen with the R&D spending tide. When the tide has been high, most of the companies in the industry have prospered, but when the tide has gone out, all the partici-pants have suffered more or less equally. If we are going into another period of industry weakness, the pain is not so likely to be shared this time around.

reference 1. J. Whalen, “Europe’s Smaller Drug Firms

Feeling Pain,” Wall Street Journal, Oct. 28, 2011. PT

Contin. from. 28If the specification is 95% and the

OOS is 89%, then the difference to be de-tected is 6%. But if the OOS is 94.4%, the difference to be detected is 0.6%. These would give very different sample sizes.

Thus, there seems to be an inherent and unintended conf lict within the industry on sample size. One is not al-lowed to adjust the number of retests depending on the results obtained, but that is the very information we need to statistically and scientifically determine the sample size.

To determine the sample size in ad-vance without knowing how far out of specification the OOS result will be, one would need to decide on a difference to detect in advance. But how to select this difference? Should it be the best guess of the analysts? How does one justify that guess? Should it be the bias in the method from the validation, if it ex-ists? If the bias is large, the sample size would be small. If the bias is very small, the sample size will be large, as can be seen from the equation. This seems to

be the opposite of what industry wants to achieve.

statistical formula with sampleEquation 1 can also be used if a first sam-ple size (e.g., seven) is available to estimate the variance. With this variance estimate and the difference between the specifica-tion and the OOS result, the sample size needed can be recalculated. Additional samples would be taken to meet the sam-ple size if greater than seven.

Equation 1 assumes a continuous re-sponse that is normally distributed. Some data, such as for a limulus amebocyte ly-sate test, may be skewed, and colony counts are both discrete and skewed, so a different model and formula must be used to get the estimate. There are books and computer programs dedicated to determining the sample size in different situations.

Further, from a laboratory management point of view, should a different number of OOS retests be pursued for each method? Do the statistical and scientific advantages of different sample sizes outweigh the need

for consistency for the analysts to prevent confusion and mistakes? Are we out of compliance if the analyst does eight retests when the method calls for seven?

conclusionTo conclude, there seems to be an inher-ent conflict in the industry’s position on sample size. Given this discussion, the seven out of eight criteria given in the Barr case may be as good as any.

references 1. United States vs. Barr Laboratories, Inc.

Civil Action No. 92-1744, US District Court for the District of New Jersey: 812 F. Supp. 458. 1993 US Dist. Lexis 1932; 4 Feb. 1993, as amended 30 Mar. 1993.

2. FDA, Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Pro-

duction (Rockville, MD, Oct. 2006). PT

The author would like to extend an open-

ended invitation to those interested in this

issue to send their comments and solutions

to [email protected]. Given

adequate response, the information will be

shared in a future column.

statistical solutions

CO

RP

OR

AT

E C

APA

BIL

ITIE

S

OUTSOURCING and Consulting Services

About Kemwell

Kemwell Biopharma is

contract provider of CMC

services to the Pharmaceuti-

cal & Biotech industry. With

manufacturing locations in

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Sweden, Kemwell offers ser-

vices ranging from Formula-

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Voted as the “Best Contract Manufacturer in

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ing multinational pharma since 1980 & offers the

entire value chain of CMC services from Phase 1

to Commercial, for Solids, Liquids, Semi-Solids,

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Our commitment to respecting IP rights and

working collaboratively with our customers has

won the confidence of the top pharma companies

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Expertise:

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Kemwell operates in two locations to service

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comprises two (2) facilities (total 280,000 sf) and pro-

vides manufacturing for solids & suppositories, as

well as full scale analytical services, and QP release

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Kemwell Biopharma

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TELEPHONE

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WEBSITE

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NUMBER OF EMPLOYEES

1000

DATE FOUNDED

1980


PHARMA CAPSULES

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Catalent Joins IPAC–RSCatalent Pharma Solutions has

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Aerosol Consortium on Regula-

tion and Science (IPAC–RS), a

scientific consortium that focuses

on the development of standards

and regulations to enhance the

availability of high-quality, safe,

and efficacious drug products for

patients. Other members include

pulmonary and nasal-drug manu-

facturers such as 3M, AstraZenaca,

Boehringer Ingelheim, Chiesi,

GlaxoSmithKline, Mannkind Cor-

poration, Merck & Co., Novartis,

Pfizer, Teva, and Vectura.

AmpliPhi Biosciences Appoints President & CEOAmpliPhi Biosciences has ap-

pointed Philip J. Young as its presi-

dent and CEO. Young is the former

president and CEO of the biophar-

maceutical company Osteologix.

He joined Osteologix in May 2007

and led the multinational com-

pany’s efforts to develop a novel

therapy for osteoporosis, which

resulted in a global licensing deal

with Servier Laboratories. He re-

mains on the Board of Directors of

Osteologix Holdings.

CEO Presesnts at Innovation EventTodd Blonshine, CEO of Mustard

Tree Instruments, addressed an

audience of pharmaceutical and

life-sciences professionals as the

featured speaker at the Innovation

in Research Triangle Park (North

Carolina) event. In his presentation,

Blonshine discussed the chal-

lenges of quality-control issues

with raw materials in the drug-

manufacturing process.

During the event, Blonshine

highlighted Mustard Tree’s VTT

1000 multivariant testing device,

which is designed to enable users

to make instant quality-control

decisions while away from the

laboratory. The device also is

intended to allow users to correct

production flow when inconsis-

tencies are found.

CoreRx Nears Completion of New FacilityThe CDMO CoreRx is expanding

its manufacturing capacity by

adding an entire cytotox process-

ing suite, a low-humidity process-

ing suite, and two dedicated

suites for the Capsugel Xcelodose

and the Mettler-Toledo Quantos

(for processing and encapsula-

tion) at their new 35,000-ft2 facil-

ity. The expansion is scheduled for

completion in early 2012. The new

suite will provide total engineered

containment of pharmaceutical

processes through customized

hard-wall isolation technologies.

CoreRx’s new potent and

cytotoxic facility will feature

processing rooms that contain in-

dependent entry and exit airlock

and access to a dedicated equip-

ment washroom and storage

room. The cyto-suite is designed

for one-way flow of materials,

personnel, and equipment. A

dedicated air handler will bring

in 100% outside air with high-

efficiency particulate air (HEPA)-in

and HEPA-out filtering at the

rate of more than 10,000 ft3 per

minute and at least 24 air changes

per hour. Pass-throughs facilitate

the export of product and waste

as well as dedicated equipment

storage. Equipment and change

parts will be dedicated exclusively

to potent and cytotoxic use, and

containment will be achieved at

levels below 50 ng/m3 of room air.

The isolated equipment that

is permanently housed inside

the potent facility will include: a

Patterson-Kelly V-shell blender, a

Vector High Shear Granulator with

1-, 2-, 4-, and 8-L bowls, Vector

FLM1 fluid–bed dryer/top-spray

granulator, Quadro Comil tech-

nology, 10-station tablet press,

capsule-filling devices, and a

tablet-film coater.

Deborah Tanner, executive vice-president and

group president of R&D laboratories at Covance

PharmTech:How will the industry

remain innovative as it

reduces spending on

research?

Tanner:Drug-development out-

sourcing appears to be

one of the best models

to reduce pharmaceuti-

cal clients’ fixed costs

and drive industry inno-

vation. For pharmaceutical companies, it’s often a matter

of determining what’s core and what’s not core to their

business. As a strategic partner to such clients as Lilly,

Sanofi, Otsuka, and Merck, we work in joint functional

teams to plan resources, share data, identify opportuni-

ties, and resolve issues for better outcomes.

Another force behind innovation and cost savings are

asset transfers, which have been a component of some

of our strategic partnerships. Since acquiring the former

Lilly site in Greenfield, Indiana, in 2008, we’ve expanded

the site to include biorepository and developmental and

reproductive toxicology services. What used to be an in-

house resource serving one company is now a hub serv-

ing more than 50 clients and driving drug development

across multiple therapeutic areas.

PharmTech:Do you see a new industry trend emerging?

Tanner:Strategic outsourcing has created the most exciting and

dynamic shift in the history of the contract research in-

dustry. It’s been a game-changer for pharmaceutical and

biotech R&D because it serves the industry’s two most

pressing, and perhaps conflicting, needs: to reduce costs

and to get safe and effective new medicines to patients

faster.

We also see some trends in certain service lines. Take

chemistry, manufacturing, and controls services. In for-

mulation, we’re seeing more and more APIs with solubil-

ity issues. Designing the most appropriate physicochemi-

cal properties and the best formulation strategy to in-

crease solubility, bioavailability, and permeability is more

important than ever. Covance has a dedicated team of

experts focused on API characterization, preformulation,

and formulation development to help clients optimize

their compounds.

INDUSTRY PIPELINE


MANUFACTURING EQUIPMENT & SUPPLIES



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

Pressure-to-

current transducerDwyer Instruments’s

Model PI pressure-to-

current transducer

accurately converts a

pneumatic input pressure

to a proportional output

current. The PI serves in

high-density and panel-

mounted applications. The

PI transducer offers high-

density DIN rail adapters

and is designed for easy

plug-in installation. Dwyer

Instruments, Michigan City,

IN • www.dwyer-inst.com •

tel. 800.872.9141

Multishaft

mixersRoss’s laboratory

multishaft mixers

are available in

1-, 2-, and 4-gal

capacities. The

machines are used for solids dispersion, dis-

solution, particle-size reduction, emulsifica-

tion, and preparing homogenous mixtures

as viscous as 1 million cP. The mixers feature

two or three independently driven agitators

working in tandem, such as a high-speed

saw-tooth disperser, a high-shear rotor–

stator, and a low-speed anchor. Ross, Charles

& Son Company, Hauppauge, NY • www.mixers.

com • tel. 800.243.ROSS

Pharmaceutical

feederThe Schenck Ac-

cuRate PureFeed

AP-300 feeder was

designed specifi-

cally for pharmaceu-

tical processes. The

feeder is designed for quick and easy disas-

sembly. Each unit incorporates a dual-arm

agitation system for maximizing material

handling versatility and a disposable, FDA-

accepted EPDM feed hopper. Feed rates

range from 0.5 to 150 kg/h. Schenck AccuRate,

Camarillo, CA • www.accuratefeeders.com •

tel. 800.558.0184

Fluid-bed

dryer bags Kavon pro-

vides custom

replacement

fluid-bed dryer

bags for US and

European equipment models. The bags are

appropriate for wet granulation, dry filtration,

and wet and dry coating applications. The

company offers flexible 1–4-bag systems in

various fabrics and also repairs bags.

Kavon Filter Products, Wall Township, NJ •

www.kavonfilter.com • tel. 732.938.3135

Biocontainer

demonstration

videosMeissner has posted

two demonstration

videos featuring

200-L TepoFlex

polyethylene bio-

containers being

deployed in FlexStation rigid outer contain-

ers for biomanufacturing applications. The

videos can be accessed through the Video

Center feature on the company’s website.

The feature provides access to icons for the

top- and bottom-ported biocontainer-filling

videos. Meissner Filtration Products, Camarillo,

CA • www.meissner.com • tel. 805.388.9911

Tablet pressThe Natoli NP-

500 provides

an extra-deep

fill capacity,

extended dwell

time, optional

internal cooling

system spe-

cifically designed

for effervescent

tableting, 10 tons

of compression

force, and forced

feeders.

Natoli Engineering Company, St. Charles, MO •

www.natoli.com • tel. 636.926.8900

Tablet-compression

accessories catalogNatoli’s redesigned tablet-compression

accessories catalog offers more than 1500

products. The 184-page, full-color catalog

is a complete accessory guide for tablet

compression. The free catalog is available in a

digital version, an online 3-D interactive ver-

sion, or in a printed version.

Natoli Engineering Company, St. Charles, MO •

www.natoli.com • tel. 636.926.8900

Radar transmitterThe Magnetrol Eclipse Model

705 Guided Wave radar trans-

mitter 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, biopharmaceutical,

and pharmaceutical industries.

Magnetrol Hygienic Measurement Solutions,

Downers Grove, IL • www.magnetrol.com •

tel. 800.624.8765

INDUSTRY PIPELINE



OUTSOURCING & CONSULTING SERVICES

CLEANROOM EQUIPMENT & SUPPLIES PACKAGING EQUIPMENT & SUPPLIES

High-speed

dispersersRoss’s high-

speed dispersers

include standard

laboratory mod-

els for batches as

small as 1–2 gal.

and production units for vessels as large as

500 gal. The dispersers are suitable for most

straightforward powder wet-out applica-

tions involving viscosities as high as 50,000

cP. The units are supplied with heavy-duty

precision bearings and drive assembly,

high-quality stainless-steel wetted parts,

and a shaft guard. Ross, Charles & Son Company,

Hauppauge, NY • www.mixers.com •

tel. 800.243.ROSS

Validation and documentationFette Compacting America offers extensive

validation and documentation specifically

related to quality control, validation, and

regulatory compliance. The company’s

documentation follows the Life-Cycle Design

model and is admissible to FDA as valida-

tion documentation. Most documentation

can be reformatted into customer-supplied

document formats. Fette Compacting America,

Rockaway, NJ • www.fetteamerica.com •

tel. 973.586.8722

Tablet pressSpecialty Measurement offers the MiniTab

press, which is designed to manufacture

tablets ranging from 0.5 to 4 mm in diam-

eter. 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

Contract

servicesPatheon is a lead-

ing provider of

contract develop-

ment and manu-

facturing services

to the global

pharmaceutical industry. The company sup-

plies products and services to approximately

300 of the world’s leading pharmaceutical

and biotechnical companies. Patheon’s fully

integrated worldwide network helps ensure

that customer products can be launched

anywhere in the world. Patheon, Research

Triangle Park, NC • www.patheon.com •

tel. 905.821.4001

Contract

servicesPatheon is a lead-

ing provider of

contract develop-

ment and manu-

facturing services

to the global

pharmaceutical industry. The company sup-

plies products and services to approximately

300 of the world’s leading pharmaceutical

and biotechnical companies. Patheon’s fully

integrated worldwide network helps ensures

that customer products can be launched

anywhere in the world. Patheon, Research

Triangle Park, NC • www.patheon.com •

tel. 905.821.4001

Pharmaceutical servicesWellSpring Pharmaceutical is a full-service

provider of clinical and commercial manu-

facturing and packaging, blinding, method

development, analytical testing, and distribu-

tion services. Highly qualified managers and

technical professionals work at the compa-

ny’s 100,000-ft2 facility to ensure that clients’

clinical and commercial products meet high

standards. WellSpring Pharmaceutical Canada,

Oakville, Canada • www.wpcoutsourcing.com •

tel. 866.337.4500

Outsourced research servicesMPI Research is a contract research organi-

zation for preclinical and clinical services,

including discovery, safety, bioanalytical, and

analytical sciences. MPI Research encourages

its experienced staff to be responsive to cli-

ent needs, and the company takes a collabor-

ative approach to its customers’ projects. MPI

places importance on maintaining enduring

relationships with its sponsors. MPI Research,

Mattawan, MI • www.mpiresearch.com •

tel. 269.668.3336

Sterile wipesVeltek offers sodium-hypochlorite and

hydrogen-peroxide wipes that are Class 10

laundered, filtered at 0.2 µm, and formulated

with US Pharmacopeia water for injection.

The products have laser-cut edges and are

guaranteed to be sterile with lot-specific

documentation. Veltek, Malvern, PA •

www.sterile.com • tel. 610.644.8335

Transfer

packaging for

prefillable syringesBD TSCF packaging

ensures the secure

transfer of sterile prefill-

able syringe components into the pharma-

ceutical filling environment. The packaging

is compatible with IDC Biosafe doors for

aseptic filling machines within isolator or bar-

rier systems. This packaging is part of the BD

SCF global offer, which features expertise in

sterile processing of preservative-free drugs;

secure, reliable, easy-to-use systems; and

drug master files and technical dossiers.

BD Medical–Pharmaceutical Systems,

Franklin Lakes, NJ • www.bdpharma.com •

tel. 800.225.3310

Packaging

solution The NextBottle

package from

Catalent and

One World De-

sign and Manu-

facturing Group

is designed to

improve patient compliance. The product’s

dial mechanism dispenses one pill at a time

and automatically reminds patients of the

last day that a pill was taken. Catalent Pharma

Solutions, Somerset, NJ • www.catalent.com •

tel. 866.720.3148

INDUSTRY PIPELINE


PACKAGING EQUIPMENT & SUPPLIES

LABORATORY EQUIPMENT & SUPPLIES



CHEMICALS, RAW MATERIALS, INTERMEDIATES, & EXCIPIENTS

Blow–fill–seal machineThe Asep-Tech Model 628 blow–fill–seal

machine from Weiler features a two-piece

stepped base design to facilitate mainte-

nance and product discharge. Model 624

tooling can be used on the Model 628 ma-

chine. The Model 628 unit produces sterile,

liquid-filled, tamper-evident containers rang-

ing in size from 0.5 mL to 250 mL.

Weiler Engineering, Elgin, IL • www.

weilerengineering.com • tel. 847.697.4900

Analytical

technologiesWaters Regulated

Bioanalysis

System Solution

is intended to

offer the best-

in-class analytical technologies that enable

robust assays with high sensitivity. The

solution addresses regulatory compliance,

helps maintain high productivity, and helps

reduce costs per sample. Waters Regulated

Bioanalysis System Solution is intended to

assist clients during the drug-development

process. Waters, Milford, MA • www.waters.

com • tel. 508.478.2000

Infrared cameraThe OSXL160 infrared

camera is equipped with

an uncooled focal plan

array microbolometer.

The camera produces a

crisp thermal image and

an accurate temperature reading to help

increase the quality and efficiency of system

maintenance. The camera offers a colored

thermal image, voice annotation, sound and

color alarms, FLASH memory storage, a USB

connection, and analysis software. Omega

Engineering, Stamford, CT • www.omega.com

• tel. 888.826.6342

Research-

grade mono-

chromatorShimadzu’s

compact,

research-grade

single monochromator UV-2600 and double

monochromator UV-2700 are suited for rou-

tine analysis as well as research applications.

The monochromators feature advanced

optical systems and Shimadzu’s Lo-Ray-Ligh

diffraction gratings, which reduce stray light,

high absorbance level to 8 Abs. The units’

measurement range extends to 1400 nm. In

addition, validation software is provided

as standard. Shimadzu Scientific Instruments,

Columbia, MD • www.ssi.shimadzu.com •

tel. 410.381.1227

Laboratory blenders MaxiBlend and MiniBlend laboratory blend-

ers are available in sizes from 0.5 to 16 qt. The

units are made of 316-L stainless steel and

supplied with V-shells, bins, or double cones.

The units feature a tabletop design and

include programmable logic controls and

safety-interlocked guards. GlobePharma, New

Brunswick, NJ • www.globepharma.com •

tel. 732.819.0381

On-line TOC analysisTo help pharmaceutical companies improve

quality and reduce costs, GE Analytical In-

struments offers a science- and risk-based

program for achieving real-time release of

pharmaceutical water. The program stream-

lines a complex process and helps companies

move total organic carbon testing from the

laboratory to the production floor in approxi-

mately six months. GE Analytical Instruments,

Boulder, CO • www.geinstruments.com •

tel. 800.255.6964

Metal-detection systemsCEIA’s THS/PH21N metal-detection systems

feature high detection sensitivity for con-

taminating ferrous, nonferrous, and stainless-

steel metals, even when the metals are pres-

ent in small quantities. When contamination

is detected, the system rejects the identified

material. The system’s failsafe operation

monitors the opening and closing of the ejec-

tion flap through a redundant conformation

sensor. CEIA USA, Twinsburg, OH • www.

ceia-usa.com • tel. 888.532.CEIA

Pharmaceutical

coating systemsSensient Pharma-

ceutical Coating

Systems specializes

in high-quality coat-

ing systems, brand-

defining color solutions, and enhanced prod-

uct performance for the pharmaceutical and

nutraceutical markets. The company provides

complete coating and visual-enhancement

solutions in addition to its personalized ser-

vice. Sensient Pharmaceutical Coating Systems,

St. Louis, MO • www.sensientpharma.com •

tel. 800.325.8110

Pharmaceutical chemicalsAvantor Performance Materials (formerly

Mallinckrodt Baker) has renamed its Mallinck-

rodt Chemicals product line Macron Chemi-

cals. The name change does not involve any

product or manufacturing changes. The

Macron Chemicals product line is identical to

the previous Mallinckrodt line and includes

high-purity solvents, acids, salts, minerals,

and sugars. Avantor, Phillipsburg, NJ • www.

avantormaterials.com • tel. 855.AVANTOR

Our Multi Media Platform

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quality peer-reviewed papers,

scientifi c reviews, and expert

analyses that defi ne the leading

edge of drug development,

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Pharmaceutical Technology

delivers practical and applicable

information to assist

professionals working in

technology and manufacturing.

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

Now, that’s smart.

THE YGS GROUP | 800-290-5460 x100 | [email protected] YGS Group is the authorized provider of custom reprints for Pharmaceutical Technology.

Smart editorial. Smart marketing.

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

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Ian Uydess and Chet Meyers

FDA regulatory oversight and en-forcement have never been more intense or potentially more costly.

According to the business intelligence firm FDAzilla, the agency is on pace in 2011 to break its record for 483s for the third year in a row, issuing well over 10,000 citations a year—that’s one every 52 minutes. For biopharmaceuti-cal companies, with their highly com-plex and expensive operations, the total cost of cGMP compliance continues to constitute a significant percentage of the cost of goods sold.

Meanwhile, a variety of factors have made compliance and quality more challenging. Complex global supply chains increase the likelihood of lapses. Economic pressures to cut costs can result in compromised processes and increased operational as well as quality risk. Conversely, anxiety about regu-latory action and inadequate under-standing of risk can lead to expensive gold-plating and redundancy in qual-ity and compliance activities. Com-pany growth, the introduction of new products, and entry into new global markets can also attract an increase in regulatory scrutiny. In mergers and acquisitions, achieving consistency in quality and compliance can be espe-cially daunting, particularly when a traditional small-molecule manufac-turer acquires a biologics manufacturer or licenses a biologic product, thereby

requiring interaction and compliance with a totally different branch of FDA with which it has little or no prior ex-perience.

In the face of these pressures, the business case for optimal quality and compliance is compelling: improved operating performance, greater pro-ductivity, less compliance risk, less rework, and fewer interruptions of supply to the market resulting in lost revenue. Yet, in many companies, compliance problems persist, often because the company culture consists more of fighting fires than of think-ing right-first-time and maintaining a reliable state of quality and compliance throughout the company. For an orga-nization to do this successfully—and sustainably—this mindset and behav-ior focused on quality compliance must start at the top and be emulated by in-

dividuals at all levels and in all func-tions within the company. Moreover, in a culture of quality, it is important that employees adopt this mindset, not because they have to, but because they understand the importance and ben-efits of this thinking and behavior and appreciate the risks of not adopting it.

Consider the wildly divergent views of quality that were uncovered when a major biopharmaceuticals manufac-turer undertook a comprehensive as-sessment of quality across a number of its global operations. The company’s manufacturing sites, as well as corpo-rate headquarters, were polled on such questions as how well leadership de-fined and communicated their vision of the desired quality culture, whether management had identified what was required to create and sustain a qual-ity culture, whether the individual had the tools and resources to get his or her job done correctly, and much more. When asked whether the right behaviors were encouraged for sustain-ing a quality culture, a strong majority of respondents at one site responded favorably, yet overall, barely one third of the staff polled at several other sites, including their corporate headquar-ters, responded positively.

Not every dimension that was as-sessed turned up such divergence. For example, nearly everyone agreed

Employee training—at all levels—is crucial

for moving forward with a successful risk- and

quality-based manufacturing strategy.

Developing and Sustaining a Quality Culture

Ian Uydess, PhD, and Chet Meyers, PhD, are managing consultants at Tunnell

Consulting, [email protected]

and [email protected]

In a culture of

quality, it is

important that

employees adopt

this mindset, not

because they have

to, but because

they understand

the importance.

Your opinion matters.To contribute to this column,

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Viewpoint

that they were held accountable for the quality of their work; and by over-whelming majorities throughout the company, respondents agreed that if they observed noncompliant activi-ties they felt comfortable calling it to someone’s attention. But in many areas there were wide divergences and in others—like whether the company’s people had the skills to do a high qual-ity job—there was low favorability al-most across the board. It also emerged that the company was perceived by em-ployees as focusing on short-term fixes in quality issues, and that personal development, teamwork, rewards, and recognition were inadequate for pro-moting a quality culture. Instead of a single, unified environment, the com-pany had many disparate cultures.

Quality culture assessmentTransforming organizations to obtain and sustain a quality culture begins with a comprehensive evaluation of the various organizational, procedural, staffing, and other parameters that im-pact quality within the organization. In other words, all of the activities, at-titudes, and interactions that together constitute culture must be considered, including elements such as:

• Quality/compliance governance

structures: Are there effective mechanisms for such activities as global change management for new product introductions, processes for regulatory changes, pharmacovigilance, product com-plaints, quality related councils, and material review boards?

• cGMP compliance activities: These

include batch/lot issuance, batch

review and disposition, devia-tion management, corrective and preventive action, change control, document control, internal audit-ing/inspection, risk identification/

remediation, annual product re-view and all of the other relevant processes and procedures. Are they uniform, compliant, and effective at each site, across sites, and across the entire organization?

• Quality metrics: These include

such measures as right first time, cycle time, product complaints, regulatory events, action plan at-tainment, reportable events, and the like. Quality metrics should be

appropriate and provide the basis for effective review of quality per-formance.

• Leadership styles and behaviors:

Do leaders take a comprehensive view of quality, communicate that vision effectively throughout the company, and behave in ways that foster and support the efforts of all employees?

• Human-resource practices: Are

personnel sourced, recruited, hired, and on-boarded in ways that promote a consistent, high-performing quality culture? This can be an even more challenging issue for manufacturers of seasonal vaccines, because they often hire many seasonal workers who may have little long-term allegiance to the company or exposure to the company’s values in regard to quality.

• Learning and personal develop-ment systems: How broad, deep

and effective is the organization’s training program? Are personnel given opportunities for further professional development?

• Quality behavior reinforcing

mechanisms: Are performance management policies, rewards, and recognition designed to moti-vate individual employees as well as teams to consistently strive for quality?

• Quality-related information sys-tems: These include not only IT and enterprise resource planning systems used for document man-agement, deviation management, change control, and the like, but also the way in which information is shared. Are best practices and lessons learned at one site commu-nicated to the other sites within the company to maintain a uniform, high-quality company culture?

• Employees’ perceptions in relation

to quality at the company: As with

the example of the biopharmaceu-ticals company described above, how do employees react to state-ments that describe the cultural norms and behaviors of a high performance organization with a strong quality culture?

On the basis of this assessment, it is then possible to characterize the or-ganization’s quality culture, or more likely, cultures, as the basis for under-taking transformation.

Key elements of a successful transformationFrom the assessment there should emerge clear recommendations for improvement, including quick wins, and goals for the short-, medium-, and long-terms. Because organizations differ, the particulars of these recom-mendations for transforming any given culture will vary. But there are some constants in the execution of such rec-ommendations. A centralized project management framework should be put in place to help guide the planning and successful implementation of the rec-ommendations.

To help drive and sustain changes, a compelling quality culture message must be developed—in effect, inter-nally branding the effort. The message must be clear, relevant, understood by all, and designed to provide a point around which every employee can rally, motivating them to contribute to the effort. Best practices in human resources, organizational development, and leadership should be followed in order to maximize employee engage-ment, assure effective rewards and rec-ognition, provide timely communica-tion of progress, and institutionalize accomplishments. Finally, appropriate operational-excellence tools should be used to further help assure successful implementation and sustainability of these efforts—as well as to provide the metrics needed to monitor and report progress along the way.

What should the resulting high per-forming, sustainable quality culture look like? Again, the particulars may vary from company to company, but

Viewpoint


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such cultures should share the follow-ing characteristics (see Figure 1):

• Employees at all levels understand

the organization’s quality objec-tives, policies, and procedures and their individual roles in helping to achieve them.

• Leadership at all levels is visibly

engaged in supporting the devel-opment of a quality culture and effectively engages and motivates others to do the same—leading to self-motivated accountability and sustainability.

• Effective communication, enter-prise-wide sharing of best practices, engagement of all employees, and rewards and recognition for both teams and individuals maintain the momentum and enthusiasm required for sustainability.

• The organization hires people who

possess the quality values, norms and work practices the company desires.

• Staged on-boarding and technical

and quality training are deployed at the company, business unit, func-tional area, and individual levels.

• Consistent and sustainable stan-dards of quality are defined clearly and deployed across the organiza-tion in conjunction with quality and compliance systems that enable the organization to achieve those standards.

• The organization distinguishes be-tween people and processes as the root cause of mistakes, and instead of blaming people looks to correct processes.

• Leaders and managers at a l l

levels establish an environment of trust and collaboration in which challenging issues can be raised without fear of reprisal.

• The organization institutionalizes

a process for capturing, analyzing, and incorporating lessons learned from past successes and failures.

• As the organization grows and

changes, the quality culture is con-tinually monitored and fine-tuned to ensure that it remains effective and sustainable.

The journey from quality culture as-sessment to transformation to sustain-ability need not take long or consume massive resources. But it does require the recognition that achieving quality and compliance is not a matter of a dis-crete, isolated process but of the larger environment in which it takes place. PT

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