Scrutinizing the Subvisible - This is title - PharmTech

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April 2011

Volume 35

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The US Food and Drug Administration Reports on Common Deficiencies in ANDAs: Manufacture and Container Closure

PEER-REVIEWED: Delivering Tamoxifen within Solid Lipid Nanoparticles

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pharmtech .com

Continued on page 10

On

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April 2011 Volume 35 Number 4

interPheX 2011 Videos➲ Visit PharmTech.com to view

taped interviews and panel ses-

sions from the INTERPHEX 2011

Main Stage, including topics on

continuous processing, business

in China, and outsourcing.

enewsletters Visit PharmTech.com/enews to

read or subscribe to:

➲ ePT : Weekly eNewsletter

keeps you current with industry

news and business notes.

➲ Sourcing and Management:

The April edition includes a

roundup of the conference

sessions at DCAT Week.

➲ Equipment & Processing

Report: The April edition covers

modifying manufacturing lines

with a QbD approach.

SupplementBe sure to check out this month’s

Solid Dosage & Excipients supple-

ment, featuring articles on quality

control, IPEC guidelines, coating

technologies, and more.

Features

special report

50 uS Steps up Scrutiny of Foreign transactionscarlos F. ortiz and michael goldklang

Companies engaged in global merg-

ers and acquisitions may be hearing

from the Department of Justice more

often to ensure that corruptive prac-

tices are not taking place.

pharma ingredients

54 advancing Small-molecule Synthesis

Patricia Van arnum

Catalysis plays a crucial role in small-

molecule synthesis, whether it be in

making an intermediate or the API.

anda reViews

62 common Deficiencies in abbreviated new Drug applications (Part 4)

aloka Srinivasan and robert iser

The reviewers aim to assist ANDA

sponsors in building quality into

their submissions by clarifying

components of the applications.

Part 4 addresses manufacture and

container-closure.

Peer-reviewed research

aseptic processing

69 revisiting interventions in aseptic Processing

James agalloco and James akers

The authors revisit their previ-

ous effort to refine the terms that

describe interventions and to dispel

confusion that arose after the origi-

nal article was published.

drug deliVerY

74 Delivering tamoxifen within Solid lipid nanoparticles

roghayeh abbasalipourkabir, aref

Salehzadeh, and rasedee abdullah

The authors evaluate the effective-

ness of tamoxifen-loaded SLNs as

a drug-delivery system in treating

breast cancers.

cover story

44 Scrutinizing the Subvisible by erik greb

Regulators question whether

particles that they can’t see hurt patients.

Illustration by Dan Ward

Images: Justin Gollmer/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.

Supplement to the April 2011 Issue 2011

Solid Dosage and Excipients

➲ On PharmTech.com

Products

28 in the Spotlight

88 industry Pipeline

94 Product and Services

Showcase/marketplace

Departments

18 in the Field

87 Pharma capsules

97 ad index

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Continued from page 8

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columns

from the editor

12 celebrity couples to Disunite

michelle hoffman

Research and development may

well be headed for divorce.

pharmtech talk

14 a QbD World for Suppliers

Patricia Van arnum

The need for greater process under-

standing raises the bar for suppliers.

agent-in-place

16 inspections gone mad

control, a Senior compliance officer

In any industry, inspections can be a

pain, and pharma is no exception.

washington report

30 health-reform controversies

Jill Wechsler

Courts and Congress seek to

reshape policies and programs.

Bioforum

38 Biotechnology loses lead in Funding

tracy lefteroff

An uncertain regulatory environment

affects funding for biotechnology.

statistical solutions

40 Pitfalls in Statistics

lynn torbeck

The hardest errors to spot are the

ones that don’t look like errors at all.

inside pda

80 Pcmo initiative gathers Strength

richard levy

A review of current efforts within

PDA’s Paradigm Change in Manu-

facturing Operations initiative.

outsourcing outlook

84 a hard look at third-Party external Supply networks

gregg Brandyberry

The complexity of third-party

external supply networks requires

new ways to manage them.

Viewpoint

97 When Patience Pays off

John castellani

PhRMA acknowledges the per-

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From the editor

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Psst. I’ve got a bit of gossip for you, a piece of news you won’t hear on TMZ or Entertainment

Tonight. Early reports seem to indicate that a huge celebrity couple, seen ev-erywhere at all the big industry firms is headed for splitsville. That’s right. That perennial couple, the so-called jewel in every pharma companies’ crown—R&D—looks like they’re on the outs. R seems to be leaving D. Or is it getting kicked out?

An article in the Feb. 10, 2011 issue of Nature reported cuts to the research staffs at both Pfizer and GSK. Pfizer, the article said, is shutting down its Sand-wich, UK, facility, thus cutting 2400 mostly research scientists. The com-pany, according to the article, is also eliminating 1100 jobs from its Groton, CT, research facility, and is slashing re-search budgets from a previously stated target of $8.0 to $8.5 billion down to between $6.5 and $7.0 billion.

For its part, GSK was quoted in the same article saying that it would be “externalizing parts of early-stage dis-covery; dismantling development in areas with low financial and scientific return.” Judy Slinn, a business histo-rian at Oxford Brooks University in UK was also quoted as saying “Pharma companies will still do development

work. They won’t do discovery.” OK. But then who will do discovery?

Pharma is looking to small biotechs to fuel its discovery engines. By most accounts, pharma will be shopping among later-stage biotech companies ready for development. Yet there still seems to be a significant funding gap to develop promising technologies out of the universities and into at least proof-of-concept stage; that is, there seems to be little money to develop technologies to the point that they become attractive to large pharma.

This funding gap—the so-called Valley of Death—is nothing new. It’s just that in an environment where everyone is cutting back on research, the problem of developing promising technologies seems more acute. The Biotechnology Industry Organization (BIO) is addressing the problem in what it is calling their “Big Thinking Project.” BIO recently commissioned the firm headed by former NIH Di-rector Elias Zerhouni to collect sug-gestions for optimal government and industry initiatives from key industry leaders. They asked for policy propos-als that would support early innovation to a point where risk-averse venture investors and big pharma firms would pick up the tab for continued develop-ment. Their responses include a mix of reforms that would reduce regulatory and financial risks.

The Obama administration is also keen on promoting innovation. In his 2011 State of the Union address, the president wasted little time pinpoint-ing the source of America’s future financial security. “The first step in

winning the future is encouraging American innovation,” he said. And the administration’s 2012 budget backs that up with funding increases for biomedical research and FDA ac-tivities. But then it curiously sounds a counter-innovative note. The same administration “now proposes to jet-tison the biotech exclusivity deal,” that had previously been approved as part of the healthcare reform package, notes Jill Wechsler in Washington Report this month. In shrinking the exclusiv-ity period from 12 to 7 years, the move threatens to disincent investor support for the very innovation it otherwise hopes to stimulate.

Interestingly, in the same State of the Union Address, the president warned of competition from overseas. “Mean-while,” he cautioned, “nations like China and India realized that with some changes of their own, they could compete in this new world. And so they started educating their children earlier and longer, with greater em-phasis on math and science. They’re investing in research and new technol-ogies.” Indeed they are. The Chinese government is spending a reported $2.4 billion to support drug develop-ment, while it introduces policies to promote its biotech sector, strengthen its intellectual property protection, and strengthen tax and lending poli-cies. In other words, research, jilted by US pharma, may find solace in China’s warm embrace. PT

Sources: D. Cressey, Nature 470, 154 (Feb. 10, 2011); H. Jia, Nature Biotech. 28 (10) 990 (2010); Podcast, A Conversation with Jim

Greenwood, www.PharmTech.com.

Celebrity Couples to disunite

Research and development

may well be headed for divorce.

Michelle Hoffman

Michelle Hoffman

is editorial director of

pharmaceutical Technology.

Send your thoughts

and story ideas to

[email protected].

PharmTech.com/forum

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14 Pharmaceutical Technology APRIL 2011 PharmTech .com

PHARMTECH TALK

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A QbD CMC World for SuppliersPatricia Van Arnum

Patricia Van Arnum

is a senior editor of

Pharmaceutical Technology.

»Read Patricia’s blogs at

blog.PharmTech.com.

After attending several events during the past few months, including con-ference sessions at Informex in Char-

lotte, North Carolina, in February, and the educational programs during DCAT Week, the week-long event of the Drug,

Chemical, and Associated Technologies Association’ (DCAT) in New York City in March, I observed the growing importance of FDA’s quality-by- design (QbD) initiative in the pharmaceutical supply chain.

The QbD approach, which encourages a greater process understanding of a syn-thesis and related manufacturing for an active pharmaceutical ingredient (API), is not confined to the efforts of the large phar-maceutical companies. At the conferences that I attended, emerging pharmaceutical companies also spoke of the importance of QbD in a chemistry, manufacturing, and controls (CMC) package for APIs and fin-ished drug products and of their interest in having a contract manufacturing organiza-tion (CMO) capable of developing a QbD-ready CMC process. Because many small pharmaceutical companies seek to partner with Big Pharma in their drug-development or commercialization efforts, making the CMC package acceptable to a potential large suitor, including incorporating QbD requirements, is important.

Large pharmaceutical companies also spoke of the need for CMOs and fine-chemical suppliers to share the process understanding in their manufacturing routes for the chemicals they supply, not just for finished APIs and advanced inter-mediates, but also for early-stage interme-diates and starting materials. As the large pharmaceutical companies develop their regulatory filings with an QbD mindset, there is the growing expectation of sup-pliers to share deeper process informa-tion to facilitate those filings in a QbD-ready CMC environment. PT

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Cautionary Tales from the Files of “Control,”

a Senior Compliance Officer

Ka-ching“Ouch,” our GMP Agent-In-Place said. “We had a deal to purchase another pharma company in another country (let’s call it Country A), and we borrowed a bunch of money from a bank in our native country (let’s call it Country B) to complete the deal. As the deal came to clo-sure, we moved the money from Coun-try B to Country A, but the government examining the deal nixed it because of monopoly-compliance issues. We moved the money back to Country A to pay off the loan. Not all was lost—we made $1 million thanks to the exchange rates.”

Uncharted“To ease the outgoing acceptable qual-ity level process, we purchased handheld slide-rule acceptable quality level charts for the inspectors to use,” our GMP Agent-In-Place explained. “Because the format was different from our previously used printed tables, we changed our standard operating procedure (SOP) to explain how to use the slide table. Unfor-tunately, the person writing the SOP did not clearly understand the new device, and he wrote the SOP incorrectly.

“Fast-forward 3 months, and this problem was noticed during an audit. We had to contract a statistician to calculate our ‘operating characteristic’ curves and graphs to show what the effect of the incorrect process actually used would be, and it turned out, luck-ily, to be a trivial effect.”

tell us again“During an FDA inspection, agency representatives reviewed various de-

viation investigations,” grumped our GMP Agent-In-Place. “One particu-lar inspector wrote a 483-observation noted a single deviation even though we had demonstrated that the devia-tion was known, investigated, and un-derwent effective corrective actions. In the observation, the agent merely noted the deviation’s existence, and wrote nothing about the investigation.

“Our response included a summary of what we had done, including the full in-vestigation, the root cause, the corrective action, and the effectiveness checks. This response was accepted and the inspection filed was closed,” explained our Agent-in-Place. “We are not sure why we had to restate our already completed actions in the response. The work created a lot of work and anxiety for everyone involved, and resulted in no improvement in qual-ity, potency, purity, identity, or safety of the drug product. In addition, the effort took time that could have been allocated to improving compliance in other areas.”

i know you know how“Like many mid-sized pharmaceutical manufacturing firms, we have several

factories around the world, and they often supply a single market,” said our GMP Agent-in-Place. “In one in-stance, we supplied a European Union market, and an inspector from that EU country performed inspections at several of our international manufac-turing sites. He was able to compare and contrast the sites, and noted that we did not have the same standards for some operations (e.g., the way we connected the sterile bulk vessel to the filling line).

“He especially didn’t like the con-nection location at one site; the room was classified as class D but the con-nection was performed under a local class-A air shower. The connection timeframe was thoroughly moni-tored environmentally, including for airborne particulate, active air-borne germ monitoring, operator- glove plates, and microbial settle plates. But,” continued our Agent, “he noted that the local class-A air shower did not negate the room classification, nor did the class-D room meet requirements. Old buildings are such a pain.” PT

In any industry, inspections can be a pain,

and pharma is no exception.

inspections gone Mad

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.

The 483 noted a

single deviation

even though we

had demonstrated

that the deviation

was known.

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18 Pharmaceutical Technology MONTH 2011 PharmTech .com18 Pharmaceutical Technology APRIL 2011 PharmTech .com

In the Field

PH

OTO: TOM BONAVENTURE, GETTY IMAGE

S

18 .....Market Report from China

22 .....PRTM and Global Healthcare Efforts

24 .....Senate Passes Patent-Reform Bill

24 .....PharmTech Poll on Equipment

25 .....Regulatory News

26 .....FDA Draft Guidance on User Fees

26 .....Hamburg on Medical Countermeasures

The contract-research industry in China is growing in leaps and bounds, and Big Pharma is leading the way.

Report from:

China

China’s contract-research industry has come a long way. In fact, it reached a milestone when Shanghai-based WuXi PharmaTech listed its initial public offering (IPO) on the New York Stock Exchange in Sep-tember 2007. In the same year, Hutchinson Medipharma established an agreement with Eli Lilly to work on novel compounds in oncology and inflammation. contin. on page 20

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IN THE FIELD

contin. from page 18Looking back, China’s contract research industry consisted

mainly of chemistry-based companies, largely as a result of a limited talent pool and accessibility of quality deliverables in the early 1990s. As the regulatory and business environment improved in the mid-1990s, however, foreign CROs found their way to Beijing and Shanghai, driven largely by demographic changes, economic trends, and the untapped potential of the Chinese market. MDS Pharma Services was the country’s first foreign-based contract research organization (CRO) followed by Quintiles Transnational, Covance, and Kendle.

Today, the CRO industry in China has developed tremen-dously. According to Jan-Willem Eleveld, vice-president for management consulting (Asia–Pacific and Japan) at IMS Health, the CRO industry has evolved from preclinical offerings to clinical studies. Established players such as Wuxi PharmaT-ech are also opening new business in the clinical-trial arena, and there has been a rise in the number of firms that have es-tablished current good laboratory practice (cGLP) facilities to carry out studies in China.

Adds Eleveld, “CROs are facing a new reality that Big Pharma [is] moving away from a pure out-sourcing model and establish-ing fully integrated R&D centers in China. Unlike past R&D outfits designed for local clinical trials for local approval, new R&D investments are for the purpose of global pipeline. As a result, they build more in-house capabilities in all aspects of R&D and use CROs (preclinical) to manage capacity overshoot. On the other hand, clinical CROs have great future because more and more new drugs will be developed in China as part of a global R&D hub.”

Recently, there have been a number of active new establish-ments and acquisition activities, resulting in the doubling of foreign CROs in the country last year alone. Several foreign companies have expanded their services into central labo-ratories and drug-supply management. In a move to remain competitive in the changing business environment, many local companies have embraced the mergers and acquisitions (M&A) approach by opening their services to international drug devel-opers. Some are also actively gaining accreditation from organi-zations, such as the American Association for the Accreditation of Laboratory Animal Care, to gain a better market position in the eyes of international clients.

In April 2010, New Jersey-based PhytoMedical Technologies signed a Letter of Intent (LOI) with Shanghai Medicilon, a pre-mier Chinese preclinical contract research company to advance PhytoMedical’s anticancer compound by conducting investiga-tional new drug studies under cGLPs on its lead drug (D11B).

The Chinese government plays a paramount role in devel-oping the contract research industry in the country. Its Con-tract Research Organization Union China (CROU) developed the first industry standard, Clinical Trial Services of Contract Research Organizations, for the sector. Johnny Huang, senior consultant on healthcare practice for Frost & Sullivan China

adds, “The Chinese government is adopting a market policy to improve its regulatory environment and CRO industry devel-opment. Its initiatives for drug discovery in past years included strengthening of intellectual propoerty rights and focusing on shrinking evaluation time for drugs. The government has also focused on its infrastructures by creating technology parks, such as Shanghai Zhangjiang Hi-Tech Park, establishing a large talent pool in the field of pharmaceuticals, and formulating nu-merous government bodies that help develop drug discovery in China.”

Perhaps the challenge for the government going forward will be to harmonize local CRO culture and international drug-re-search standards, he says. Some leading pharmaceutical com-panies have taken initiatives to help local CROs improve their practices in this area. For example, Pfizer is working with lead-ing academic institutions to educate scientists in state-of-the-art practices for drug R&D.

Overall, to achieve success in the Chinese market, CROs need to adopt a cost-effective approach for their business. Huang says, “Flexibility and scalability of operations allow companies to be more nimble and respond to change faster. In the long term, CROs in China have to create their advantages in local talent pool, unique service, and strong partnership with local clinical experts. These are the key ingredients to success, especially in multicentered clinical trials in China.”

—Jane Wan, a freelance writer based in Singapore

CSR and sustainability forum

Pharmaceutical Technology’s Sourcing and Management eNewsletter

provides specialized coverage of the bio/pharmaceutical industry’s

activities in corporate social responsibility (CSR) and sustainability

as well as developments from other business sectors, government

organizations, professional, trade, and scientific associations, and

nongovernmental organizations. In the April issue (available at www.

PharmTech.com/PTSM):

• Chan Harjivan and Diana Elkis with the management-consulting

firm PRTM analyze manufacturing and access for public-health,

government, and developing-world markets.

• A look at the International Federation of Pharmaceutical

Manufacturers and Associations’ report on technology transfer as a

collaborative approach in global-health initiatives.

• Review of the Women in the World Summit, held in New York City in

March 2011, on CSR, government, and NGO efforts to advance social,

economic, and development goals.

• 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].

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IN THE FIELD

In recent years , t he le t ha l form of m a l a r i a h a s grown resistant to older drugs used for treatment. Ar-temisinin-based combination ther-apies (ACTs) are the most preferred

method of treatment for malaria, as designated by the World Health Or-ganization (WHO), because of their reduced likelihood of resistance. How-ever, they can be 10 times more expen-sive than competing therapies, making them less accessible to the millions of people that need treatment.

PRTM, a management consulting firm, joined The Global Fund to Fight AIDS, Tuberculosis, and Malaria’s Af-fordable Medicines Facility-malaria (AMFm) unit to help develop a frame-work to enable supply-chain managers to get timely, affordable ACT supplies to the locations where they are needed most. The Global Fund is a public–private partnership that focuses on health financing to prevent and treat HIV/AIDS, tuberculosis, and malaria. The partnership began in July 2010 and ended in December 2010. The goal in developing this framework was to reduce the barriers for effective distri-bution in resource-constrained areas where malaria is endemic.

The framework used was the Sup-ply Chain Operations Reference model (SCOR, a registered trademark of the Suppy-Chain Council, a global nonprofit organization that works to improve supply-chain performance), which is considered industry best practice for optimizing supply opera-

tions in “hard to reach” and resource-constrained geographies throughout the world. The framework has had par-ticular success in the public sector clients by adapting the supply chain practices and metrics of commercial companies to meet the unique needs of the public sector.

Beneficiaries of the project included public and private organizations that procure, store, and distribute health commodities, including essential drugs and medical supplies (e.g., sy-ringes, bandages). The framework en-abled these organizations to measure current and historical performance and to prioritize opportunities for im-provement, including the identifica-tion of and reference to best practices for supply-chain management.

“By allowing users on the ground to diagnose the root cause of perfor-mance issues, organizations can make more informed strategic investment decisions, thereby better positioning themselves to streamline and optimize distribution processes,” says Chan Harjivan, lead director of the PRTM effort.

He adds, “Improving the effective-ness and efficiency of the supply chain for each organization involved in end-to-end distribution can contribute to public health goals of improved avail-ability and affordability and access to critical health products.”

Visits to Tanzania and Niger in September and October 2010 pro-vided a unique opportunity for the team to meet with public and private stakeholders and to identify com-mon challenges. Stakeholder visits included drug manufacturers and im-porters, distributors, policy makers,

grant recipients, ministries of health, and nongovernmental organizations. According to Harjivan, discussions focused on improving supply-chain processes, including how to best place orders with manufacturers, account for inventory, and manage distribution to customers.

Part of the project also assessed met-rics contained within the framework to ensure that they could be measured with the data available (e.g., the date and time when an order is received and the date/time when it is shipped). The trips proved to be extremely valuable in further customizing the framework into a valuable tool for supply-chain managers, says Harjivan. The project also empowers local organizations to identify and prioritize issues.

Looking ahead, some of the great-est challenges to be addressed in dis-tributing ACTs throughout developing countries include unpredictable or in-sufficient funding, which often leads to product rationing for crucial drugs. Adds Harjivan, “Difficulties in deter-mining true consumer demand limits forecasting capabilities and can result in lengthy periods where products are not available to consumers.” An-other challenges is a lack of adequately skilled and trained personnel in de-veloping countries. Harjivan further notes that, although the framework proposes strategies for dealing with the challenges identified, it’s not a complete solution. The benefit of the framework is that users can apply their own knowledge of the environment to develop solutions that are most appro-priate for their organization.

Now that the framework design has been completed, the Global Fund is evaluating and developing a strategy for implementation. Tailoring of the framework will be needed for each country in which it will be adopted.

Global Healthcare on the GroundFramework Set for Supply-Chain Improvement

by Christina I. Ortiz

Chan Harjivan

Published 3/11 PATH0175R1

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IN THE FIELD

» Worth AttendingPDA Annual Meeting ExcipientFest/IPEC

Apr. 11-13, San Antonio, TX Regulatory Conf.

www.pda.org May 10-11, Baltimore, MD

excipientfest.com

» Worth Watching PharmTech.com

Weren’t able to attend INTERPHEX 2011? You can still catch our

video program, taped live at the conference.

» Worth Reading blog.PharmTech.com

Check out the latest trends on PharmTech Talk, the daily blog

of Pharmaceutical Technology. Recent posts address vaccines,

continuous processing, pharma’s role in the Japanese earthquake

recovery, and more.

Zone in on: Manufacturing Senate Passes Patent-Reform Bill

Erik Greb

In early March, the US Senate approved the “America Invents

Act,” which is intended to reform the nation’s patent system. If it

becomes law, the bill will establish a first-to-file system by defining

an invention’s effective filing date as the actual filing date of the

patent or patent application.

The bill is intended to reduce the backlog of pending patent

applications at the US Patent and Trademark Office (USPTO) by pro-

viding the office with funds needed to review the applications. The

bill also would establish additional USPTO satellite offices.

In addition, the bill would change the US patent system in the

following ways:

• By creating a supplemental examination process

• By providing increased incentives for government laboratories

to commercialize inventions

• By placing restrictions on false-marking claims (i.e., using a pat-

entee’s name or number on a product without consent)

• By providing additional patent assistance to small businesses

through an ombudsman program.

“The America Invents Act will promote American innovation,

create American jobs, and grow America’s economy, all without

adding to the deficit,” said Senator Patrick Leahy (D-VT), one of the

bill’s sponsors, in a press release. “It is common-sense legislation

that will help preserve America’s position as the global leader in

invention and innovation.”

“Our patent laws should be in the iPad age, not the sock hop

age,” said Senator Orrin Hatch (R-UT), another of the bill’s sponsors,

in a press release. “This bill will bring our nation’s patent system

squarely into the 21st century and will better position our inven-

tors and entrepreneurs to compete in today’s global economy.”

The Obama administration and the Biotechnology Industry

Organization have expressed support for the America Invents

Act, which is based on a patent-reform act that Representative

Lamar Smith (R-TX) and Representative Howard Berman (D-CA)

introduced in the US House of Representatives in 2005. At press

time, the Senate had sent the America Invents Act to the House of

Representatives for consideration.

From which region do you buy

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43% Asia

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4% Other

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Pharmaceutical Technology APRIL 2011 25Pharmaceutical Technology APRIL 2011 25

Regulatory Roundup

» FDA and EMA announced on Mar. 16,

2011, that they would carry out a joint pilot

program for parallel assessment of quality-

by-design-based new drug applications. The

pilot applies to applications submitted to

both agencies. According to an agency press

release, the “parallel evaluation within this

voluntary pilot program means that reviewers

from both agencies will separately assess the

quality/chemistry, manufacturing and control

(CMC) section of the new drug applications

(NDAs) submitted to the FDA and marketing

authorization applications (MAAs) submitted

to the EMA.”

» The US Pharmacopeia (USP) is seeking

scientists from around the world for its 2011-

2012 fellowship program. The two $50,000

research fellowship awards will be presented

to the students whose proposed research best

directly addresses specific USP scientific or

research needs, according to a USP notice on

the program. The deadline for submissions is

May 20, 2011. Full details are online at www.

usp.org/aboutUSP/careers/fellowship.html.

» In addition to the implementation training

programs that ICH has been conducting around

the world during the past year, the organization

is now posting on its website a consolidated

training package . This package covers the

integrated implementation of the ICH Q8,

Q9, and Q10 guidelines, including details

on technical development, manufacturing ,

pharmaceutical quality systems, and regulatory

expectations (e.g., dossier preparation,

assessment, and GMP-inspections), according

to an ICH press release.

IN THE FIELD


Zone in on: Regulation FDA Issues Draft Guidance on User-Fee Waivers, Reductions, and Refunds

Angie Drakulich

FDA issued a draft guidance for industry on Mar. 11, 2011, titled User-

Fee Waivers, Reductions, and Refunds for Drug and Biological Products,

that offers recommendations to applicants seeking such actions under

the Federal Food, Drug, & Cosmetic Act (FD&C Act). A similar draft

guidance was issued in July 1993. The new document clarifies the

types of waivers, refunds, and reductions available under the user-fee

provisions of the FD&C Act as well as the procedures for handling

these requests, including how to appeal an FDA decision.

The guidance is tied to the Prescription Drug User-Fee Act (cur-

rent version IV), which allows FDA to assess and collect user fees from

applicants for certain human drug and biological products. In addition,

FDA can assess annual product fees for certain approved drug and bio-

logical products, as well as annual establishment fees for the facilities

in which those products are made in final dosage form, states the draft

guidance. However, the amount FDA collects in total from these fees is

“independent of the number of waivers or reductions in fees that are

granted… Therefore, the more waivers or reductions are granted, the

more fees must be increased the following year for applications, prod-

ucts, and establishments subject to fees to meet the annual statutory

revenue targets.”

The new draft guidance explains how an applicant may qualify for a

waiver or reduction in user fees. Three potential qualifications for appli-

cants are available to protect the public health; to avoid a barrier to

innovation (i.e., the assessment of the fee would present a significant

barrier in developing the product because of limited resources); or to

maintain a small business (i.e., the applicant is a small business submit-

ting its first drug application for review). The guidance goes into detail

about each potential qualification for a waiver or reduced fee, and pro-

vides examples of how a company might meet the requirements.

For example, if a company is requesting a waiver because its drug

product protects the public health, the company might explain to FDA

how the drug product offers a significant improvement compared

with other marketed products, including other dosage forms or routes

of administration and nondrug products or therapies; whether the

drug is designated as a priority drug (e.g., fast-track status, new molec-

ular entity); and whether the drug product demonstrates an increased

effectiveness in the treatment, prevention, or diagnosis of disease.

Additional considerations for applicants provided in the draft guidance

document regarding barriers to innovation and costs for small busi-

nesses are provided in the draft guidance document.

The draft guidance also provides clarification of timing for when to

request a waiver or reduced fee (i.e., no later than 180 calendar days

after the fee is due). The consequences of not paying the application

fee, and when to submit a request for a waiver or reduced fee to avoid

paying the application fee (about three to four months before submit-

ting an application) also are addressed. Finally, the document provides

information about the content and format of such requests, and about

how to handle refund requests as well as appeals or requests for

reconsiderations should FDA deny an application.

Industry and public comments on the draft guidance are due

within 90 days of the document’s publication date.

Hamburg Describes Efforts to Develop Medical CountermeasuresErik Greb

At a conference on preserving national security at the Univer-sity of Pittsburgh Medical Center in early March, FDA Com-missioner Margaret Hamburg stressed the importance of medi-cal countermeasures for responding to natural and deliberate threats to public health. The Obama administration has man-dated the development of these countermeasures, and FDA will contribute to the initiative in three ways, Hamburg said.

First, the agency will foster enhanced review and novel manufacturing approaches for medical countermeasures of the highest priority. From the development process onward, FDA will collaborate with developers and government part-ners to define viable regulatory pathways. The collaboration will aim to anticipate and resolve bottlenecks and to identify and resolve scientific problems, thus speeding drugs’ progress toward product approval.

Scientific opportunities are ‘outstripping our ability to translate new discoveries and opportunities into new products,’ —FDA’s Hamburg

Second, FDA will work with government agencies, includ-ing the US Department of Health and Human Services, to examine the legal framework, including regulatory and pol-icy approaches, for developing medical countermeasures and making them available. The agencies will assess the adequacy of this framework and identify improvements that could sup-port preparedness and response to public-health threats.

Third, the agency will try to advance regulatory science and improve the development and evaluation of countermeasures by strengthening FDA’s own scientific capacity and establish-ing partnerships with government, industry, and academia. Scientific opportunities are “outstripping our ability to trans-late new discoveries and opportunities into new products,” said Hamburg. Advancing regulatory science will help develop new ways to evaluate product efficacy, flexible approaches to product development and manufacturing, new methods to improve product stability, and new statistical approaches to assessing efficacy with limited data, she added.

FDA also will seek partners with whom to pool products, re-sources, and knowledge to develop medical countermeasures.


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: ANALYTICAL INSTRUMENTS

Probe improves monitoring of cell-culture growthFOSS NIRSystems’s Optimized BioProcess probes are available with a fixed

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specific applications to allow sufficient flow through the gap and maximize

sensitivity to low-level constituents.

The Optimized BioProcess probe, designed for use in bioreactors, has a

small diameter that allows it to fit into standard bioreactor ports. Operators

can use the smallest BioProcess Probe in a disposable bioreactor after it has

been autoclaved with a proper aseptic-insertion device. The probes have

several source and detector fibers that improve its ability to detect the light-

scattering cells present in the bioreactor with a good signal-to-noise ratio.

Chromatographysystem reduces solvent useThe Waters ACQUITY UPSFC system combines the advantages of sub-2-µm particle technology and the efficiency of supercritical-fluid chromatography. The system reduces run times by a fac-tor of 10 and reduces solvent usage by as much as 95%. The system lets scientists conduct normal phase chromatographic separations using carbon dioxide as the primary mobile phase, rather than ex-pensive and toxic solvents.

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To exert fine control over a manufacturing process, operators must have

a detailed understanding of how that process works. Personnel also need

means of verifying that their processes yield dosage forms of the appropriate

strength, quality, and purity. This month’s products illustrate ways in which

analytical instruments can help in these and other applications. A new chro-

matography system from Waters provides results quickly and reduces solvent

use. Malvern’s Zetasizer µV lessens the importance of column calibration. A

new probe from FOSS monitors cell growth in biopharmaceutical facilities.

Instrument enhancesprotein characterizationMalvern has introduced its Zetasizer µV

SEC-LS instrument, which provides the

capability of a sensitive size-exclusion

chromatography (SEC)–light scattering

detector, and that of a research-grade

batch dynamic light-scattering system.

The incorporation of light scattering into

the device improves protein character-

ization by SEC because it eliminates the reliance on column calibration and the

interference from unexpected sample-column interactions. Dynamic light scatter-

ing also enables fast screening for sample aggregates that may indicate formula-

tion problems or batch contamination.

The instrument contains Malvern’s OmniFACE and OmniSEC software pack-

ages. The OmniFACE product enables operators to connect the instrument to

third-party systems. Users thus can add light scattering to their SEC system’s capa-

bilities without buying a new system. The OmniSEC software is designed to allow

scientists to convert raw data to results quickly.

Operators can change the sensitive Zetasizer µV instrument from flow mode

to batch mode in seconds. The device’s 8-µL flow cell is intended to virtually elimi-

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Alittle more than a year ago, lead-ers of the pharmaceutical industry negotiated a deal to provide bil-

lions of dollars in discounts and fees designed to make drugs more affordable to Americans. In return, manufacturers anticipated a larger market for prescrip-tion medicines in a reformed national healthcare system, plus favorable policies governing research and development (R&D) and marketing— without explicit price controls.

Now there’s considerable uncertainty about how the Obama healthcare-reform program will be implemented, and how well the system will support bio-medical innovation and new drug devel-opment. Federal courts are weighing the constitutionality of the Affordable Care Act (ACA), while reform critics in Con-gress are challenging specific policies and curbing funds needed to implement reform initiatives. Some states face seri-ous budget problems and are looking to limit Medicaid programs, including drug benefits. The Obama administration’s budget plan for 2012 offers extra fund-ing for biomedical research and for FDA operations, but it’s uncertain whether these proposals will survive the budget-cutting battle on Capitol Hill.

Killing the dealThe search for additional funds to pay for healthcare-reform initiatives and gov-ernment health programs, moreover, is driving the Obama administration to ask Big Pharma to ante up even more. During the healthcare-reform debate of

2009, the Pharmaceutical Research and Manufacturers of America (PhRMA) agreed to pay higher Medicaid rebates and additional taxes, and to subsidize the cost of drugs prescribed to seniors caught in the “doughnut hole” of the Medicare drug benefit— all adding up to some $80 billion over 10 years. A primary gain for biomedical companies was the promise of substantial protection for innovator biotech therapies in the face of more ag-gressive generic competition.

The administration now proposes to jettison the biotech exclusivity deal and boost consumer access to generic drugs to help gain some of the $54 bil-lion needed to support Medicare pay-ments to physicians. Shrinking the ex-clusivity for innovator biologics from 12 to seven years and thus speeding less costly biosimilars to patients, ac-cording to Obama’s 2012 budget plan,

would save about $2.3 billion over 10 years. The Biotechnology Industry Organization (BIO) warned that such “questionable short-term budgetary savings” could jeopardize development of new breakthrough cures.

John Castellani, president of PhRMA, said in a press release that the proposal “flies in the face” of the administration’s talk about supporting “innovation, bio-medical research, jobs and US competi-tiveness.” But US Health and Human Services (HHS) Secretary Kathleen Se-belius told the House Energy and Com-merce (E&C) Committee last month that the administration now feels that a seven-year exclusivity period will permit innovator firms to realize an appropri-ate return on investment, while ensur-ing that new breakthrough medicines are widely available and affordable.

Another administration proposal would end pay-for-delay deals between brand-name and generic drug mak-ers that postpone when a new generic

WASHINGTON REPORT

Jill Wechsler

is Pharmaceutical

Technology’s Washington

editor, 7715 Rocton Ave.,

Chevy Chase, MD 20815,

tel. 301.656.4634,

jwechsler@advanstar.

com.

Courts and Congress seek to reshape policies

and programs affecting drug costs and access.

Health Reform Controversies Pose New Challenges Jill Wechsler

The administration

may jettison the

biotech exclusivity

deal to boost

consumer access to

generic drugs.

In Washington this month

• Congress and the Obama

administration reconsider

data-exclusivity periods for

follow-on biologics.

• House Republicans challenge

numerous Affordable Care Act

programs and policies.

• FDA hopes to gain some

budget increase for 2012,

along with higher user-fee

revenues.

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Washington Report

product comes to market. The Generic Pharmaceutical Association (GPhA) ap-plauded the shorter biotech exclusivity period, but criticized the curb on settle-ments as “misguided.” Castellani agreed with the generic-drug makers, noting that these “pro-consumer settlements” do not delay generic entry and often bring low-cost drugs to market sooner. Federal Trade Commission officials, however, have been pushing hard to curb such arrangements, which they insist are anti-competitive and costly to consum-ers. The numbers-crunchers predict that banning pay-for-delay deals will save the government $540 million next year and nearly $8.8 billion through 2021.

The generic-drug gains together pro-vide only a small portion of the resources needed to finance the “doc fix.” Most of the money would come from proposed reductions in federal payments to state Medicaid programs, stiffer scrutiny of certain Medicare reimbursement to in-surers, and proposals to reduce Medicare fraud and abuse. The plan also proposes

to increase tracking of high prescribers in Medicaid programs to reduce exces-sive drug utilization by states. And man-ufacturers would be hit with additional penalties if they fail to pay appropriate Medicaid drug rebates and to comply with rebate rules and FDA policies for listing drugs on databases. But these policies generate virtually no tangible savings, and it’s questionable whether the squeeze on biotech exclusivity is worth the rather small budgetary gain to the government.

More oversightAlthough pharmaceutical companies traditionally look to Republican allies in Congress to champion patent protection and product exclusivity, GOP leaders still are smarting over PhRMA’s support for Obama’s healtchare plan. As part of its investigation into HHS implementation of healthcare reform, House E&C Com-mittee Chairman Fred Upton (R–MI) is looking hard at the “secret negotiations” between the White House and healthcare

interest groups, including pharmaceuti-cal companies, leading to enactment of the reform legislation. E&C Committee Republicans complained in a Feb. 18, 2011 letter to White House Aide Nancy-Ann DeParle (formerly head of the White House Office of Health Reform) that instead of the open and transpar-ent debate on healthcare legislation that Obama had promised, deals were made behind closed doors with providers, drug companies, and others.

Upton and his colleagues are scruti-nizing the HHS process for determining whether states and healthcare providers and payers should receive waivers from complying with specific ACA rules, a process they believe indicates widespread problems associated with implementing the reform law. The E&C Committee also wants to know more about HHS support for establishing state-based in-surance exchanges and for developing new rules governing insurers, including standards for “essential benefits” that will shape medical and drug coverage

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Washington Report

[see sidebar, “Keeping drugs ‘essential’”]. FDA operations and policies are also

under scrutiny by GOP leaders. The E&C Health subcommittee held a hear-ing in February to examine whether FDA’s slow process for approving more complex medical devices for market is harming US device makers. And Re-publicans once more are examining the three-year-old heparin crisis, complain-ing in a Feb. 23, 2011 letter to FDA Com-missioner Margaret Hamburg that still no one knows the source of the adultera-tion nor the Chinese culprits—all while imports in pharmaceutical ingredients from that China are booming.

Unraveling the piecesIn addition to hauling administration of-ficials up to Capitol Hill to explain their actions, Congress is moving forward with efforts to revise portions of the ACA, after failing in January to repeal the legislation. In the low-hanging fruit department, Democrats and Republicans agree on the need to repeal the 1099 re-porting policy, a burdensome rule that requires businesses to report to the IRS any expenditure over $600—a require-ment that has little to do with healthcare. President Obama has signaled support for killing the program, but the challenge is to find the $22 billion or so needed over the next 10 years to offset potential revenue gains from the policy.

President Obama and Congressional leaders also are eyeing medical-liability reform as a way to reduce spending on

unnecessary healthcare services in-curred as a defense against malpractice charges. A bill recently approved by the House Judiciary Committee would cap noneconomic and punitive dam-ages, limit the time for filing suits and curb attorneys’ contingency fees. Such proposals face considerable opposition from lawyers and some patient advo-cates, yet Obama expressed interest in revising malpractice policy in his State of the Union speech and included $250 million in his 2012 budget plan to sup-port grants to help states rewrite their malpractice laws and establish health courts. Reform could move forward if there’s clear evidence that damage caps would save money by reducing defen-sive medicine and other costs.

But there’s little bipartisan support for improving ACA implementation. President Obama recently voiced sup-port for legislation that permits states to opt out of exchanges and the individual mandate, provided the state can devise alternative ways to cover more uninsured individuals. Although this action was considered a major concession by ACA supporters, Republicans labeled it a “fig leaf” that didn’t increase local choices.

The battle continues over Republican efforts to limit federal spending overall. Policymakers avoided a government shutdown in early March by agreeing to a short-term fix on funding the federal government for the current (2011) fiscal year. But Republicans still demanded some $100 billion in cuts for this year, as

well as curbs on many ACA provisions, including individual coverage require-ments, medical-loss ratio rules, health insurance exchanges, and Medicaid ex-pansion plans.

Critics also are looking to eliminate a number of entities established by ACA, but seen by Republicans as examples of a federal government over-reach into state and private sector activities. Although health prevention has broad appeal, Re-publicans want to dissolve the Preven-tion and Public Health Fund, which is supposed to dispense some $15 billion over 10 years to support state and local prevention and health initiatives. This prevention “slush fund,” say Republicans, is excessive—and its resources could be tapped to offset the cost of repealing the 1099 IRS reporting requirement.

Republicans also don’t see a need to spend $10 billion over 10 years to fund the Center for Medicare and Medicaid Innovation (CMMI), which was established by ACA to support re-search and testing of reimbursement and coverage approaches for Medicare and other health programs. There’s also skepticism among Republicans about federal investment in compara-tive effectiveness research (CER), when private plans and local organizations have funded technology assessment on their own. Some Republicans would like to shutter the Patient-Centered Outcomes Research Institute (PCORI) and use its $500 million a year in ap-propriated funds for other purposes.

Pharmaceutical companies have their eyes on an initiative at the US

Department of Health and Human Services (HHS) for defining “essential

health benefits” that will have to be offered by all health plans

participating in future health insurance exchanges. HHS will decide just

how comprehensive and detailed those benefit categories are–or whether

bare-bones packages will fly–with help from an Institute of Medicine (IOM)

blue-ribbon panel that was formed to analyze the options and advise HHS

by September on how to proceed. Prescription-drug coverage is listed in the

Affordable Care Act (ACA) as 1 of 10 essential benefit categories, but there is

room for different levels of coverage and copays, provided that the packages

conform to “typical” employer benefit packages.

At the first meeting of the IOM committee in January, MIT economist

Jonathan Gruber described the crucial tradeoff between offering generous

coverage and keeping benefits affordable. Don’t “get greedy,” he advised

the panel, noting that ACA already improves coverage by eliminating

discrimination based on pre-existing conditions and curbing annual and

lifetime coverage limits. More comprehensive benefits, he explained, impose

higher costs on private payers, as well as on federal and state governments.

It is no surprise, however, that a long list of providers and patient

groups want their services and products covered. Chiropractors want to

be considered essential, as do fertility specialists, rehabilitation clinics,

psychiatrists, and plastic surgeons. Oncologists fear curbs on coverage of

certain costly treatments, as do patients with rare conditions. Pharmaceutical

companies similarly are leery of limits on reimbursement of more expensive

medicines, and pharmacists want compensation for counseling on proper

medication use. States want flexibility to keep local mandates in place,

while employers and payers advise against considering state mandates as

“essential.” Stay tuned.

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Washington Report

Pharma companies generally support development of standards and policies for CER research, but probably won’t expend much effort fighting to pre-serve PCORI.

There’s not much good news for the pharmaceutical industry regarding the battle to repeal and revise healthcare reform. Manufacturers already are paying stiffer Medicaid rebates and absorbing 50% discounts on drugs for Medicare Part D beneficiaries caught

in the coverage gap. The IRS is estab-lishing rules for collecting some $2 to $3 billion in new industry taxes be-ginning this year, based on company sales of branded drugs. At the same time, more onerous legislation is on the table. Once again, there is biparti-san support for a Senate bill to permit reimportation of high-cost medicines from Canada. And Democrats want to eliminate tax deductions for direct-to-consumer advertising.

Funding FDAStiffer FDA user fees are on the horizon as well. The Obama administration has requested a $4.3 billion budget for the agency in 2012, a reasonable increase given the tight funding environment in Washington. But most of the gain would come from higher user fees on medical product manufacturers, and most of any added appropriations would fund a huge expansion in food safety oversight autho-rized by Congress, but without support from food industry fees.

Any extra money for FDA’s Center for Drug Evaluation and Research is designated to support development of medical countermeasures and biosimi-lars, to expand monitoring of imported medical products, and to improve the safety of certain high-risk products such as vaccines and human tissue. New generic-drug user fees, which at long last appear to be moving toward reality, would improve the review of generic drugs, while other proposed fees would support more field inspec-tions. There’s a small amount of money earmarked for improving regulatory science at FDA, which would primar-ily complete work on a new laboratory complex for drugs and biologics at the agency’s White Oak, Maryland campus. Without an extra $24 million to get the new laboratory operational, FDA would have a new facility with no equipment, and still have to pay rent on an old, ob-solete laboratory.

FDA is negotiating with manufactur-ers on its next five-year plan for collect-ing fees from industry under by the Pre-scription Drug User Fee Act (PDUFA). Meanwhile, the agency wants drug and biotech firms to ante up some $850 mil-lion in PDUFA fees in 2012, up more than $275 million over 2010. About $600 million will fund drug oversight, and $125 million will support regulatory activities involving vaccines and other biologics. Combined with all the added costs imposed by healthcare reform, and apparent threats to expanding healthcare coverage to some 30 million uninsured Americans, manufacturers have to worry about the erosion of resources to support new drug development. PT

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The pulse of the biotechnology in-dustry feels somewhat weaker since its lifeblood, venture capital fund-

ing, proved disappointing during the last half of 2010. Gains made during the second quarter of last year faded quickly during the third quarter and dropped off steeply during the fourth quarter, placing biotechnology second for the year behind software in venture capital funding.

For the full year, dollars raised by the industry rose a modest 3% over 2009 to $3.7 billion, according to the MoneyTree Report by PwC and the National Venture Capital Association, based on data from Thomson Reuters. Deal volume declined 8% to 460 deals in the same period.

The decline in venture capital funding for the biotechnology industry undoubt-edly reflects an increasingly difficult US regulatory environment. Biotech com-panies and investors perceive a lack of transparency in the approval pathway.

In a recent survey by PwC and BIO-COM, 60% of life–sciences companies responding said that FDA had changed its position on at least one review dur-ing the past two years. Approximately 40% of respondents agreed that FDA denied some approvals primarily be-cause of inadequate resources. Other concerns raised in the survey were that FDA sometimes changed reviewers and clinical–trial requirements midstream, and that reviewers repeatedly asked for additional data.

Regulatory uncertainty has a huge im-pact on the cash–burn rate of start–ups and on venture capital firms’ willing-

ness to invest. No one can predict how much capital a company will require just to see a drug through the approval pro-cess. During the past three years, many start–ups have exhausted their research and development funds, even after cut-ting staff and costs to the bone, and many have gone under. The possibility of high returns may no longer be enough to entice reluctant investors to take a chance on fledgling biotechs when the chances of failure appear to be increasing.

A glimmer of hope lies in a recent pickup in the exit market. The biotech-nology space has seen some liquidity during the past six months, following a dearth of exit activity during 2008 and 2009. Biotechnology captured three of the 32 US venture–backed initial public offerings (IPOs) in the fourth quarter of 2010.

Pacific Biosciences at $200 million, the largest biotech IPO of the year, and Complete Genomics at $54 million, generated excitement for the indus-try. These companies are working to reduce the cost of genomic sequenc-ing, a highly promising tool in terms of advancing the field of personalized medicine. The positive IPO trend has continued into the beginning of 2011.

An uptick in mergers and acquisi-tions toward the end of 2010 and con-tinuing into 2011 also has helped to free up capital and time for venture funds, allowing them to seek out and nurture new enterprises. Big Pharma continues to buy large and small bio-techs with products in late–stage clinical trials to replenish diminish-ing product pipelines as blockbuster patents expire. Big Biotech is also pur-suing a similar course, buying smaller

biotechs with promising products in late–stage development.

In part because of stepped–up exit activity, early-stage funding rose 6% for biotechnology last year—not a big jump but enough to reflect renewed interest on the part of venture capitalists. Exits by late–stage companies put more money on the table for early–stage ventures.

In contrast to the overall investment picture for the sector, the outlook for companies receiving funding for the first time improved during 2010. Biotechnol-ogy was second to software in the value and volume of first–time funding. This ranking bodes well for start–ups with voracious appetites for research and de-velopment funds but little or no revenue.

The San Francisco Bay area, which includes San Francisco–Berkeley and San Jose, continues to attract the high-est level of venture funding for the US biotechnology industry. California serves as a nurturing ground for the industry:•More than half of US venture funds

are based in the state•The San Diego and San Francisco

Bay regions are home to several high–quality research institutions, which serve as biotechnology incu-bators•A skilled workforce and entrepre-

neurial culture helps foster and staff biotech start–ups.

Although California should continue to lead in funding for the near term, the uncertain US regulatory environment could send more investors offshore to look for opportunities. More transpar-ency and upfront guidance from FDA could go a long way toward lifting the venture capital outlook for the biotech-nology industry. PT

Tracy T. Lefteroff is a partner in the life

sciences practice of PwC US,

[email protected].

An uncertain regulatory environment

affects funding for biotechnology

Tracy Lefteroff

Biotechnology Loses Lead in Venture Capital Funding

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We all have a scrupulous eye for subjects we are passionate about. Foodies insist on using

the most authentic ingredients for their favorite dishes. Classic-car collectors require the smallest details to be as close to the original as possible. And statisticians cajole nonstatisticians to avoid classic pitfalls in applied statis-tics. In this latter case, however, it is not a matter of taste or authenticity. Incorrect statistical practices can result in erroneous calculations and poor conclusions. Some errors are small, but others can be monumental, and since we never know which way the apple will fall, we should treat them all the same.

Although there is always a large scope for error in a statistical project, some mistakes are more common than others. Those that appear to be correct on the surface are what we call pitfalls.

the most common and deadliest pitfalls This section highlights some of the most common challenges facing statisticians.

Reportable values. Reportable value or result is not defined for the data and the analysis (1). By definition, the re-portable value is the end result of the complete measurement method as doc-umented. It is the value compared with

the specification and the official value most often used for statistical analysis. If different people or departments have different definitions, confusion reigns

and out-of-tolerance and out-of-speci-fication investigations multiply.

averages. The average of a set of aver-ages is correct only if the sample sizes are the same. Otherwise, the averages are weighted by the sample sizes (2). In addition, avoid averaging standard deviations even when the sample sizes are the same. The variance is the stan-dard deviation squared. Variances can be averaged when the sample sizes are the same. If the sample sizes are not the same, then a weighting formula is used (2).

the percentage relative standard devia-

tion. The percentage relative standard deviation (%RSD) is not a substitute for the standard deviation because they measure different aspects of variation. Report both with the sam-ple size. Also, avoid trying to average %RSDs or calculate %RSD on data expressed as percentage recovery. The data is already a percentage, so the av-erage and the standard deviation will

also be percentages.Sample size. Always report the sample

size. Remember the famous rat study where one third of the rats got better, one third got worse and the third rat ran away?

Summaries. Avoid gratuitous sum-mary statistics without a clear purpose; they cloud the interpretation. Likewise, printing out massive lists of all possible summary statistics of all possible sets, subset and sub-subsets isn’t worth the paper it is printed on.

Values and ranks. Give absolute values when looking at relative changes. For example, 2 out of 100 million versus 1 out of 100 million is a 100% increase, but it is still only 2 out of 100 million. Trust your reader to understand the practical implications of the data.

Ranking anything without giving absolute values and/or some sense of comparison to practical importance can be misleading. For example, con-sider that we ranked schools using a metric that results in one school being at the bottom of the list and another school at the top. But then, we realize both schools produced Nobel Prize winners. Does the ranking therefore have any meaning?

charts and graphs. Avoid pie charts unless your goal is to deliberately con-fuse your reader. Graph the data before starting a formal statistical analysis. Common graphs include histograms, time plots, and scatter plots. Attempt to get cause and effect on the same page (3).

underlying data. Attempt to deter-mine the underlying distribution of the data before starting a formal statistical analysis. While the normal distribu-

Remember the

famous rat study

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The hardest errors to spot are the ones that

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Lynn Torbeck

Pitfalls in Statistics

Lynn D. Torbeck

is a statistician at

Torbeck and Assoc.,

2000 Dempster Plaza,

Evanston, IL 60202,

tel. 847.424.1314,

[email protected],

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Statistical Solutions

tion is the most common, many other distributions, such as the log-normal, are also found.

If the data are symmetrical around the average, use the average and the standard deviation. If the data are skewed, the median and interquartile range is preferred. This is not a hard and fast rule, just good practice.

assay results. Correcting or adjust-ing one assay result with the result of

a second assay that has the same as or larger variance than the first will re-sult in more total variability, not less, because the variances add up. This is known as the “weight to run” problem, in which tablet weight is adjusted using an assay test for potency. This problem can lead to rejecting good lots of ma-terials and products. In most cases, setting the weight equal to the target results in less variation.

Population paremeters. Recognize that the population parameters, such as mu (µ), the population mean, and sigma (σ), the population standard devia-tion, are single values, whereas sample estimates of the population mean and sample estimates of the population standard deviation are random results from a distribution. Every additional sample gives slightly different results, so problems arise when sample esti-mates are treated as if they are popula-tion values. This leads to treating other sample estimates such as %RSD and Cpk as if they are without variation. Confidence intervals should be cal-culated for these statistics to estimate their uncertainty.

Definitions and intervals. Define in exact detail what the phrase “within the variation of the method” means for specific applications because there is no universally accepted definition. Try not to use use confidence intervals to set specification criteria. Instead, use tolerance intervals to get a starting point. Overlapping or non-overlapping confidence intervals are not a signifi-cance test.

The most egregious pitfall of all is calculating the sample average plus and minus three times the sample stan-dard deviation without considering the sample size and distribution, and then using it for confidence intervals, set-ting specification criteria, identifying outliers and all other manner of ad-hoc comparisons. It is not a universal statistical tool. In fact, this equation came about in the 1920s via Dr. Walter Shewhart for defining control charts and is no longer of much use today.

Of course, there are many more potential pitfalls, and when in doubt, contact your local statistician.

References 1. L. D. Torbeck, “Analytical Validation”

supplement to Pharm. Technol. 23, 21-23 (1999).

2. M. Spiegel and L. Stephens, Schaum’s Outline of Statistics Fourth Edition (Mc-Graw Hill, NY, NY, 2008).

3. E. R. Tufte, The Visual Display of Quan-titative Information (Graphics Press, Cheshire, CT, 1983). PT

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Protein aggregates in biological drugs have the potential to trig-ger an immune response in the

patient, which, at the very least, can decrease the drug’s effectiveness, and at worst could cause potentially harmful side effects. Part of the industry’s ef-forts to limit the presence of aggregates in their therapies entails testing for subvisible particles, which potentially are the most immunogenic aggregates. Subvisible protein particles are relatively large assemblies that contain anywhere from thousands to millions of protein molecules. US Pharmacopeia <788> “Particulate Matter in Injections” lim-its the number of particles equal to or larger than 10 µm that are allowed per container of drug (1).

The disregarded particlesUSP does not address particles smaller than 10 µm in parenteral drugs, how-ever. This omission drew little comment until it was mentioned in a 2009 article by John F. Carpenter, associate professor of pharmaceutical sciences at the Univer-sity of Colorado Health Sciences Center. “If only particles > 10 µm were quanti-fied in a given product, there could be gaps in understanding of important deg-radation products and in product-quality assessment,” wrote Carpenter (2).

Carpenter and his coauthors, includ-ing eight officials at FDA’s Center for Drug Evaluation and Research, raised the possibility that particles smaller

than 10 µm could affect the safety and efficacy of therapeutic protein products over their shelf lives. Manufacturing operations sometimes create hundreds of thousands of particles 1.5–3 µm in size, the authors noted, and protein particles can accumulate over time during storage of the final product. Yet recommendations for detecting such particles are lacking.

Carpenter called for industry and aca-demia to define current particle-counting instruments’ capabilities to observe par-ticles as small as 0.1 µm, recognizing the potential need for new instruments. The effect of protein aggregates on immuno-genicity also should be examined, includ-ing “studies of the role of protein class, amount of aggregate, size of aggregates, and protein conformation in aggregates,” wrote Carpenter (2).

The regulators’ responseCarpenter’s article attracted the attention of drug companies and regulatory bodies around the world. To gather information about the topic, USP held a discussion about particle characteristics and their effect on liquid and aerosol products dur-ing their workshop on particle detection and measurement on Dec. 8–10, 2010.

Participants spoke about sampling techniques and methods for data expres-sion and interpretation, according to Scott Aldrich, principal consultant for Ultramikro and member of the 2010–2015 USP Dosage Forms expert com-

mittee. Much of the workshop discussion focused on the difficulties in adequately measuring the sizes and concentrations of particles in the sub-10-µm population for biotherapeutic formulations.

USP is assembling an expert panel to determine whether to establish a new particle-limits chapter for biotherapeutic pharmaceutical injections. “We antici-pate any new chapter to provide meth-ods tailored to the sensitivities of these formulations, with options for method-ologies and a discussion of typical effects upon particle size, yet with no plan for limits specific to the biomolecular for-mulation,” says Aldrich.

FDA has not published regulations about particles smaller than 10 µm, partly because so few data are available. But the agency has asked firms to start assessing the background and control of subvisible particles in that size range, which previously had been ignored. FDA is interested in determining whether particles smaller than 10µm correlate with adverse reactions reported through USP’s or FDA’s medical-awareness sys-tems, says Cherris. The data also could help the agency decide whether to issue a guidance.

FDA primarily is approaching biophar-maceutical firms because they must moni-tor their products for intrinsic protein-based particles and control the extrinsic particles that might infiltrate their pro-cess, according to Roy Cherris, managing partner of Bridge Associates International. Large biopharmaceutical companies are highly interested in trying to determine whether particles smaller than 10 µm are a major cause for concern, says Cherris.

The particles’ originsVarious types of particle smaller than 10 µm can be present in a parenteral drug, but regulators’ primary concern is with proteinaceous particles because they are more likely to cause immunogenic-ity than extrinsic particles. Denaturation can lead to aggregation that causes the native monomeric therapeutic protein to form dimers, trimers, or polymers. Dur-ing development, proper consideration of the formulation, the way the material is suspended in the formulation, and the

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formulation’s dynamics over time can help prevent intrinsic particles from forming or agglomerating.

Stresses during product manufacture (e.g., freezing, thawing, agitation, and foaming) also could lead to the forma-tion of aggregates. These concerns, too, can be addressed during formulation and process development, and the indus-try already knows a good deal about these concerns. “The risk for aggregate and po-tential proteinaceous particle formation is really product dependent. Certain mole-cules are more sensitive than others,” says Satish K. Singh, research fellow at Pfizer. “It is imperative that the formulation- development scientist understand the weaknesses of the molecule and the im-pact a drug-product manufacturing pro-cess can have on it.”

The most common type of extrinsic particle that is present in this size range is silicone oil, which manufacturers use to coat cartridges, syringes, and stoppers. Particles of glass and stainless steel, com-mon materials in pharmaceutical manu-facturing, conceivably could migrate into parenteral products, too. Piston fillers and filters reportedly have shed particles into parenteral products, and it is possible for hair or fibers shed from wipes to get into the product, too.

Although the potential for extrinsic contamination always exists, industry professionals believe that current controls for preventing it are adequate. “In aseptic processing, liquids pass through one or more 0.22-µm filter media. In our current environment, control of visible to subvis-ible particle content is believed to control the sub-10 µm content,” says Aldrich.

The industry’s perspectivePharmaceutical manufacturers generally view FDA’s concerns about these subvis-ible particles as legitimate. Scientists sus-pect that proteinaceous particles smaller than 10 µm may have caused certain reported immunogenicity issues. In ad-dition, glass and stainless-steel particles in that size range have spurred several recent product recalls, says Cherris.

Yet drugmakers are not necessar-ily convinced that the particles are al-ways hazardous. Companies agree with

regulators about the need to monitor protein-based particles smaller than 10 µm because of their potential immuno-genicity. But human clinical data on the connection between protein aggregates and immunogenicity are equivocal be-cause a multitude of factors determines a patient’s immune reaction, and it is dif-ficult to identify the effect of a specific quality parameter, says Singh. “Animal-model data indicate that immunogenicity can be triggered by protein aggregates or particles, but it is also clear that not all aggregates or particles cause immunoge-nicity,” he says.

Most of the standard, small-volume parenterals probably are not a cause for concern, says Cherris. Many of them either are not proteins or are proteins that do not cause problems. For exam-ple, vaccines generally have not been indicated in any of the reported im-munogenicity problems, he adds.

Whether these subvisible particles can affect drugs’ efficacy also is a matter of de-bate. “These particles cannot decrease the effectiveness of protein drugs directly be-cause they often represent only nanograms or micrograms of protein” and would not measurably decrease the amount of avail-able drug, says Singh. If the particles cause an immune reaction, however, the result-ing antibodies can either have no effect,

have an indirect effect through pharmaco-kinetics or pharmacodynamics, or directly negate the drugs’ efficacy. “The worst-case scenario is if these antibodies are neutral-izing against a nonredundant endogenous protein also, in which case, the antibodies become a safety risk,” says Singh.

The nature of the subvisible particle may determine whether it causes adverse reactions. Not every biological product necessarily is associated with immuno-genicity, says Cherris. “I would say that there are only subtle indicators of that [problem] in specific product cases, many of which in the biotech world are still in development,” he adds.

Others agree that the risk of immuno-genicity appears so far to be associated with certain products. “Specific char-acteristics in the aggregates, probably related to the structure of the protein in the aggregate and the nature of the ex-posed epitopes, cause some aggregates to be immunogenic whereas others are not, says Singh. Likewise, the risk that par-ticles smaller than 10 µm will decrease a drug’s efficacy also is likely to be limited to specific products or formulations.

Some drugmakers point out that no injectable solution is required to be com-pletely free of subvisible particles, which have been present in marketed products for some time. Nevertheless, the link

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between immunogenicity and particles smaller than 10 µm has not been studied thoroughly, and our understanding of what these particles do is limited.

“I think it would be in everyone’s best interest for people to develop an under-standing of subvisible particles, their gen-eration, and analysis, so as to respond if we determine that they present any type of risk,” says Morrey Atkinson, chief scientific officer and vice-president of research and development at Cook Phar-mica. Companies can begin by generat-ing the data during product development, while the drug is still in the clinic. If these subvisible particles are stable over time, they are not likely to pose a risk.

The appropriate methodsCompendial methods. Measuring and ana-lyzing particles smaller than 10 µm is challenging for quality-control personnel because the standard tests on parenteral products don’t examine particles in this size range. But the required technology is relatively straightforward and readily avail-able, according to industry sources.

The preferred method for the first round of testing is light obscuration, which is described in USP <788> (1). Light obscuration detects particle sizes between 2 µm and hundreds of microm-eters. Companies commonly calibrate the instruments to 2 µm, yet most firms out-side the biopharmaceutical industry gen-erally don’t examine the region of par-ticles smaller than 10 µm, says Aldrich.

The technique has known limita-tions, however. Air and immiscible oils in a product could lead to an artificially high particle count using light obscura-tion. And the method sometimes fails to properly size nonspherical particles and those with a refractive index close to that of the liquid formulation, thus resulting in inaccurate and low counts.

Scientists can use the membrane-microscopic technique as an alternate or secondary method. This method is a more direct revelation of particle content than light obscuration is because it isolates solids or semisolids from the sample liq-uid onto microporous media and counts particles in size thresholds. Membrane microscopy has a wide detection range

(i.e., from 5 µm to many millimeters). The technique also has shortcomings,

though. “Because it is [an] optical-mi-croscopy evaluation at 100 × [magnifi-cation] with reflected illumination, par-ticles below 10 µm are difficult to resolve on the porous membrane surface,” thus making accurate counting difficult, says Aldrich. Inherent proteinaceous particles also may be difficult for the microscopist

to count or size. Air and immiscible oils are not problematic, however, because particles are observed in a dry state and may appear as stains.

In addition, the membrane microscopic method is tedious, and no company will resort to it “unless they have a real need to, or if they had to use that methodology to verify the counts they received during light-obscuration counting,” says Cherris. Some equipment automatically counts and identifies particles on a filter surface, but it is much more expensive than light-obscuration particle counters are.

The most economical way to test for particles smaller than 10 µm is to use au-tomated particle counting first, then to use microscopic and spectroscopic techniques to identify the particles on a membrane surface, says Cherris. “Most companies that have recently purchased new light-obscuration particle counters have the sensor technology now to start counting down in that range.”

Noncompendial methods. Many biophar-maceutical companies use alternate, non-compendial methods to understand the subvisible particle population. These tech-niques are reliable, but have a measure-ment gap from 0.1 to 1 µm, says Aldrich.

One such approach is the Coulter prin-ciple, which uses a dilution of a product in conducting liquids to measure particles between 0.4 and 50 µm, depending on instrument setup. Formulation buffering

and preparation affect the measurements, but the technique measures particles and aggregates in a solution to reveal a rele-vant particle–product state.

The flow-imaging approach is an ex-tension of optical microscopy that uses cameras to detect and record in situ particles in product fluid. The method detects particles from 0.7 µm to 1 mm, depending on their shape. This tech-nique’s ability to capture particle images for subsequent analysis allows the evalua-tion of the particle population under vari-ous shape and size contexts, says Aldrich.

Investigating particles in this size range is important and requires more than one method. Monitoring particles smaller than 10 µm “can provide valu-able information on changes in product stability, protein aggregation, and prod-uct attributes that affect patient safety,” says Dan Berdovich, manager of quality assurance and regulatory affairs at Micro Measurement Laboratories.

The next stepsCertain drugmakers are collecting in-formation about particles smaller than 10 µm at FDA’s request. Although its goal is sound, FDA must agree with industry on the most appropriate stan-dardized testing methodology, accord-ing to Cherris. “If we don’t collect data in the 2–10-µm range in a comparable way, it will be a long road, and probably the wrong road to follow in understand-ing these particle populations,” he says.

The industry, through large nonprofit organizations focused on bettering phar-maceutical quality, should sponsor this data-collection program, not the govern-ment, according to Cherris. The Parenteral Drug Association or the US Pharmacopeia should create a scientific committee to col-lect and study the data, and possibly draft a new standard, he says. “Without that type of industry rally in an organized manner, the requests from FDA to collect this in-formation will not be widely effective.”

References 1. USP 23–NF 18 (US Pharmacopeial Con-

vention, Rockville, MD, 1995), pp. 1813–1819

2. J.F. Carpenter et al., J. Pharm. Sci. 98 (4), 1201–1205 (2009). PT

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DOJ officials have been clear about their intentions to closely scrutinize over-seas business dealings of US pharmaceuti-cal companies with an eye toward viola-tions of the Foreign Corrupt Practices Act (FCPA). Speaking at the annual Pharma-ceutical Regulatory and Compliance Con-gress last November 2009, US Assistant Attorney General Lanny Breuer pulled no punches, promising that DOJ “will be vigilant in holding companies and indi-viduals who break the law accountable,” and that application of FCPA to the phar-maceutical industry is going to be “a focus for the Criminal Division in the months and years ahead.”

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company or issuer of “anything of value” to “foreign officials” in an effort to secure business. Such payments made to foreign officials through subsidiaries, intermedi-aries, or third-party agents are as illegal as direct payments if made knowingly or with conscious disregard for the law. US issuers, including foreign companies on US exchanges, are required to maintain a sufficient set of FCPA-related internal con-trols pursuant to relevant federal securities laws under the SEC-enforced provisions. Violations include purposely recording payments to foreign officials improperly, mislabeling bribes as “commissions,” or other expenses, omissions of payment en-tries, and similar actions.

FCPA was enacted in 1977 but was used sparingly for a long time. During its first 20 years of existence, it was used to prosecute just 17 companies. Over the last five years, however, DOJ has prosecuted 57 compa-nies for FCPA violations—more than the total number of prosecutions brought be-tween 1977 and 2005—and during the past two years, it has launched approximately 260 related investigations. Historically, healthcare and pharmaceutical companies have accounted for about 11% of FCPA en-forcement activity, but it’s no mystery why DOJ is focusing its scrutiny in those indus-tries. Nearly one third of pharmaceutical companies’ total sales are now generated outside US borders, where health systems are regulated, operated, and financed by government entities to a significantly greater degree than in the United States. As a result, companies doing business overseas are likely to interact with foreign officials on a fairly frequent and consistent basis.

The bottom line for the pharmaceuti-cal industry is increased exposure to risks of FCPA-related infraction. Many clinical trials and research now take place abroad, often in a decentralized manner involving third parties. These actions raise signifi-cant monitoring and compliance problems for pharmaceutical firms, including the expansive definition of “foreign official.” Companies may be working for govern-ment healthcare programs or institutions or for state-owned organizations which, in turn, may be considered “foreign officials” for purposes of the FCPA. For example, because Chinese regulators are involved in most business enterprises, most hospi-tals and employees of hospitals—including

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doctors and technicians—are considered “foreign government officials.”

DOJ is working with the Health Care Fraud Unit, FBI, US Attorneys’ Offices, and IRS’s Criminal Investigation Division to examine all international business trans-actions of pharmaceutical companies, and its efforts extend to investigation and pros-ecution of senior executives. “[For] enforce-ment efforts to have a real deterrent effect, culpable individuals must be prosecuted and go to jail,” Breuer insisted.

Violations by pharmaceutical and healthcare companies that are currently under investigation include bribing doc-tors to purchase drugs, paying company sales agents commissions that are passed along to doctors, paying researchers to in-fluence the reliability or integrity of data in clinical trials, and paying regulators to win drug approvals.

Other payments considered illegal may not be so apparently “corrupt,” because the statute applies to “anything of value.” If made in an effort to secure business, pro-hibited conduct may also include inviting officials to participate in overseas travel for purposes of attending conferences and educational seminars or to promote a particular product, funding postmarket-ing studies, and gifts of free pharmaceuti-cal samples. Even payments to charitable foundations can be problematic. In 2004, a US-based pharmaceutical company settled with the SEC for a violation of the FCPA’s accounting provisions after its Polish sub-sidiary made a series of payments to a local charity to induce the group’s president (who was also a Polish government official) to influence the purchase of the company’s pharmaceutical products.

In the context of merger and acquisition activity, pharmaceutical companies must be wary not to “purchase” FCPA liabil-ity by failing to conduct due diligence on proposed transaction partners. Such “suc-cessor liability” generally attaches in stock transfers or mergers, but may also attach in an asset purchase. Prior to any merger, the acquiring company should assess cor-ruption levels of the countries in which the target entity conducts business; search for government affiliations; review the target’s existing FCPA compliance program and controls; test the adequacy of the target’s books and records; and insert contract pro-

visions in the merger agreement that would indemnify the acquirer against FCPA vio-lations and include representations and warranties that the target has made no corrupt payments to foreign officials.

Penalties for running afoul of FCPA can be substantial. Companies convicted under the act’s antibribery provisions are subject to criminal fines up to $2 million per violation, and individuals face up to five years’ imprisonment, along with criminal fines of up to $100,000 per violation. Ac-counting provision violations can trigger fines as high as $25 million for companies while individuals face up to $5 million in fines and 20 years’ imprisonment. In ad-dition, the SEC can impose civil penalties up to $10,000 per violation. The cost of the investigation may also run into the hun-dreds of thousands of dollars. In December 2008, a German corporation and three of its subsidiaries pleaded guilty to criminal violations of FCPA’s internal controls and account provisions. They paid criminal fines of $450 million, disgorged profits totaling $350 million, and paid approxi-mately $856 million in additional fines and disgorgement of profits imposed by the German government.

Some of DOJ’s “red flags” for pharma-ceutical company FCPA violations include:

• Lack of transparency in expense and ac-count records

• Transactions with a foreign third-party

clinical research organization (CRO) that has ties to government officials or relies on government contracts

• Unusual payment patterns

• Collaborations with CROs based in

countries or geographic regions with rep-utations for bribery (e.g., Russia, China, Middle East, Africa, Italy, Greece).To avoid running afoul of FCPA and

its enforcement agencies, pharmaceutical firms should:

• Develop an FCPA compliance policy,

setting the right tone at the top of the or-ganization and communicating it regu-larly to senior executives so that compli-ance is aligned with corporate policy.

• Translate the company code of con-duct into the languages of each coun-try where the company does business and ensure the translation is distrib-uted to officers, employees, and agents in each office.

• Require interactive Internet-based train-ing for both foreign-based employees and foreign agents. Training should be in the recipient’s native language, ac-companied, whenever possible, by per-sonal training conducted by in-house counsel or ethics officers.

• Review sales and marketing operations

in high-risk countries, particularly where there is dependence on third-party agents.

• Conduct documented due diligence on

all CROs prior to engagement to identify any potential FCPA-related risks.

• Prohibit compensation packages for

foreign agents that would incentivize corrupt payments, such as success fees, to foreign officials.

• Include a contractual right to audit

CROs for compliance and subject all ex-penditures by foreign agents to frequent and random audits.

• Require foreign agents and distributors

to operate under written contracts that specify prohibited conduct under the FCPA and obtain signed certifications that they understand and will comply with those provisions.

• Require written prior approval by an

identified compliance officer for any-thing that could be construed as a pay-ment to a foreign official.

• Make FCPA review part of merger-

and-acquision due diligence; insur-ance policies generally will not cover FCPA violations.

• Institute confidential reporting

mechanisms.Overall, the best approach for phar-

maceutical companies dealing with third parties that are involved in the pharmaceutical industry abroad is to proceed under the assumption that the third parties are government officials in some shape, manner or form, and that for purposes of FCPA compliance, they are all “foreign officials.” Consider any pay-ment to these “foreign officials” as poten-tially creating a risk. Heightened scrutiny should be exercised to evaluate all expen-ditures made to these “foreign officials” to assess their reasonableness and connec-tion to a legitimate business purpose, and to ensure that, if made, the payments are accurately documented in the company’s books and records. PT

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Catalysis plays a crucial role in small-molecule synthesis, whether it is in mak-ing an intermediate or the final active pharmaceutical ingredient (API). The effective development and application of a catalyst system can improve reaction conditions, yield, and optical purity as well as produce more efficient chemical

transformations. As recent developments show, chemocatalysis and biocatalysis continue to be an active area of academic research and business investments.

Advances from academiaOxidative enamine catalysis. Researchers at the East China University of Science and Technology, the Shanghai Institute of Materia Medica, and the University of New Mexico recently reported on a new chemical transformation, oxidative enamine catalysis, a potentially valu-able approach in synthesizing chiral intermediates. The researchers noted that although iminium catalysis, which involves the transformation of iminium IM

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ions to enamines, has been extensively studied, the reverse process, convert-ing enamines to iminium species, has not been well examined. In their work, the researchers described oxidative en-amine catalysis, or the direct oxidation of an enamine, to produce an iminium species. The researchers showed that the use of o-iodoxybenzoic acid as an oxidant in the presence of a secondary amine catalyst is an effective system for converting enamines to iminium ions. The work was carried out for the direct asymmetric β-functionalization of simple aldehydes. The research was used in other enantioselective cascade transformations, including triple and quadruple cascades, for a one-pot synthesis of chiral building blocks and structural frameworks that begin with aldehydes (1, 2).

Light-driven molecular motors in asymmetric

reactions. Researchers at the University of Groningen in The Netherlands recently reported on a light-driven molecular motor with a switchable catalytic func-tion in catalytic asymmetric reactions. Specifically, the researchers reported on a light-driven molecular motor with integrated catalytic functions in which the stepwise change in the configura-tion during a 360° unidirectional rotary cycle dictated the catalyst performance with respect to activity and absolute ste-reocontrol. During one full rotary cycle, catalysts were formed that produced ei-ther racemic (R, S) or preferentially the Ror the S enantiomer of the chiral product of a conjugate addition reaction. The re-searchers noted that in situ switching of the chiral preference of a catalytic system had been difficult to achieve. The cata-lytic system in their work showed that different molecular tasks can be per-formed in a sequential manner and the sequence was controlled by the direction-ality of the rotary cycle (3, 4).

Palladium-catalyzed reactions. A research team, lead by Stephen Buchwald, professor of chemistry at the Massachusetts Institute of Technology (MIT), reported on a new way to attach a trifluoromethyl group to certain compounds, which has important implications for pharmaceutical com-pounds. A trifluoromethyl group may be attached to a pharmaceutical compound as a strategy to prevent the drug from break-ing down too rapidly in the body. The

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trifluoromethyl group is a component of several drugs, including the antidepres-sant Prozac (fluoxetine hydrochloride) by Eli Lilly, the arthritis medication Celebrex (celecoxib) by Pfizer, and the antidiabetes drug Januvia (sitagliptin phosphate) by Merck & Co., according to a June 24, 2010, MIT press release.

According to the MIT researchers, no general method existed for install-ing trifluoromethyl groups onto func-tionalized aromatic substrates. Com-

monly used methods either required the use of harsh reaction conditions or had limited substrate scope. In their work, the researchers reported on the palladium-catalyzed trif luorometh-ylation of aryl chlorides under mild conditions to permit transformation of various substrates, including hetero-cycles. The process tolerated functional groups, such as esters, amides, ethers, acetals, nitriles, and tertiary amines, thereby making them useful for late-

stage modifications of advanced inter-mediates (5). An important component to the palladium-based catalyst system was the BrettPhos ligand, a biarylmo-nophosphine ligand. During the re-action, a trif luoromethyl group was transferred from a silicon carrier to the palladium, displacing a chlorine atom. Subsequently, the aryl–trifluoromethyl unit was released, and the catalytic cycle began. The researchers tried the synthesis with various aryl compounds and achieved yields ranging from 70 to 94% of the trif luoromethylated prod-ucts, according to the MIT release.

Buchwald previously reported on the BrettPhos ligand in a catalyst system for carbon–nitrogen cross-coupling reactions. The system enabled the use of aryl mesylates as a coupling part-ner in carbon–nitrogen bond-forming reactions. He and his research team reported on the use of the BrettPhos ligand in a catalyst system to achieve the selective monoarylation of various primary aliphatic amines and anilines at low catalyst loadings with fast reac-tion times, including the monoaryla-tion of methylamine (6).

Biocatalytic route to simvastatin. Re-searchers at the University of Cali-fornia Los Angeles (UCLA) recently reported on a biocatalytic route to sim-vastatin, the active ingredient in Merck & Co.’s anticholesterol drug, Zocor and also now off patent as a generic drug (7, 8). Simvastatin is a semisynthetic deriv-ative of lovastatin. Adding a methyl group to convert lovastatin into simvastatin requires a multistep chemical synthesis that includes protecting and deprotect-ing other functionalities in the lovastatin molecule. In one process route, lovastatin is hydrolyzed to the triol, monacolin J, fol-lowed by protection by selective silylation, esterification with dimethyl butyryl chlo-ride, and deprotection (7). Another route involves protection of the carboxylic acid and alcohol functionalities, followed by methylation with methyl iodide and de-protection. Both routes had less than 70% percent overall yield. The UCLA research-ers developed an improved biocatalytic route based on directed evolution of the biocatalyst (7).


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The researchers first cloned and iden-tified LovD, a natural acyltransferase in Aspergillus terreus, which is involved in the synthesis of lovastatin and can accept nonnatural acyl donors. LovD converts the inactive monacolin J acid into lovastatin. LovD can also synthe-size simvastatin using monacolin J acid and a synthetic α-dimethylbutyryl thioester although with less-than op-timal properties as a biocatalyst. The researchers used directed evolution to improve the properties of LovD toward a semisynthetic route of simvastatin. Mutants with improved catalytic ef-ficiency, solubility, and thermal stabil-ity were obtained, with the best mutant displaying an approximate 11-fold in-crease in an Escherichia coli-based bio-catalytic system (7, 8).

Business developmentsCatalysis, both chemocatalysis and bio-catalysis, is an active area of investment of fine-chemical companies, contract manufacturers, and technology providers specializing in catalysis. In March 2011, Materia announced plans for a catalyst manufacturing and research and develop-ment facility in Singapore. Materia special-izes in olefin-metathesis catalyst technol-ogy based on the work of Robert Grubbs, professor at the California Institute of Technology, the 2005 Nobel Laureate for Chemistry, and a member of Materia’s sci-entific advisory board and board of direc-tors. Olefin-metathesis technology is used in fine-chemical manufacture and in other industrial chemical sectors.

Materia expects to complete the site-selection process in the third quarter of 2011 and begin construction by the end of the year. The facility will have initial operating capacity of 10 metric tons by the end of 2012. In addition to catalyst manufacturing, the plant will house research, development, and technical-service resources. Earlier this year, Ma-teria received a $17-million investment by a group of private investors.

The contract development and manufacturing organization (CDMO) Almac is expanding its biocatalysis business with a $4-million investment for discovering new biocatalytic plat-

forms and for other research areas. These areas include hyperactivation of biocatalysts to reduce enzyme load-ings, drivers for cofactor recycles, and resolving problems with equilibriums. In 2009, Almac launched carbonyl reductase, transaminase, hydro-lase, nitrilase, and nitrile hydratase enzyme-screening kits. In adddition to screening kits, the company offers services for enzyme-screening kits and custom transformations, and supply of chiral intermediates.

In January 2011, Codexis formed a biocatalysis collaboration with Dainip-pon Sumitomo Pharma (DSP). Under the agreement, Codexis is supplying biocatalysis-screening products and services to DSP for use in selected undisclosed therapeutic products in DSP’s development pipeline. Also, in January 2011, Codexis and DSM Phar-maceutical Products, the custom-man-ufacturing organization of Royal DSM, formed an enzyme-supply agreement. The agreement grants DSM rights to

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use Codexis’ custom biocatalysts and services and secures supply of Codexis enzymes for commercialization of pharmaceutical manufacturing routes developed by the InnoSyn route-scout-ing services of DSM. In early 2010, Codexis formed two separate pacts for applying its biocatalyst technology for two other CDMOs, Ampac Fine Chem-icals and Dishman Chemical and Phar-maceuticals, for their use in manufac-turing intermediates and APIs.

Codexis recently worked with Merck & Co. to develop an enzymatic process to make sitagliptin, which is the active in-gredient in Merck’s Januvia. The process improvements in the sitagliptin synthesis were recognized by the US Environmen-tal Protection Agency’s 2010 Presidential Green Chemistry Challenge Awards. The earlier manufacturing process in-volved an asymmetric catalytic hydro-genation of an unprotected enamine, but had some challenges, including in-adequate stereoselectivity that required

a crystallization step and high-pressure hydrogenation (at 250 psi) that required the use of a rhodium catalyst (7).

Collaboration between Merck and Co-dexis led to an improved, greener route for the manufacture of sitagliptin. Start-ing from an R-selective transaminase, with some slight activity on a smaller, truncated methyl ketone analog of the sitagliptin ketone, Codexis evolved a bio-catalyst to enable a new manufacturing process to supplant the hydrogenation route. The evolved transaminase had a compounded improvement in biocata-lytic activity of more than 25,000-fold, with no detectable amounts of the unde-sired, S-enantiomer of sitagliptin being formed. The streamlined, enzymatic process eliminated the high-pressure hy-drogenation, metal catalysts (i.e., rhodium and iron), and the chiral purification step. The benefits of the new process included a 56% improvement in productivity, a 10–13% overall increase in yield, and a 19% reduction in overall waste generation (7).

In October 2010, Codexis expanded its portfolio of screening kits to include two commonly used enzyme classes, ketoreductase and transaminase en-zymes. The company also entered its panels for ketoreductase biocatalysts for producing chiral secondary alco-hols, which are used as intermediates in asymmetric API synthesis, for consid-eration in EPA’s 2010 green chemistry awards. Codexis developed processes for chiral alcohol intermediates of four generic APIs with variants identified from its KRED (i.e., ketoreductase) panel screens. Codexis also has other enzyme panels of transaminase, ni-trilase, acylase, halohydrin dehaloge-nase, and “ene” reductase biocatalysts.

Johnson Matthey recently integrated its biocatalyst offerings from X-Zyme, which Johnson Matthey acquired in July 2010. Johnson Matthey expanded the biocatalyst offerings into product and service offerings in its catalysis and chiral-technologies businesses.


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The portfolio from X-Zyme includes enzymatic catalysts for scalable pro-duction of highly pure chiral amines and alcohols. The biocatalysts and re-lated technology complement the che-mocatalytic technology and related expertise of Johnson Matthey. Also, in March 2010, the CDMO Cambrex acquired IEP, a technology company located in Wiesbaden, Germany, to build its portfolio for offering custom-ized biocatalytic process development

and sales of enzymes to the pharma-ceutical industry.

Among pharmaceutical companies, Pfizer recently highlighted some im-provements in API manufacturing routes, which included developing a biocatalytic route for pregabalin, the API in the pain treatment Lyrica (7, 9). A biocatalytic route and other green-chemistry improvements resulted in reducing solvent use by 5 mil-lion gallons per year and eliminating more than 150 tons of a nickel catalyst by

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using a third-generation synthesis in the manufacture of pregabalin. Other process improvements in other API manufacture involved a reduction by 65% of the total organic waste (3.5 million liters per year of methanol and tetrahydrofuran) and the elimination of liquid nitrogen in one step in manufacturing atorvastatin, the API in Pfizer’s Lipitor. The company also eliminated 25,000 tons of waste per year in the manufacture of voricanazole, the API in Vfend through a green-chemistry modification in the manufacturing pro-cess. The synthesis used two innovative types of chemistry: an ultra-efficient syn-thesis of the key pyrimidinone intermedi-ate and the development of a novel highly diastereoselective Reformatksy coupling reaction (9).

In general process improvements, Sigma-Aldrich recently reported on a route for manufacturing polyamino acids, which have properties that mimic proteins, thereby making them suitable for targeted drug delivery. Their produc-tion involves the intermediate amino acid N-carboxyanhydrides (NCAs) and poly-mer processing. For NCA production, the company eliminated repeated NCA re-crystallizations and minimized manufac-turing runs by 30%, and reduced the use of phosgene and tetrahydrofuran by 30% and ethyl acetate and hexane by 50% (7).

References 1. S .L . Z ha ng e t a l . , Nat . Comm . ,

DOI:10.1038/ncomms1214, Mar. 1, 2011. 2. S. Borman, Chem. & Eng. News 89 (10),

9 (2011). 3. J. Wang and B.L. Feringa, Science 331

(6023), 1429–1432 (2011). 4. B. Halford, Chem. & Eng. News 89 (7), 9

(2011). 5. E.J. Cho et al., Science 328 (5986), 1679–

1681 (2010). 6. S. Buchwald et al., J. Am. Chem. Soc. 130

(41), pp 13552–13554 (2008). 7. EPA, The Presidential United States

Environmental Protection Agency Green Chemistry Challenge Agency Awards Pro-gram Summary of 2010 Award Entries and Recipients (Washington DC, 2010).

8. Y. Tang et al., Chem. Biol. 16 (10), 1064–1074 (2009).

9. B. Kovats and K.Ball, Pharm. Technol. 33

(9), online exclusive (2009), pharmtech.findpharma.com/pharmtech/article/ar-ticleDetail.jsp?id=624208&pageID=1&sk=&date=, accessed Mar. 15, 2011. PT

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Chemistry reviewers in the US Food and Drug

Administration’s Office of Generic Drugs provide

Part 4 of an overview of common deficiencies

cited throughout the Chemistry, Manufacturing,

and Controls section of abbreviated new drug

appplications (ANDAs). The reviewers aim to

assist ANDA sponsors in building quality into

their submissions by clarifying components of the

applications. Part 4 addresses manufacture and

container-closure.

Aloka Srinivasan, PhD,* is a team leader, and Robert Iser,

M.S., is an acting director, both at the Office of Generic

Drugs within the Office of Pharmaceutical Science, under

the US Food and Drug Administration’s Center for Drug

Evaluation and Research, [email protected].

*To whom all correspondence should be addressed.

ANDA Reviews

As part of FDA’s Office of Generic Drugs’ (OGD) on-going effort to streamline the review process and re-duce the number of deficiencies cited for abbreviated new drug applications (ANDAs), a series of articles

is being published to provide transparency and clarity to applicants submitting applications in the question-based review (QbR) format. The articles highlight the need and significance of science-based justification in establishing drug substance (DS) and drug product (DP) specifications, in-process controls, choice of formulation, selection of a product design, and selection of the manufacturing pro-cesses. Part 1 of this series, which dealt with the deficien-cies cited in the drug substance section, was published in January 2010 (1). Part 2 of the series regarding drug product composition and excipients and Part 3, regarding the control of the drug product and stability, were published in August 2010 (2) and February 2011 (3), respectively.

The current article is the last of this series, with the focus on providing clarification regarding some common defi-ciencies cited in the drug product manufacturing (3.2.P.3) and the container closure system (3.2.P.7) portions of ANDA submissions using the Common Technical Document (CTD) and Question-based Review–Quality Overall Sum-mary (QbR-QOS) format as a guide. See the sidebar for a list of some of the deficiencies and comments related to these sections. This is not an all-inclusive list of comments and deficiencies pertaining to the drug product manufacturing and container closure controls and information; but includes some questions that are cited frequently.

2.3.P.3 Manufacture1 There are a myriad of manufacturing processes related to dosage forms available in the market. It is beyond the realm of this article to cover all this information. Thus, the focus will be chief ly on the deficiencies and other comments raised while reviewing the in-process data and controls.

Common Deficiencies in Abbreviated New Drug ApplicationsPart 4: Manufacture (2.3.P.3) and Container Closure System (2.3.P.7) Aloka Srinivasan and Robert Iser

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ANDA Reviews

In-process controls (IPCs) and manufacturing data for the exhibit batches represent sections of ANDA submissions where a majority of manufacturing deficiencies are cited.

Before delving into IPCs, we would be remiss without noting a common deficiency with regard to proposed batch formula. A deficiency is often cited when the information regarding the actual manufacturing formula for the exhibit lot and the proposed commercial lots is not provided. It is preferable that the quantities of all the raw materials used in the formulation including those, which do not appear in the final formulation, be provided in a clear tabular format

for ease of comparison. Any overages should be indicated clearly and justified. Overages and their acceptability have been discussed in detail in Part 2 of this series (2).

In-process controls and resultsGenerally speaking, there are several areas in the manu-facturing section related to in-process controls and exhibit batch results that raise questions during the review of an ANDA. These areas can be broken down further into the following general categories: reconciliation, in-process tests, and the manufacturing process.

1. Based on your commercial batch formula, it appears that an x% excess of

API is being proposed. Please justify this proposed excess.

2. We note that the reconciliation of your exhibit lots is very poor. Please include

any investigations done to account for these losses and steps proposed to

avoid similar losses during the production of the commercial lots.

3. We were unable to locate a clear list of in-process controls with the

proposed acceptance criteria in the QbR–QOS or the body of data. Please

provide the same.

4. Based on the fact that the limit for assay of the tablets during release is

95.0–105.0%, we recommend that an in-process composite blend assay

is included with a range that is commensurate with the assay of the drug

product during release testing.

5. In view of the low concentration of the active pharmaceutical ingredient

in the final blend and also the dry blending and compression process used

for manufacturing, please provide available information regarding the

segregation potential of the blend under your manufacturing conditions,

and the possible impact on the content uniformity.

6. Please justify the proposed hardness range for the drug product by

demonstrating that it meets the dissolution and friability criteria at the

highest and lowest points of the proposed range.

7. Your description of the granulation end point is very subjective. We

request you to provide us with information regarding an end point of

the granulation stage based on the process development studies. Please

provide information regarding the steps to be taken if a suitable granulate

is not formed by allocated time of mixing and its effect on the quality of

your final product.

8. Please provide a justification for the moisture level proposed at the end of

the wet granulation process and studies done to assess its impact on the

quality of the granulate and the final product.

9. Please clarify if you have a continuous monitoring program for the

weight checks during tablet compression. In absence of this, the control

strategy during compression appears to be inadequate. Please increase

the frequency of tests for all critical quality attributes such as hardness,

friability, and weight check (both average and individual) during the

validation and commercial manufacturing to better ensure the product

quality.

10. We note that your proposed design for the drug product consists of the

modified release beads in capsules that may be sprinkled. Based on

currently published literature regarding sprinkle capsules and the OGD

draft guidance, Guidance for the Industry, Size of Beads in Drug Products

Labeled for Sprinkle, we recommend that you include suitable control for

the particle size of the coated beads in your drug product.

11. A list of materials, approved for use in the manufacturing process of your

drug product (a parenteral dosage form), are listed in the provided batch

records. However, no justification is provided regarding the compatibility

of the listed materials and the proposed drug product solution. Please

provide your justification for listed process materials; and include any

compatibility studies that may have been performed with the proposed

drug product.

12. Please justify the proposed fill volume for your drug product (parenteral)

based on the excess recommended in USP <1151>. Alternatively provide

us with pharmaceutical development studies performed to assure that

the proposed fill volume is sufficient to permit withdrawal of the labeled

amount.

13. Please provide information regarding performance testing of the

containers based on USP <671>.

14. Please provide moisture permeation data for the proposed blister

pack.

15. Please provide the results of leak test performed on the blister pack.

16. In terms of extractables, it is stated that during accelerated stability

analysis, no recordable levels of new impurities were observed. Please

comment on the adequacy of the proposed method with respect to the

method capability of detecting and quantifying possible extractables

from the stoppers.

17. During the extraction testing for the proposed stoppers, both water and

IPA were utilized as extraction agents. However, there is no information

provided regarding the use of drug product placebo solution in the

extraction studies. As the drug product formulation includes excipients,

which can act as chelating agents, please provide rationale why the drug

product placebo solution was not used in the extraction studies; and if

extraction data is available please provide these data.

18. We note that based on the size of the proposed bottles, there will be

significant amount of headspace for the package of x tablets. Since the dosage

form is orally disintegrating tablets with low friability, mechanical shocks

and abrasion during the transportation and storage can lead to chipping,

abrasion or even breakage. Please provide any studies that were performed to

demonstrate integrity of tablets during transportation and storage.

* Comments are usually not deficiencies and are found in section B of

deficiency letters.

Examples of Commonly Cited Manufacturing (3.2.P.3) and Container Closure System (3.2.P.7) Deficiencies and Comments*

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C103


Reconciliation. An issue that is often unaddressed in the ANDAs is unjustified, low reconciliation of the exhibit lots. In the QbR–QOS, as well as, the body of data, a table for reconciliation should be provided. Yield should be cumula-tive and all losses accounted for with adequate rationale for the losses. Applicants are routinely asked to demonstrate how the low reconciliation observed in the exhibit batches will be corrected or mitigated for the commercial process. ANDA applicants are encouraged to include a reference to any applicable investigation of losses to avoid deficiencies cited on this topic.

In-process tests. Often, a clear description of the stages of manufacturing at which the sampling is performed for in-process controls is requested. On many occasions, ANDA applicants do not provide this information either in the QbR–QOS, or the Section 3.2.P.3.4, but reference the executed and the proposed commercial batch records, in-stead. To facilitate the review of the ANDA, this information should be provided and the QbR FAQ document provides additional guidance on this point (4).

Also, the frequency of testing during compression or other similar processes should be proposed and justified based on batch size and equipment used. Additionally, when changes are made to the release or regulatory/shelf-life spec-ifications for the drug product, the applicant should assess the impact on the proposed in-process controls and revise them accordingly (e.g., disintegration, dissolution, residual solvents, etc.). In general the in-process controls should not be more relaxed than the drug product release criteria.

A frequently asked question for solid oral dosage forms is regarding adequate in-process control of the blend, based on the acceptance criteria for the assay of the drug product. This is especially common when the release assay criterion for the drug product is tighter than the commonly proposed range of 90.0–110.0% of the labeled amount. In these cases, a composite blend assay with proposed range comparable to that of assay of the drug product during routine release analysis is desirable.

For parenterals, deficiencies are often cited regarding adequate or excess fill volume. Usually, containers for par-enterals are filled with volumes in slight excess of the la-beled amount that is to be withdrawn. The excess volume is meant to be sufficient to permit withdrawal and administra-tion of the labeled amount. It is recommended that the US Pharmacopeial Convention’s USP <1> and <1151> should be followed for excess volume (5). However, excess volume may be justified at lower than recommended in USP <1151>. This may be justified based on data, on multiple containers, demonstrating that the intended volume can be extracted consistently or by inclusion of a routine extractable volume test. Large overfills, exceeding USP <1151>, should also be appropriately justified as this excess may pose a potential safety concern.

Manufacturing process. For manufacturing processes which involve dry blending, the ANDA applicant is frequently ques-

tioned regarding the possibility of powder segregation. It is well known that achieving and maintaining homogeneous blends of powders are critical for establishing the quality of the solid pharmaceutical dosage forms, especially in formu-lations involving small amounts of highly potent compo-nents. In most cases, the individual components of the blend are powders with differing physical characteristics such as particle size distribution, density, shape, and cohesiveness. These materials may demonstrate tendency to segregate and lead to lack of homogeneity of the final blend. Thus, it is desirable that the ANDA applicant demonstrate a thor-ough understanding of the blending process and possibility of powder segregation in the pharmaceutical development section, 3.2.P.2. Additional controls for a blend may include, but should not be limited to, particle size distribution of the various components of the blend, particle size distribution of the final blend, flow characteristics and density.

The justification of the proposed tablet compression con-trols (usually the hardness range) is often requested from the ANDA applicant. The proposed range of hardness during compression and during release or stability testing, should to be justified by demonstrating that the drug product meets the dissolution and the friability criteria at the lowest and the highest points of the proposed ranges. However, the ANDA applicant may refer to studies performed during pharmaceutical development as justification for the pro-posed range.

When an applicant uses a wet granulation process, it is preferred that a quantitative end point determination is pro-posed. As factors such a solvent addition and granulation time may be critical to producing consistent, high quality product process, adequate controls should be in place. In many cases, a deficiency is cited if no control or justification is provided by the applicant and the sole control proposed is a subjective, visual observation. For high shear processes, suitable controls may be related to the change in power con-sumption with respect to the granulation equipment (e.g. amperage). For fluid bed processes, moisture content can be a suitable control for end point of the desired granules. The applicant may also choose to justify the proposed processing ranges of solvent addition, granulation time, etc., during pharmaceutical development studies.

Other issues that arise during review of ANDA submis-sions, with respect to use of wet granulation processes, are controls for the granulation solvent used. If organic solvents are used in the granulation, appropriate controls should be proposed during the process and/or in the drug product release specification. The following of the recommenda-tions found in USP <467> and OGD Q&A documents may ensure that the residual solvents are adequately identified controlled (5, 6). If water is used as the granulating solvent, it is recommended that a control for water content be pro-posed, with rationale for the proposed criterion as a func-tion of impact on the stability and quality of the product. Studies to assess impact of water content on product stabil-

ANDA Reviews

Pharmaceutical Technology APRIL 2011 67

ity and quality may be performed during pharmaceutical development.

Dosage forms comprising multi-unit beads (pellets) or multi-particulates in capsules are a growing area for ANDA applicants. These dosage forms are convenient as they have the capability of providing optimal release profiles (e.g. some varied combination of immediate, delayed and extended release) for single drugs or drug combinations. An added advantage of these dosage forms are as the possibility of al-ternative administration techniques for certain populations, such as sprinkling beads (pellets) onto soft food. Since many of the beads (pellets) are manufactured as coated, modified release products in order to retain their integrity during mastication, it has been proposed in a draft guidance from the FDA (7), that the bead size be limited to not more than 2.0 mm. Thus, it is recommended that in-process controls be incorporated which establish the final bead size for these dosage forms. In addition, if the dosage form is comprised of multiple controlled release delivery systems (i.e., immediate, delayed and/or extended release pellets), in-process controls need to put in place at the appropriate manufacturing stages for the beads, which establish and monitor the release profile of the beads.

Finally, deficiencies may be cited in the case of parenter-als, and other liquid formulations, when justification is not provided regarding the compatibility of the listed manufac-turing equipment process materials and the drug product solution. Again, compatibility of the dosage form with the process materials which come in direct contact with the dos-age form during manufacturing is recommended to be a part of pharmaceutical development studies.

These comments only scratch the surface with regard to types of in-process controls and data that are provided in submitted applications. Deficiencies will be cited for these and other manufacturing processes if it is apparent the pro-cesses are not well understood; and it is imperative that ad-equate justification be provided so that the risk of problems occurring during commercialization be minimized.

2.3.P.7 Container Closure SystemWith respect to the container and closure system (CCS), there are related questions in 2.3.P.2.4 and 2.3.P.7 of the QbR–QOS. Often information in one or both sections are missing or inadequate. There are assumptions made, based on previously approved ANDAs, which lead to ANDA appli-cants not providing necessary information in their submis-sions. While it is generally appropriate to reference approved CCS from other ANDA, it may not always be appropriate if specific drug substance or drug product characteristics need to be mitigated by the use of a specific CCS (e.g. mois-ture protection, light protection, droplet size, use of an inert system, etc.). If a statement is provided referencing products that have been approved using the same packaging system, then a copy of the test results for the components should be provided in the body of data, and in some cases, justifica-

tion that this previously approved system is appropriate to the specific product based on the existence of similar drug substance or product characteristics.

In the development section (2.3.P.2.4) of the QbR–QOS, the following question is linked to the rationale for choice of the container closure system: •What specific container closure attributes are necessary

to ensure product performance?Whereas in 2.3.P.7, specific details on the chosen system

should be provided to answer this QbR question:•What container closure system(s) is proposed for pack-

aging and storage of the drug product? Has the con-tainer closure system been qualified as safe for use with this dosage form?

In the development section, the rationale for choosing a CCS should be provided. This is an opportunity for the sponsor to discuss any studies conducted to identify any critical at-tributes including suitability (protection, compatibility, and performance) and safety of the CCS. It is recommended to take into consideration the recommendations and informa-tion found in current FDA guidance (8) to decide critically of attributes based on the dosage form.

Suitability for use. Suitability for use includes multiple characteristics of the CCS with respect to performance, functionality, and safety. In too many cases, testing that will be used to ensure CCS performance and safety is not provided or is poorly documented. Relevant compendial test results and controls (e.g., USP <381>, <87>, <88>, <660>, <661>, and <671>) should be also provided, as appropriate (5). These tests are intended to demonstrate CCS identity, performance, suitability, compatibility and safety. If this information is lacking deficiencies will be cited.

Any other testing or certification, such as Code of Federal Regulations (CFR) references to demonstrate suitability of use for pharmaceutical products, should be also provided. (e.g., 21 CFR sections 174–186 provide a list of materials that are safe for use in direct or indirect food contact) (9).

In many cases, for solid oral products, the most crucial container closure development studies are related to drug product chemical stability. Although tablet integrity (physi-cal stability) may need to be studied for low hardness or highly friable tablets such as orally disintegrating tablets (ODTs) or chewable tablets. Further discussion on this topic can be found later in the article.

For any drug products that incorporate delivery de-vices (e.g. nasal sprays, inhalation products, oral solutions, ophthalmics, etc.), pharmaceutical development studies conducted with respect to demonstration of performance should be discussed. Performance testing of the CCS might include dropper consistency, calibration of delivery device, droplet size, etc. It may also be necessary to compare the ANDA product performance with the reference listed drug (RLD) to demonstrate similar dosing will occur.

Specific cases. In the case of parenteral products, and other drug products that are solutions or suspensions, compatibil-


ity testing should be provided (e.g., extractables and leach-ables for the stoppers or the CCS materials, as applicable, dye or adhesive migration from labeling, etc.). If this informa-tion is not provided, deficiencies have and will continue to be cited. Also, the analytical method used for the analysis should be appropriate for the detection of the extractables and leachables from the CCS. While proposing quality or safety limits for the extractables and leachables, it should be remembered that these are not covered by the International Conference on Harmonization (ICH) Q3B (R2) guideline or the related ANDA impurity guidance (10, 11). Thus, the acceptance criteria proposed should be supported by sound rationale, based on available toxicological information in the public domain, or information provided in the applicable CFR sections (9).

In USP <1>, closures for multiple-dose containers per-mit the withdrawal of the contents without removal or de-struction of the closure (5). The closure permits penetra-tion by a needle and, upon withdrawal of the needle, closes at once, protecting the container against contamination. Suitable controls (e.g., coring, seal-sealing, fragmenta-tion, etc.) should be in place to demonstrate that the stop-per is adequate if it is intended to be used in a multiple use product.

With respect to blister packages, an often cited deficiency is a lack of data to demonstrate that the blister components protect the product from moisture. We recommend that data be provided for moisture permeation of the proposed blister pack. Additionally, as an in-process, and in some cases for release and stability analysis, a leak test may be necessary.

Occasionally inquiries are made regarding integrity of tablets during transportation and storage. This is common when the dosage form is an ODT or some other low hard-ness tablet (e.g., chewable tablet), which are packaged in bottles having large headspace. It is well known that tablets are constantly subjected to mechanical shocks and abrasion during the transportation and storage. Such stresses can lead to chipping, abrasion or even breakage of orally disin-tegrating tablets, which are known to have low friability. It is therefore important for the ANDA applicant to demonstrate that the tablets are able to withstand such stress without damage and provide information to assure the integrity of the tablets during transportation and storage. In use and “shipping” studies should be taken into consideration when designing low hardness products, as well as, other dosage forms that may be affected by transportation.

ConclusionThis concludes our discussion on the commonly cited defi-ciencies in ANDA submissions. To summarize the entire se-ries, ANDA applicants should endeavor to demonstrate prod-uct and process understanding; and provide sound scientific and regulatory justification for all information provided and all controls that are proposed in their applications.

As stated throughout, this series is not intended to be an all-inclusive list of deficiencies cited, but only a survey of what types of information are being requested from ANDA applicants, since the implementation of the QbR-QOS for-mat. Throughout the series, the authors have attempted to provide some rationale for citation of common deficiencies. The phrase “pharmaceutical development” has appeared like a refrain in every section of every article. This underlines the importance of adequate pharmaceutical development stud-ies, performed during the initial development of the drug product, which in turn leads to justification for the chosen materials, formulations and processes; and may reduce the instances of such deficiencies being cited.

1 Numbering in section heads correspond to those in the Common

Technical Document (CTD).

AcknowledgmentsThe authors wish to acknowledge Keith Webber, PhD, Acting Office Director, OGD; Lawrence Yu, PhD, Deputy Director for Science, OGD; and Vilayat A. Sayeed, PhD, Director of Chemistry Division III, OGD, for their input and encouragement as the authors put together this series of articles. We would also like to thank Devinder S. Gill, PhD, Deputy Director of Chemistry Division III, OGD, for his contributions as co-author of Parts 2 and 3 of this series.

DisclaimerThe views and opinions in this article are only those of the authors and do not necessarily reflect the views of policies of FDA.

References 1. A. Srinivasan and R. Iser, Pharma. Technol. 34 (1), 50–59,

(2010). 2. A. Srinivasan, R. Iser and D. Gill, Pharma. Technol. 34 (8), 45–51

(2010). 3. A. Srinivasan, R. Iser and D. Gill, Pharma. Technol. 35 (2), 58–67

(2011). 4. FDA, QbR Frequently Asked Questions (June 4, 2007). 5. USP 33–NF 28 (US Pharmacopeial Convention, Rockville, MD,

2011). 6. FDA OGD, Residual Solvents in ANDAs: Questions and An-

swers (Rockville, MD, Oct. 28, 2008), www.fda.gov/downloads/AboutFDA/CentersOffices/CenterforDrugEvaluationandRe-search/ucm119607.pdf.

7. FDA, Draft Guidance for Industry: Size of Beads in Drug Products Labeled for Sprinkle (Rockville, MD, January 2011).

8. FDA, Guidance to Industry: Container Closure Systems for Packag-ing Human Drugs and Biologics (Rockville, MD, May 1999).

9. FDA, “21 CFR 176 Indirect Food Additives: Paper Board and Pa-perboard Components through 21 CFR 186 Indirect Food Addi-tives Affirmed as Generally recognized as safe (Rockville MD, Apr. 1, 2010).

10. ICH, Q3B, Impurities in New Drug Products (R2) (Geneva, July 2006)

11. FDA, OGD, Guidance for Industry: ANDAs: Impurities in Drug Products ((Rockville, MD, November 2010). PT

ANDA Reviews


In a previous article, the authors stressed

that operator interventions should be

avoided because they carry an inherent risk of

contaminating the drug product. The article

defined two main categories for interventions

and explained how they should be conducted.

In this article, the authors revisit their previous

effort to refine the terms that describe

interventions and to dispel confusion that arose

after the original article was published.

James Agalloco* is president of Agalloco &

Associates, PO Box 899, Belle Mead, NJ 08502, tel.

908.874.7558, [email protected]. He also is a member

of pharmaceutical Technology’s editorial advisory

board. James Akers is president of Akers Kennedy &

Associates.


Position Paper: Aseptic Processing

In 2007, the authors published an article on interventions in aseptic processing to bring attention to the contamination risk associated with human workers in cleanrooms (1). The authors made the salient point that interventions are associated with

contamination risk and should be avoided. In fact, as the authors previously suggested, no intervention is safe or risk-free, and the perfect intervention is the one that isn’t necessary. Interventions should be avoided at all times because each one exposes the prod-uct, and ultimately the patient, to increased risk.

The authors’ original effort was concise and sorely needed at the time, but hindsight reveals that it was incomplete. This article reflects the authors’ recognition that more needs to be said about this important subject. As consultants, the authors are in almost daily conversations about aseptic processing, and interventions often are directly or indirectly central to the topic of discussion. For example, discussions regarding environmental-monitoring is-sues often relate to personnel and interventions just as those about media-fill contamination or product-testing issues do.

The current article does not reflect a change in the authors’ original position with respect to interventions. It is, rather, an at-tempt to clarify how that position should be understood within the industry. The authors also will elucidate how interventions should be defined and managed. The authors hope that this expanded dis-cussion leads to a pragmatic consideration of risk assessment and management, hence more efficient and effective quality-improve-ment programs, as well as better standard-setting and regulation.

Inherent and corrective interventionsThe authors’ first effort defined interventions as either routine or nonroutine. The intervening years have provided reason to estab-lish more definitive categories than before. Two major categories still are appropriate, but they should be defined somewhat differ-ently. The previous paper stated that routine interventions were predominantly inherent and that nonroutine interventions were largely corrective. The distinction appeared to be sufficiently clear, but were chagrined to find that some individuals and firms mis-understood or ignored the distinction. For example, at least one particular corrective intervention was considered routine because it had to be performed frequently during the execution of a batch.* This interpretation violates the principle that no intervention is safe, and it is disturbing to note that an intervention was toler-ated as an acceptable activity largely because of the frequency with

Revisiting Interventions in Aseptic ProcessingJames Agalloco and James Akers



which it had to be performed. This misinterpretation denies the very concern that the authors wished to highlight: that interven-tions are inherently risky and the goal should be to reduce their number. To dispel confusion, this article will restate the author’s perspectives with respect to interventions in aseptic processing. Also, the benign acceptance of frequent mechanical problems or component feed difficulties is cause for concern. Experience has taught us that interventions that produce line stoppages are avoidable. Under continuous process improvement, ongoing ef-ficiency problems should be resolved for commercial as well as contamination-risk reasons.

Inherent interventions. Inherent interventions are operator-per-formed activities that are an integral part of the process without which the process can either not occur or cannot be adequately controlled. Examples of inherent interventions are: the initial setup of the aseptic process (which is a series of manual interventions to make the equipment ready for use); product and package resupply; monitoring of process operation (i.e., weight or volume checks and in-process environmental sampling); recordkeeping; and any other activity whose execution is needed to keep the process running.

The frequency of inherent interventions is largely fixed by ex-ternal factors and not subject to significant variation once initially established. The frequency of their execution may be defined in procedures or by operational requirements. The following inherent interventions are a required part of every aseptic process because their absence would prevent its execution:•The initial aseptic assembly of a fill line in preparation for

filling entails essentially the same interventions for each lot (and perhaps for other similar products in the same scale container).•Component replenishment is a function of line speed and

sterilization quantity. Once defined, it should be constant for similar containers and closures.•The frequency of weight or volume checks is directly linked

to the ability of the filling equipment to maintain constant delivery, and is largely fixed by standard operating procedure (SOP).•Environmental-monitoring frequency is defined in sampling

SOPs that are rarely adjusted once established, although ex-cessive monitoring, which generally is associated with regula-tory inspections, has little justification.

Inherent interventions are also an integral part of every process simulation and occur at essentially the same rate during a filling process as they would for a product lot with the same container components. Some firms increase the frequency of environmental monitoring during process simulations, but it is safe to say that the execution rate for inherent interventions in a process simulation is nearly the same as that experienced during a product fill for the same container-closure system.**

The setup of the aseptic processing line entails the assembly and positioning of sterilized product-contact parts on the filling machine or line. Containers and closures are introduced and fed through the equipment, and adjustments are made as necessary to ensure reliability of operation. Product material (liquid or powder) is then connected to or introduced into the equipment, and initial

weight or volume settings are established. The setup is essentially one lengthy inherent intervention from beginning to end. The in-tensity of the necessary activities is such that setup represents the greatest potential risk of contamination.

Corrective interventions. Corrective interventions are operator-performed activities required because of a fault or difficulty in the execution of the process. These interventions are necessary to address problems with equipment, materials, or procedures that require action to return the process to proper operation. Typical reasons for corrective interventions include container breakage, component misfeed, product leak, weight or volume adjustments, and equipment malfunction that interrupts operations.

The need for corrective interventions during an aseptic opera-tion can vary substantially and can be affected by factors largely within the firm’s control. In an ideal world (e.g., one with perfect equipment, materials, components, and procedures), it is conceiv-able that an aseptic process could be executed without the need for a single corrective intervention. Although this situation might not seem possible, it is reality for a substantial number of aseptic processing systems that use advanced technologies. However, even with less technology, the goal should always be to minimize the incidence of interventions. Corrective interventions are the result of one or more of the following causes:•Components with great variability in either specification or

preparation that result in difficulties in subsequent processing•Poorly designed equipment that requires frequent adjustment

or difficult assembly•Loosely defined setup procedures that result in variable per-

formance.At the present time, the incidence rate of corrective interven-

tions can be expected to vary. Differences in the product, container, and closure can influence the need for interventions. When a line requires extensive adjustment during the set-up (i.e., inherent in-terventions), its operating performance likely will vary, even when the materials are unchanged, and the need for corrective inter-vention will also vary. Our industry should be seeking to reduce corrective intervention rates (actually interventions of all kinds) with the goal of completely eliminating them.† The Akers–Agal-loco method provides a means for reviewing interventions with respect to their frequency, proximity, and criticality, and provides guidance for the development of criteria that can evaluate their impact (2, 3).

Three subcategories of corrective interventions warrant further discussion. Critical interventions are manual activities that involve repeating a portion of the initial setup. The risks associated with manipulating sterilized product-contact parts must be considered comparable to those associated with initial setup. Given the nature of the tasks required, an extensive clearance of the processing en-vironment is generally required. The only factor that would not require clearance would be the use of separative technologies to mitigate the risk associated with critical interventions.

During the execution of an aseptic process, a situation may call for a heroic intervention, one that entails an inordinate amount of risk. The first inclination of many operating personnel may be to perform the intervention regardless of the associated risk. Caution


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is in order when the intervention requires activities likely to result in contamination. As a general rule, certain activities should never be permitted in conjunction with an aseptic process because they violate the principles of aseptic technique.

The execution of an aseptic process may require a new intervention, one that has not been considered previously (see the follow-ing section). Before proceeding with a new intervention, its consequences should be evaluated. The decision to proceed with a new intervention should be made by super-vision and evaluated in the release decision. Again, unusually intrusive new interven-tions could be allowed in processes that use separative technologies such as isolators. In such cases, provided isolator integrity is re-tained, the risk of contamination caused by humans is negligible.

Intervention managementThe importance of interventions in aseptic processing requires a degree of structure to be established to ensure that practices are consistent across the organi-zation. The authors recommend that the following sequence of activities be used to accomplish this.

1. Conduct an informal poll of the en-tire aseptic processing staff about the interventions they perform. This poll should ask about inherent and correc-tive interventions for all processing lines. Surprising as it might seem, the list of interventions will differ from individual to individual.

2. The interventions should be cat-egorized as inherent or corrective for each line, process, or configuration. Each list should be reviewed in detail because some of the identified inter-ventions may represent an inordinate contamination risk. Production, qual-ity, and microbiology experts should determine which interventions should be retained as acceptable practice for that process. Heroic interventions should be avoided.

3. In conjunction with the aseptic opera-tors, the interventions should be de-fined with adequate detail to ensure that all personnel can execute them in a nearly identical manner (see sidebar, “Intervention procedures”). Techni-

cally competent individuals should evaluate the individual intervention procedures to minimize their con-tamination potential. The procedure should specify the number or location of any components or filled contain-ers to be removed from the line. The extent of the line clearance should vary with the location and severity of the intervention. For example, if an unfilled vial falls over on the line without breaking, its removal may be sufficient to return the line to full op-eration.†† Were an unstoppered, filled vial to break and spill, the extent of the necessary line clearance and interven-tional activity would increase.

4. Once a preferred approach for execut-ing an intervention has been chosen, it should be incorporated into an SOP. Procedures for corrective interven-tions must allow for flexibility to ad-dress their variability.

5. The aseptic operators should be trained in the various intervention procedures they are expected to per-

form. Videos of execution and se-quential photographs of the interven-tions can be beneficial in this effort.

6. The batch records for production lots should maintain a record of each corrective intervention performed. These records should support the frequency of corrective interventions during process simulation. Inherent interventions already are defined by other procedures for operation and monitoring of the process, so record-ing their execution in the lot record may not be necessary.

7. When the need for a new interven-tion arises, the supervisory decision may be not to proceed with the new intervention. In these circumstances, a lot-termination procedure can help secure product materials.

Sterility by designThe authors’s article titled “The Myth Called ‘Sterility’” reviewed the current controls for aseptic processing (4). In that article, the authors stated that the existing



controls for assessing aseptic processing performance are largely inadequate to ensure the sterility of the materials being produced. Although industry might not understand it fully, reliance on sam-pling and monitoring is no longer adequate. In fact, some unscien-tific compliance approaches imply that sterility can be monitored, validated, or tested into a process.

The capabilities of modern aseptic processing exceed the ability of the current measurement tools. The authors previously outlined the components of aseptic operations that should be considered to attain sterility. The description of these components focused on design considerations that minimized or eliminated the need for operator intervention. The concepts embodied in that article are perhaps most directly applicable to the design of new aseptic processing facilities, or to equipment or component selection. Nev-ertheless, the article includes the following recommendations that can be applied without significant capital investment:•Glass and plastic containers, elastomeric closures, and other

primary package components with tight acceptable quality levels can reduce the need for interventions.•Robustly controlled and validated preparation and silicon-

ization procedures that are consistent can reduce handling difficulties and the interventions needed to remediate them.•Applying the suggestions about intervention management

can help reduce the impact of interventions.Sterility—or, more accurately, microbiological safety suitable for

injectable medicines—is accomplished through design more than any other means. Excessive tolerance of interventions, whether inherent or corrective, amounts to settling for an inferior design. Given the negative outcomes that can result from interventions, the goal must be to minimize them. Facility, equipment, and pro-cedures must be designed, specified, and defined with that intent.

ConclusionThe authors’ vision of the future is one in which advanced aseptic processing is universal and direct human interaction with sterile materials never occurs (5–8). Until these systems are universal, the need for aseptic interventions will persist, and firms should

organize their interventional activities to mitigate the risk of con-tamination. The authors maintain that interventions should be avoided at all times. It is instructive to remember Hank Avallone’s important lesson: “It is useful to assume that the operator is always contaminated while operating in the aseptic area. If the procedures are viewed from this perspective, those practices which are expos-ing the product to contamination are more easily identified” (9).

References 1. J. Agalloco and J. Akers, “Aseptic Processing” supplement to Pharm.

Technol. 31 (5), s8–s11 (2007). 2. J. Agalloco and J. Akers, Pharm. Technol. 29 (11), 74–88 (2005). 3. J. Agalloco and J. Akers, Pharm. Technol. 30 (7), 60–76 (2006). 4. J. Agalloco and J. Akers, “Bioprocessing and Sterile Manufacturing”

supplement to Pharm. Technol. 34 (3), s44–s45 (2010). 5. J. Akers, J. Agalloco, and R. Madsen, Pharm. Manuf. 4 (2), 25–27 (2006). 6. J. Agalloco and J. Akers, “Aseptic Processing” supplement to Pharm.

Technol. 29 (3), s16–s23 (2005). 7. J. Agalloco, J. Akers, and R. Madsen, “The Future of Parenteral Manufac-

turing,” in Pharmaceutical Dosage Forms: Parenteral Medications, Vol. 3, S. Nema and J. Ludwig, Eds. (InformaUSA, New York, 3rd ed., 2010).

8. J. Agalloco and J. Akers, “Future of Aseptic Processing,” in Advanced Aseptic Processing Technology, J. Agalloco and J. Akers, Eds. (Infor-maUSA, New York, 2010).

9. H. Avallone, J. Parenter. Sci. Technol. 43 (1), 3–7 (1989). PT

*While helping to revise the Parenteral Drug Association’s Technical Report

(TR) 22, “Process Simulation for Aseptically Filled Products,” the authors

learned that other task-force members had had similar experiences. The

revised TR has a similar perspective on interventions as this article does. The

authors provide here a more complete understanding of the problem that

resulted from the slightly vague terminology used in their 2007 effort.

**Please note that the text indicates the same rate of intervention, not the

same number of interventions.

†Much like the goal for the amount of contamination in aseptic processing

simulations, the goal for the number of interventions also should be zero.

††Mandating the removal of a specific number or segment of additional

units in the execution of all corrective interventions increases the risk of

contamination if that removal requires increased access to the critical zone.

Inherent interventions

All operators should be able to execute inherent interventions in an essentially

identical manner. Many inherent interventions require the same operator

interaction each time they are performed. This interaction should be defined clearly

enough for each execution to be the same. Each operator should be able to perform

the inherent interventions by adhering to the defined procedure. The individual

interventions’ similarity lessens the risk associated with their performance. An

analogy can be made with bowling a strike. Knocking all of the pins down requires

each bowler to follow the same basic approach. Varying widely from the defined

methodology will result in an imperfect outcome.

Corrective interventions

The essence of corrective interventions is that they occur at random times and in a

random fashion. Although some corrective interventions (e.g., weight or volume

adjustments) may be repetitive, the majority (e.g., glass breakage, fluid leakage,

and microswitch failure) vary in location, complexity, and frequency. Most corrective

interventions should be treated as unique events. Procedures for addressing corrective

interventions should define basic methodologies rather than execution details to

accommodate the unique nature of the required corrective action. Executing corrective

interventions requires preliminary analysis, materials and tools, the completion of the

corrective action (including material clearance where and to the extent necessary), the

resanitization of surfaces, and a resumption of operation. Because these activities are

unique, the risk associated with executing a corrective intervention must be considered

higher than that associated with inherent interventions. To extend the bowling

analogy, corrective actions resemble the second ball of each frame, in which the target

varies depending on the number and location of the remaining pins. Bowling a spare

requires analysis and adjustment to ensure a successful outcome.

Intervention procedures

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Solid lipid nanoparticles (SLNs) have been

proposed as an alternative colloidal drug-

delivery system for water-soluble drugs. The aim

of this study was to prepare and characterize

physiochemically and biologically tamoxifen-

loaded SLNs to evaluate their effectiveness as a

drug-delivery system to treat breast cancers.

Roghayeh Abbasalipourkabir* is a biochemistry

lecturer, and Aref Salehzadeh is an associate professor

of toxicology, both at Hamadan University of Medical

Science, Hamadan, Iran, tel. +98 811 251 4227, fax

+98 811 827 6299, [email protected]. Rasedee

Abdullah is a professor of biochemistry at University

Putra Malaysia.


Submitted: Apr. 9, 2010. Accepted: Nov. 22, 2010.

Drug Delivery

The antiestrogen molecule tamoxifen is a strong, hy-drophobic endocrine drug widely used for treating breast cancers and high-risk patients (1). The antitu-moral function of tamoxifen results from its link to

the intracellular estrogen receptor on breast-cancer cells and the blocking action of the steroid hormones (2). Depend-ing on the dose and the tissues targeted, the function of tamoxifen can be estrogenic or antiestrogenic. The dose-dependent side-effects of tamoxifen include liver cancer, increased blood clotting, and ocular adverse effects, such as retinopathy and corneal opacities (3). These findings suggest that small doses given through colloidal delivery systems would be useful for long-term treatment of breast cancers. Nanoparticulate delivery systems in the form of nanospheres and nanoparticles were used by Chawla and Amiji, in 2003 (4). The basis of this formulation is the at-tainment of adequate dose of the drug at the tumor site for a known period of time and the reduction of adverse effects on normal organs. Recently, solid lipid nanoparticles (SLNs) were recommended by Fontana et al. for drug-delivery sys-tems (1). The main benefit of SLNs is their lipid-matrix com-position, which is physiologically tolerable and entails little acute or chronic toxicity. Additional advantages are their widespread application, the scalability of production with-out the need for organic solvents, their high bioavailability, their ability to protect drugs from degradation agents, and their ability to control drug release (5–6).

A useful drug-delivery system should possess high ca-pacity for incorporating drugs between fatty-acid chains or lipid layers, or in crystal imperfections. Whether the drug is located within the core of the particles, in the shell, or as a molecular dispersion throughout the matrix depends on the drug-to-lipid ratio and the drug’s solubility within the lipid (7). The mode of drug incorporation influences the drug release, particle size, and physical stability, and modifying the lipid matrix, surfactant concentration, and production parameters can affect the drug-release profile (8).

The aim of this study was to prepare a tamoxifen-loaded SLN using homogenization. The authors characterized the

Delivering Tamoxifen within Solid Lipid Nanoparticles

Roghayeh Abbasalipourkabir, Aref Salehzadeh, and Rasedee Abdullah


tamoxifen-loaded SLN and determined the optimum drug loading and in vitro release profile.

Materials and methodsHydrogenated palm oil (Softisan 154 or S154) was a gift from Condea. Hydrogenated soybean lecithin (Lipoid S100-3, containing 90% phosphatidylcholine, including 12–16% palmitic acid, 83–88% stearic acid, oleic acid and isomers, and linoleic acid] was a gift from Lipoid. Thi-merosal, mercury((o-carboxyphenyl)thio)ethyl sodium salt, and Sorbitol, (2S,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol, were purchased from Sigma. Oleyl alcohol (octadecenol or cis-9-octadecen-1-ol) was purchased from Fluka. Tamoxi-fen, [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT), Fetal bovine serum and Roswell Park Me-morial Institute (RPMI)-1640 medium were obtained from Sigma-Aldrich. Bidistilled water was used.

Cell line. Breast cancer cell line, MCF-7, was kindly offered by Teo Guan Young (Institute Bioscience, UPM). Cells were maintained at 37 ∘C in a humidified atmosphere of 5% CO

2

in RPMI medium supplemented with 10% fetal bovine serum, 100 µg/mL streptomycin, and 100 IU/mL penicillin.

Preparation of tamoxifen-loaded SLNs. Tamoxifen-loaded SLNs were prepared using the high-pressure homogeniza-tion technique (9). A mixture of S154 and Lipoid S100 at a ratio of 70:30 was ground in a ceramic crucible. The mix-ture was then heated to 65–70 ∘C while being stirred with a PTFE-coated magnet until a clear-yellowish lipid matrix (LM) solution was obtained. A solution containing 1 mL oleyl alcohol, 0.005 g thimerosal, 4.75 g Sorbitol, and 89.25 mL bidistilled water (all w/w) at the same temperature was added to 5 g of LM. A pre-emulsion of SLN was obtained using the homogenizer (Ultra Turrax, Ika) at 13,000 rpm for 10 min and high-pressure homogenizer (EmulsiFlex-C50 CSA10, Avestin) at 1000 bar, 20 cycles, and 60 ∘C. The lipo-philic drug tamoxifen (1 mg) was dissolved in oleyl alcohol and mixed with 5 mg of SLN pre-emulsion using the Ultra Turrax homogenizer at 13,000 rpm for 10 min. This mixture was then incubated overnight at 50–60 ∘C, stirred periodi-cally with a PTFE-coated magnet at 500 rpm, and finally exposed to air to solidify.

Characterization of tamoxifen-loaded SLN. Physical characterization

of tamoxifen-loaded solid lipid nanoparticles. The mean particle sizes (i.e., diameter + standard deviation) and size distribution (polydispersity index or PI) of SLNs and tamoxifen-loaded SLNs were determined using a high-performance particle sizer (HPP5001, Malvern Instruments). Measurements were performed at 25 ∘C in triplicate. Before measurement, each sample was dispersed in filtered bidistilled water by a sonic water bath. The zeta potential (i.e., electrophoretical movement) of the SLN and tamoxifen-loaded SLN was then measured by an analyzer (Zeta sizer, ZEN-2600, Malvern) in triplicate.

Morphology and crystallinity of tamoxifen-loaded solid lipid nanopar-

ticles. The morphology of tamoxifen-loaded SLNs was viewed

using a transmission electron microscope (Hitachi H-7100, Hitachi). After dispersion with water, the samples were negatively stained with 1.5% (w/v) phosphotungstic acid for viewing.

The melting points of the bulk lipid and SLN formulation were measured using differential scanning calorimetry (DSC). The DSC analysis was performed using the Mettler DSC 822e (Mettler Toledo), and thermograms were recorded in the 20–120 ∘C temperature range with a heating rate of 5 ∘C/min. An empty aluminum sample pan was used as a reference. Wide-angle X-ray diffractometry (WAXD) was used for the determination of the crystal characteristics of the SLN preparation and also drugs in the case of nanoparticle samples. The WAXD analysis was performed over range 2θ, using Philips PW 3050/60 dif-fractometer (Kasel, Germany) with a copper anode. Specimens of 10 mm length were placed into standard X-ray plate and ex-posed to 40 kV, 30 mA with scan speed of 0.005/s, step size 2ϴ and slit 100 mm.

Entrapment efficiency and drug loading. High performance liquid chromatography was accomplished by using Waters 2695 series liquid chromatography with ultraviolet-visible detector. The analytical column as stationary phase used was reversed-phase C18 (µ Bondpak, 5 mm, 250 × 46 µm i.d., Waters) with the following analytical conditions: mobile phase solution consisting of methanol /0.1 M: phosphate buffer saline, PBS (95:5, v/v, pH 7.4) and flow rate of 1 mL/min at 25 ∘C. The mobile phase was monitored at wave-length 250 nm. A series of tamoxifen concentrations ranging from 10 to 150 ppm was used to obtain a calibration curve (Y = 0.239X − 0.245) with linear regression r = 0.9994. To determine entrapment efficiency (EE) and drug loading (DL), tamoxifen-loaded SLNs were dispersed in methanol. The dispersion was centrifuged at 40,000 g for 60 min to remove SLNs. The amount of drug in the supernatant that was not incorporated into the SLNs was analyzed by high-performance liquid chromatography (HPLC). The EE% and DL% were obtained using the following equations:

EE% =

W initial drug — W free drug × 100%

W initial drug

DL% =

W initial drug — W free drug × 100%

W lipid

Tamoxifen release from nanoparticles in human plasma. The tamoxifen release profile from SLNs was assayed in vitro. Eight similar batches of tamoxifen-loaded SLNs containing 500 µg of tamoxifen in 1 mL of human plasma were pre-pared. The experiment was conducted in a 37 ∘C water bath with mechanical stirring. At predetermined intervals, each sample was centrifuged at 40,000 g for 60 min and the SLN removed. Plasma protein in the supernatant was precipitated at a 1:2 ratio with methanol and centrifuged at 1500 g for 15 min. The amount of free drug in the supernatant that was neither incorporated into the SLNs nor linked to albumin


was estimated by HPLC. Free drug at concentrations rang-ing from 10 to 60 ppm in plasma was used to obtain the calibration curve.

Determination of half maximal inhibitory concentration (IC50

). The viability of MCF-7 breast-cancer cells in the presence of tamoxifen and tamoxifen-loaded SLNs was assessed by MTT assay. The breast cancer cells were maintained in RPMI-1640 culture medium, supplemented with 10% fetal bovine serum at 37 ∘C in a humidified incubator contain-ing 5% CO

2 and 95% air. The cells were allowed to grow to

a concentration of 105 cells/mL before being seeded into a 96-well plate. The cells were treated with tamoxifen and tamoxifen-loaded SLNs at concentrations ranging from 3.25 to 60 µg/mL for 24, 48, and 72 h. The control wells received PBS as the vehicle. The percentage of cell viability and IC

50

versus free tamoxifen and tamoxifen-loaded SLN concentra-tions were determined.

ResultsAll data were subjected to one-way analysis of variance fol-lowed by post hoc multiple comparison and Duncan tests after verifying that data were distributed normally. The authors used high-pressure homogenization to prepare SLNs because the matrix lipid composed of palm oil (i.e., a triglyceride mixture of natural, hydrogenated, and un-

branched fatty-acid chains) was suitable for the incorpora-tion of lipophilic drugs, such as tamoxifen (10). Soy lecithin was the most useful surfactant in SLN dispersions. SLNs and tamoxifen-loaded SLNs were characterized in vitro for particle size, particle-size distribution, and zeta potential

Duge Dlivyluy

Table I: Particle sizes, particle-size distribution (PI), specific surface area (Aspec

), and zeta potential of solid lipid nanoparticle formulations of tamoxifen. Formulation Particle size (nm) PI A

spec (m2/g) Zeta potential (mv) Drug loading (%) Entrapment

efficiency (%)

SLN 152.87 ± 9.91a 0.22 ± 0.05 19.67 ± 1.24 a −15.7 ± 1.12 - -

TAM-SLN 251.65 ± 33.02b 0.48 ± 0.11 12.05 ± 1.56 b +10.16 ± 0.22 17.99 ± 1.9 89.98 ± 1.5

a, b Means are statistically different (p < 0.05).

Data were assessed three days after preparation. Values represent the means (n = 3) + standard deviation.

Figure 3: Wide-angle X-ray diffraction patterns of bulk lipid, solid

lipid nanoparticle (SLN), tamoxifen (TAM), and TAM-loaded SLN.

Figure 1: Micrographs of tamoxifen-loaded solid lipid nanoparticles

by transmission electron microscope (bar = 500 nm).

Figure 2: Thermograms of bulk lipid, solid lipid nanoparticles (SLNs),

and tamoxifen-loaded SLNs (TAM-SLN). The thermograms were

recorded within seven days of preparation (scan rate: 5 ∘C/min).

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Drug Delivery

(see Table I). In this study, the average size of tamoxifen-loaded SLNs was significantly larger than that of the free SLNs, and the surfaces of tamoxifen-loaded SLNs carried a positive charge.

The transmission electron microscopy (TEM) image of tamoxifen-loaded SLNs is shown in Figure 1, where the par-ticles have a round and uniform shape. The DSC thermo-gram and melting point of tamoxifen-loaded SLNs is shown in Figure 2. The melting point of the bulk lipid matrix was 58.88 ∘C. Drug-free SLNs prepared using lecithin and oleyl alcohol had a melting point of 57.88 ∘C, and incorporat-ing tamoxifen into the SLNs reduced the melting point to 56.56 ∘C. The WAXD pattern for the bulk lipid was different from that of the nanoparticle, showing relatively sharper peaks compared with SLN and tamoxifen-loaded SLNs (see Figure 3). The WAXD pattern also showed that the typical peak shape associated with free tamoxifen was absent in the tamoxifen-loaded SLN.

The EE and DL of tamoxifen-loaded SLN were 89.98 ± 1.5% and 17.99 ± 1.9%, respectively (see Table I). The release profile of tamoxifen-loaded SLNs in human plasma is shown in Figure 4. The release rate remained low for the first 8 h, increasing by a mere 2% for that period. Immediately after 8 h, there was a sudden burst of drug release approaching 10% by 11 h after drug incorporation.

The cytotoxicity test suggested that tamoxifen-loaded SLNs had an equally efficient cytotoxic effect on MCF-7 cells compared with free tamoxifen. The IC

50 of tamoxifen-

loaded SLNs on breast-cancer cell lines was generally lower than those for free tamoxifen (see Table II).

DiscussionParticle size is an important characteristic for pharmaceuti-cal applications because it significantly affects in vitro and in vivo studies (11). When tamoxifen was incorporated into SLNs, the increase in particle size suggested that loaded tamoxifen was either adsorbed onto the particle surface or entangled in the aliphatic chains of triglycerides. Zeta potential is also an important factor when evaluating the stability of colloidal systems (12). In the presence of 1 mg of tamoxifen, some of the negative charges were neutralized by the complex formation, thus leading to a less negative or positive zeta potential (see Table I). The positive charge also might be raised by the tamoxifen amino group and by tamoxifen localization on the surface of SLNs (13). The TEM image shows that some particles were in the 40–100-nm di-ameter range (see Figure 1). This particle-size distribution could allow regional drainage if it is directed into or close to the primary tumor or surrounding tissues attacked by cancer cells (14).

With regard to the melting point and crystallization be-havior of SLNs, incorporating tamoxifen reduced the melt-ing point from 57.88 to 56.56 ∘C. Tamoxifen thus is probably in an amorphous state and not crystalline (see Figure 2). A substance with a less ordered crystal or amorphous state requires less energy to overcome lattice forces, and perfect crystalline substances require high melting enthalpy. Hence, the lipid-phase of SLN is less-ordered crystal than the bulk lipid (15). The shape of the bulk-lipid DSC thermogram was a sharp trough, whereas those of the drug-free SLNs and tamoxifen-loaded SLNs were broader (see Figure 2). The shape of the latter could be associated with the surfactant and the dispersion of lipid, and the DSC thermogram of tamoxifen-loaded SLNs displayed only one endothermic

Table II: The half maximal inhibitory concentrations (IC50

) of tamoxifen (TAM) and tamoxifen-loaded solid lipid nanoparticle (SLN) formulations on MCF-7 cells.

Treatment

IC50

(µg/mL)

After 24 h After 48 h After 72 h

TAM 13.45 ± 0.46 13.00 ± 0.98 12.50 ± 0.91

TAM–SLN 13.18a ± 0.66 12.50a ± 1.50 11.78b ± 0.18

All values represent the means ± standard deviation (n = 5).a,bMeans in each row with different superscripts are significantly

different.

Figure 5: Drug loading of three batches of tamoxifen-loaded solid

lipid nanoparticles (SLN). Mean values are represented (n = 3).

Figure 4: Entrapment efficiency of three batches of tamoxifen-loaded

solid lipid nanoparticles. Mean values are represented (n = 3).


melting point (see Figure 2), also indicating dispersion (9). The WAXD pattern for the bulk lipid was different from that of the nanoparticle, showing relatively sharper peaks than for SLN (see Figure 3). In the tamoxifen-free and tamoxifen-loaded SLNs, less-ordered crystals were predominant, and the amorphous state may contribute to high drug-loading capacity (15). This study showed that the tamoxifen was fully entrapped into the SLN during preparation.

The EE of tamoxifen-loaded SLNs was quite high (i.e., 89.98%). The palm oil used to prepare the SLN dispersion produced the highest entrapment efficiency. Triglycerides with various fatty acids offer relatively better drug solubi-lization (16). In 2004, Wong et al. used doxorubicin, vera-pamil HCl, propranolol HCl, and quinidine sulfate in SLNs stabilized with tween 80, and showed that increasing drug concentration led to a significant increase (p < 0.05) in DL and significant decrease (p < 0.05) in EE (17). These effects were a result of reduced SLN dispersions and high solubility of the drug in high lipid concentrations. Other researchers showed a positive correlation between particle size and drug loading (18, 19).

Among the factors that support fast drug release from SLNs are a large surface area, small molecular size, low ma-trix viscosity, and short diffusion distance of the drug (20). In the authors’ study, however, the release of tamoxifen from SLN, which contains a lipid matrix, was retarded. Character-ization of tamoxifen-loaded SLNs suggested that tamoxifen was either encapsulated within the matrix and membrane of palm oil or entrapped in aliphatic chains. This situation could explain the burst release of the drug from SLNs after eight hours. Considering that SLN is solid at room tempera-ture and that the incorporated drug is released relatively slowly, SLNs have potential as a sustained-release drug car-rier. When tamoxifen was incorporated into the SLN car-rier system, its antitumoral activity was maintained, sug-gesting that SLN is a good drug carrier. Tamoxifen-loaded SLNs showed an equally efficient cytotoxic activity against MCF-7 cells, compared with free tamoxifen, and the IC

50 of

tamoxifen-loaded SLNs was generally lower than that of free tamoxifen. This result indicates that tamoxifen’s cytotoxic-ity may result from improved drug internalization through encapsulation into the SLN matrix and endocytosis (21). A previous study had a similar finding, with reduced MCF-7 cell viability in the presence of tamoxifen-loaded SLN (1). It seems that the improved cytotoxicity of the incorporated drug did not depend on the composition of the SLN. In fact, the IC

50 value of drug-loaded SLNs composed of different

materials was lower than that of the free drug solution (18).

ConclusionThe tamoxifen-loaded SLNs showed high entrapment ef-ficiency and drug loading. Characterization of tamoxifen-loaded SLNs indicated that the drug was encapsulated within the membrane of palm oil or entrapped in aliphatic chains. The authors concluded that SLN can serve as a good drug carrier for the sustained released of tamoxifen.

AcknowledgmentThe authors would like to thank Condea and Lipoid for their kind support with materials, and the Universiti Putra Ma-laysia for financial support and facilities.

References 1. G. Fontana et al., Drug Deliv. 12 (6), 385–392 (2005). 2. V.C. Jordan, Br. J. Pharmacol. 110 (2), 507–517 (1993). 3. E. Memisoglu-Bilensoy et al., J. Control. Release 104 (3), 489–496

(2005). 4. J.S. Chawla and M.M. Amiji, Int. J. Pharm. 249 (1–2), 127–138

(2002). 5. K. Jores et al., Pharm. Res. 22 (11), 1887–1897 (2005). 6. H. Yuan et al., Colloids Surf. B. Biointerfaces 61 (2), 132–137

(2007). 7. K. Westesen, H. Bunjes, and M.H.J. Koch, J. Control. Release 48

(2–3,), 223–236 (1997). 8. A.Z. Mühlen, C.Schwarz, and W.Mehnert, Eur. J. Pharm. Bio-

pharm. 45 (2), 149–155 (1998). 9. M.A. Schubert and C.C. Müller-Goymann, Eur. J. Pharm. Bio-

pharm. 61 (1–2), 77–86 (2005). 10. R. Lander et al., Biotechnology Progress 16 (1), 80–85 (2000). 11. A.A. Attama and C.C. Müller-Goymann, Int. J. Pharm. 334 (1–2),

179–189 (2007). 12. I. Mountasser, H. Fessi, and A.W. Coleman, Eur. J. Pharm. Bio-

pharm. 54 (3), 281–284 (2002). 13. I. Brigger et al., Int. J. Pharm. 214 (1–2), 37–42 (2001). 14. F. Ikom, G.K. Hanna, and G.W. Schmid-Schmid, Lymphology 32

(3), 90–102 (1999). 15. D.Z. Hou et al., Biomater. 24 (10), 1781–1785 (2003). 16. H.L. Reddy et al., Pharm. Dev. Tech. 11 (2), 167–177 (2006). 17. H.L. Wong et al., J. Pharm. Sci. 93 (8), 1993–2008 (2004). 18. H. Yuan et al., Int. J. Pharm. 348 (1–2), 137–145 (2008). 19. A. Maschke et al., Eur. J. Pharm. Biopharm. 65 (2), 175–187

(2007). 20. S.A. Wissing, O. Kayser, and R.H. Müller, Adv. Drug Deliv. Rev.

56 (9), 1257–1272 (2004). 21. L. Serpe et al., Anticancer Drug 15 (5), 525–536 (2004). PT

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

Figure 6: Human plasma-concentration profile of tamoxifen-loaded

solid lipid nanoparticles (SLN). Mean values are represented (n = 3)

± standard deviation.


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A review of current efforts within PDA’s Paradigm

Change in Manufacturing Operations initiative.

PCMO Initiative Gathers Strength Richard Levy

In June 2008, the Parenteral Drug As-sociation (PDA) Board of Directors approved the development of a new

initiative called the Paradigm Change in Manufacturing Operations, or PCMOSM

for short. The goal of the PCMO pro-gram of activities is to provide an over-arching framework for topics which will become the subject matter of future PDA technical reports and other docu-ments and training events.

BackgroundBy virtue of the PCMO governance, there is a steering committee made up of PDA Advisory Board members and as well as a number of task forces. As part of the PCMO governance process, each topic is prioritized to maximize the value of the expected deliverables to pharmaceutical manufacturers of investigational medicinal products (IMPs) and commercial products.

The steering committee has developed a portfolio of current deliverables (see Table I) to facilitate the implementation of the guidelines from the International Confer-ence on Harmonization (ICH) guidelines Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Phar-maceutical Quality System.

Generally on PCMO project teams, an effort is made to incorporate membership

from small, local to large, global pharma-ceutical and biotechnology companies, technology enablers, and, in some cases, regulators from the US and Europe. There is an understanding among participants that PDA is working toward the common objective of delivering output that embod-ies the best experiences of our members and, in so doing, creating consensus-based approaches that are not only grounded on ICH principles, but also are pragmatic and scalable such that they can be implemented by any size of company.

PCMO projectsThe PCMO portfolio of projects follows the product life-cycle concept and has the following broad strategic intent:

• Enable an innovative environment for continual improvement of products and systems

• Integrate science and technology into manufacturing practice

• Enhance manufacturing process ro-bustness, risk-based decision-making and knowledge management

• Foster communication among indus-try and regulatory authorities.

Accordingly, PCMO projects have been grouped into four broad catego-ries: life-cycle approach, quality sys-tems, process management, and quality risk management. These categories are also consistent with ICH guidelines and with the focus of the majority of PDA technical reports and ongoing projects. There are currently 19 PCMO projects in progress (see Table I). Additional projects will be added as necessary to satisfy the needs of the industry as recognized by PDA membership and approved by its Advisory Boards.

Progress has been made on several proj-ects already, and many will be completed this year. The following section highlights some of this work.

Q01–Knowledge Capture. According to ICH Q10, knowledge management is defined as a systematic approach to acquiring, analyz-ing, storing, and disseminating informa-tion related to products, manufacturing processes and components. It is expected that complex information is captured, managed, and shared during the product life cycle. The Q01 PCMO technical report focuses on the continuum of data collec-tion through to understanding of both the process and product and will consider the feedback loop of decision-making. As-pects included in the draft report include explicit knowledge, converting tacit knowl-edge (nonwritten personal knowledge of employees), and the means of capturing knowledge from data interpreted as infor-mation. The draft will focus attention on collecting prior knowledge from experi-ence, which can include experience ob-tained from similar processes (e.g., internal knowledge, industry scientific and techni-cal publications), published information (e.g., external knowledge: literature and peer-reviewed publications), pharmaceu-tical-development studies (e.g., mechanism of action , structure/function relationships), technology-transfer activities, and process-validation studies as well as other down-stream life-cycle sources. There is much to learn and the technical report will provide guidance in this regard.

P01–Process Validation and Verification: A

Life-cycle Approach. Great progress has been made by the PCMO Process Validation and Verification task force. As with other PCMO deliverables, this report focuses on

Richard Levy, PHD, is senior vice-president

of the Parenteral Drug

Association (PDA),

[email protected].

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Strategies in Bioavailability

Enhancement of Poorly Permeable

Small & Large Molecular Entities (BCS III & IV)

LIVE WEBCAST: Tuesday, May 3, 2011, 11:00AM–12:00PM EDT

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During this webcast we will review:

■ Design Principles

■ Physiology & novel models

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■ Processes

■ Case studies


INSIDE PDA

process validation and continued verifica-tion, and is being optimized for global use as recommended in ICH Q8, Q9, and Q10 (the product life cycle). A key task-force goal is to promote the implementation of process-validation concepts from a practi-cal perspective.

The scope of the PCMO validation technical report includes all drug prod-ucts included in the FDA January 2011 guidance on process validation (e.g., pharmaceuticals, both sterile and non-sterile; biologicals, active pharmaceuti-cal ingredients [APIs]; radiopharma-ceuticals; and veterinary drugs). It also includes the drug-product component of combinations of drug and medical device. Consistent with FDA guidance, this technical report will exclude medi-cal devices, dietary supplements, medi-cated feed and human tissues, as well as cleaning validation because cleaning is

covered in other PDA technical reports (TR-29 and TR-49).

The bottom line is that this technical re-port is intended to assist in the design and execution of process-validation studies to ensure the reproducibility and robustness of the processes. The report is not intended to be all encompassing. Other means of ap-proaches or even traditional process valida-tion may still be applicable in some regions of the world. PDA anticipates publishing this document at the end of 2011.

P04–Utilization of Statistical Methods for

Production and Business Processes. As manu-facturers seek to improve quality, statisti-cal methods have been rediscovered as crucial tools for the successful develop-ment and manufacture of pharmaceuti-cal products. Manufacturers seek to con-sistently produce products that conform to predetermined quality characteristics, and statistical methods have shown value

in providing objective evidence toward meeting this goal. ICH, the International Standards Organization (ISO), and the Eu-ropean Union have provided guidance on the use of statistical methods.

The primary objective of the PO4 task force is to convey the appropriate use (for each application) of statistical methods at a level that most industry users can under-stand. The purpose of the technical report is to present relevant and easy to use statis-tical process control methods that are ap-plicable to our industry. Advanced statisti-cal methods, such as multivariate models and design of experiments (DoE), will not be considered. The team has completed its first draft of the technical report and will begin the final review process in the second quarter of 2011.

R01–Risk-Based Manufacturing. PDA’s 2008 Technical Report No. 44 Quality Risk Management for Aseptic Processes provides an excellent case study for aseptic processes. The PCMO task force on risk-based manufacturing is expanding the concepts presented in TR-44. Specifically the task force is charged with defining an approach for implementing quality risk-management (QRM) practices that are grounded in ICH Q9 principles. The task force is divided into four teams that are working on multiple deliverables, includ-ing implementation details for a QRM program for manufacturing operations and specific case studies. This new con-tent will provide “how-to” details for im-plementing an integrated QRM program for manufacturing operations.

Additionally, there are three supporting teams developing specific risk-assessment case studies for biotech manufactured APIs, drug product (liquids and solids), and packaging & labeling. The case stud-ies will use the concepts discussed in the QRM implementation document and have been selected to illustrate the use of various risk-assessment tools for different types of manufacturing operations.

To close, the projects highlighted above are expected to conclude this year. As we move into 2012, PDA will have a plan for bringing to completion additional PCMO projects. We expect to report in more detail on these and other projects in Pharmaceu-tical Technology in Fall 2011. PT

Table I: PCMO project portfolio.

Life-cycle approach

#L01 IMP manufacturing and distribution

#L02 Implementation of quality by design in Manufacturing

#L03 Technology transfer (including discontinuation)

#L04 From warehouse to patient

(supply chain/good distribution practice)

Quality systems

#Q01 Capture knowledge management during commercial manufacturing

#Q02 Management of suppliers and contractors

#Q03 Establishing a quality management system (QMS)

#Q04 Concepts for training

Process management

#P01 From process validation to process verification

#P02 Concepts for cleaning validation

#P03 How to improve robustness of a manufacturing process

#P04 Utilization of statistical methods for production and business processes

#P05 Corrective and preventive action (CAPA)

Quality risk management (QRM)

#R01 Risk-based manufacturing

#R02 QRM for biotech manufacturing (API)

#R03 QRM for sterile APIs (Annex to TR 44)

#R04 QRM for drug (medicinal) products (liquids/solids) (Annex to TR 44)

#R05 QRM packaging & labeling

(Annex to TR 44)

#R06 Risk-based scheduling of audits

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OUTSOURCING OUTLOOK

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PharmTech.com/outsource

Ihad dinner recently with an old and very insightful Big Pharma colleague of mine and after speaking together, he

revealed an important concern. “Gregg, I’m worried,” he said. “I think the com-plexities of our current global supply chain outweigh our capability to control the network,” he continued. He was talking about his company’s third-party external supply network.

It’s a scary thought, the idea of being too big and complex to adequately control an organization’s supply chain properly. But as my colleague and I discussed this in more detail, I definitely understood why he felt that way. For the past 20 years and especially the past decade, the indus-try has watched the evolution into “gigan-tic pharmaceutical drug-makers,” such as Johnson & Johnson, Pfizer, Roche, Merck & Co, Novartis GlaxoSmithKline, and sanofi-aventis, all $40-billion-plus annual revenue behemoths.

These global giants are the results of mergers, acquisitions, and myriad comar-keting, in-licensing, and other growth strategies to make up for the disappointing failures of traditional research and develop-ment. The resulting manufacturing “mash-ups” have created third-party external sup-ply networks that are difficult to manage because of the overall number of contract

manufacturing organization (CMOs) in-volved, long-term contracts (some with substandard organizations), contracts with no provisions for ongoing cost reductions and a host of other nuances that result in the buying organization having a higher risk profile than desired.

Now, there is no doubt that making changes to the network can be difficult and expensive due to product registra-tions and other regulatory hurdles on a country-by-country basis. But if a com-pany is willing to play a longer game, with a forward vision, it is possible for it to optimize its third-party external net-work to reduce all types of supply risk and ensure the ability to manufacture products cost effectively.

There is a new methodology, called collaborative optimization, which I’ve had the chance to become familiar with through my work as senior advisor for A.T. Kearney Procurement and Analytic Solutions. The methodology has its roots in optimizing transportation logistics. It’s been successfully used in many direct and indirect categories of spend as diverse as packaging, chemicals and temporary labor and also to simultaneously optimize mul-tiple categories of spend used in sequential

manufacturing processes. It was designed for complex categories of spend when the complexity comes from many specifica-tions, many potential suppliers with a mul-titude of capabilities, and regional or global manufacturing and distribution needs.

Collaborative optimization has three important components. First, it is estab-lishes deep analytics in the cost makeup of a product or service through the creation of an extremely detailed cost breakdown. Second, it gives all suppliers the abil-ity to quote in multiple ways, including creatively (i.e., quote on parts of the busi-ness that plays to an individual suppliers strengths and/or provide new ways to meet the requirements that are more cost efficient). This function is called expres-sive bidding and makes ups the “guts” of a very new type of request for quotation that has an abundance of cost-rich informa-tion and cost-reduction ideas.

The real differentiator with collab-orative optimization is the ability to use combinatorial optimization through an embedded combinatorial analyzer that allows for scenario comparisons to be rapidly generated. These comparisons determine the most desirable outcome based on what a corporation must have. This requirement might be the lowest total price or the best total cost when cer-tain constraints are added. This method overcomes many of the limitations in to-day’s procurement approaches by foster-ing creativity into the quotation process and handling large amounts of data in a fast and efficient way, thereby enabling the buying entity to determine the best solution for its specific needs. What I like the best about collaborative optimization

A Hard Look at Third-Party External Supply Networks

The complexity of third-party external supply

networks requires new ways to manage them.

Making changes

to an external

supply network

can be difficult

and expensive.

Gregg Brandyberry

Gregg Brandyberry is CEO of Wildfire

Commerce, and

senior advisor

for A.T. Kearney

Procurement and

Analytic Solutions,

tel. 215-327-5739,

greggbrandyberry@

yahoo.com.

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Outsourcing Outlook

is that it does not pit supplier against sup-plier the way traditional procurement practice often does. Instead, it identifies the best way forward that is beneficial to buyers and suppliers alike.

So, how could this methodology be ap-plied to a third-party external network? To start, a corporation would need to decide it wants to fix the “mess” (a word used by the late, great systems thinker, Russell L. Ackoff, PhD, to describe most current state situations). The company also would need to recognize that the fix might take 5 to 10 years to fully imple-ment. For a corporation that was willing to play the long game using collabora-tive optimization, the benefits would be substantial. One benefit is that it allows a company to identify where new contract-manufacturing opportunities should be sourced. It also allows a company to un-derstand where existing contract manu-facturing should be sourced and if there is a financial or risk-based business case to support working through regulatory and/or contractual barriers. This method also

ensures that the best CMO network had been identified to reduce all types of risk and provide real cost competitiveness.

When a company thinks about its the third-party external supply network, a crucial question to consider is whether the company is using a CMO’s total capabilities across its total product re-quirements on a global basis. From my experience, which includes more than 30 years in procurement, the supply chain, and related operations, including 10 years as vice-president of procure-ment of global systems and operations at GlaxoSmithKline, I’m fairly confident that the answer would be “no.” And that reply is really no fault of an individual or an organization. It goes back to what my colleague and I were discussing: the complexities of what an organization is dealing with are greater than its abil-ity to control unless there is a commit-ment to develop a long-term vision and a willingness to adapt and use different approaches in managing a third-party external supply network. Collaborative

optimization offers the potential for an-nual incremental savings and potentially a lower overall risk profile.

The key factor for effective supplier management is that once a company has established what its end-state third-party external network should look like and what suppliers should constitute that network, it is imperative that there is an ongoing collaborative environment and culture in place that ensures that future supply partners are always incented to improve and innovate. This evaluation may make an organization take a hard look at the skills or lack of skills that it has in place to support third-party external manufacturing relationships. My guess is that there are some gaps in relation-ship management. Identifying and fill-ing those gaps is a first crucial step in improving supplier management. PT

To gain additional insight from Gregg Brandyberry and other experts, view an educational webcast, “How to Optimize CMC Development and Manufacturing,” at the multimedia section at PharmTech.com.

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PHARMA CAPSULES

Q&A with Aveva Hires New Director of Alliance ManagementAveva Drug Delivery Systems

hired Paul Davis as director of

alliance management. Davis

will report directly to Robert

J. Bloder, the company’s vice

president. Davis’s strong foun-

dation in complex project

management and regulatory

compliance will help the com-

pany’s globalization efforts.

Davis has more than eight

years of pharmaceutical in-

dustry experience, including

a period at Beckman Coulter.

In his last four years at that

company, Davis worked in

business development and

alliance management, where

he was responsible for more

than 30 alliances, ranging

from formulation design and

codevelopment to contract

manufacturing, distribution,

and licensing arrangements.

Glatt Increases Manufacturing CapacityGlatt Pharmaceutical Services

added new commercial-scale

contract-manufacturing ca-

pacity at its 86,000-ft2 New

Jersey facility for tablet and

capsule production. The new

capacity includes high-shear

wet and fluid-bed granulating

and drying, tablet compres-

sion and pan coating, Wurster

pelletizing and coating, direct

pelletizing, oven-tray drying

and curing, blending, milling,

sieving, and quality-control

production capabilities. The

site is equipped to handle

organic solvents or aqueous

and controlled substances.

“We’ve made this investment

in commercial-scale opera-

tions in order to provide our

clients the speed-to-market

and high quality standards

demanded in today’s com-

petitive market,” said Oliver

Mueller, the company’s execu-

tive vice-president of business

development, in a company

press release.

Hawk Measurement Purchases Fluidic Flowmeters Hawk Measurement pur-

chased Fluidic Flowmeters,

a manufacturer of specialty

flow-measurement products

for industrial process-control

systems. The acquisition of

Fluidic Flowmeters’s flow-

measurement product line

will allow Hawk Measurement

to participate in the global

process-measurement mar-

ket. Fluidic Flowmeters has

become Hawk’s division for

the direct measurement of the

volumetric flow of liquids. The

former company’s products

are designed to accommodate

hard-to-measure liquids that

are nonconductive, high vis-

cosity, cryogenic, or corrosive.

Catalent Marks Facility’s 50th AnniversaryCatalent Pharma Solutions

celebrated the 50th anniver-

sary of its Schorndorf, Ger-

many, facility, which special-

izes in modified-release tech-

nologies and clinical-supply

services. The facility supports

global pharmaceutical com-

panies, such as Eli Lilly.

PharmTech:What is the big-

gest industry

challenge you’re

now facing?

Weaver:Product color

and appearance

are increasingly

important, but

the pharmaceuti-

cal industry is still

at an entry level

in its integration

of color-control

instrumentation.

Ultraviolet-visible

(UV-vis) spectrophotometers are common in most compa-

nies. While they technically measure the same spectral range

as the human eye, UV-vis spectrophotometers do not cor-

relate with the way it sees color. Application-specific color

spectrophotometers are routinely used by the chemical

industry for production quality control of fine and specialty

chemicals. However, in many pharmaceutical companies, an

application-knowledge gap still exists regarding the science

of color and appearance. Color-technology awareness and

applied solution engineering continue to be at the forefront

of our industry focus.

The US Pharmacopeia and the European Pharmacopoeia

color standards are commonly used for color specification,

but they only cover a small range of the color gamut as seen

by the human eye. True, it is easier to add a visual test than to

add an analytical-instrument step in the development and

production process. However, visual indexing and validation

have limitations and are by nature subjective methodology.

PharmTech:Do you see a new industry trend emerging?

Weaver:Today, consumers equate product quality to an expected

appearance. The first things humans notice are a product’s

size, color, and shape. Color is an important component of

branding and recognition. Increasingly, manufacturers are

implementing instrumentation to ensure product color

quality in many ways. Examples include measuring a lack of

color in a liquid or the degree of whiteness of a compound,

which correlates to purity or a lack of product degradation.

Applications and technology development continue and are

extending implementation to the production line.

Bob Weaver, president of HunterLab

A flowmeter from Fluidic

Flowmeters

INDUSTRY PIPELINE


MANUFACTURING EQUIPMENT & SUPPLIES



INDUSTRY PIPELINEIN U T Y P EY INDUSTRY PIPELINE

Culturing set SGM’s DriAmp

biological-indicator

culturing set features

Releasat medium and

is designed for high-

temperature, direct-

air exposure or sub-

mersion in nonwater-

based solutions. The

DriAmp BI is a 1-mL, snap-top glass ampul

containing inoculated silica. The Releasat

medium provides a reduced incubation time

of 72 h. A color change indicates positive test

results. SGM Biotech, Inc., Bozeman, MT • www.

sgmbiotech.com • tel. 406.585.9535

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

Plunger-rod-inserting machineThe Hasta plunger-rod-inserting machine

is available in speeds of 12,000 or 24,000

pieces/h. The unit has the flexibility to

interface with upstream and downstream

machines, can be customized for additional

capabilities, and is pre-engineered to add a

backstop-inserting unit to the syringe. MG

America, Fairfield, NJ • www.mgamerica.com •

tel. 973.808.8185

Industrial

vacuumThe Model 860/02

industrial vacuum

is designed to help

eliminate drum

handling and col-

lect and discharge

powders in a safe,

dust-free way. The

vacuum uses VAC-U-

MAX’s Air-Powered

Vacuum cover with

manual pulse-jet filter cleaning and nonstick

filtration that captures 99.9% of particles as

small as 0.5 µm. VAC-U-MAX, Belleville, NJ •

www.vac-umax.com • tel. 800

Protein

purificationThe SciPure 200

single-use system

is a purification

platform designed

to automate, docu-

ment, and optimize

protein purification.

The system performs automated concentra-

tion and diafiltration and uses disposable

fluid pathways. Its disposable tangential-flow

filtration tube manifold incorporates tem-

perature, pressure, and conductivity sensors.

SciLog, Middleton, WI • www.scilog.com •

tel. 800.955.1993

Light-induced

fluorescence

sensorNatoli’s Light-

Induced Fluores-

cence (LIF) sensor

was designed for

blend uniformity

and end-point de-

tection during the

blending of powders, as well as for liquid

applications, including cleaning validation.

The advanced technology of the LIF Sensor

enables real-time monitoring of fluorophore

solutes through intrinsic fluorescent sensing

in the solid state. Natoli Engineering Company,

St. Charles, MO • www.natoli.com •

tel. 636.926.8900

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

Fluid-bed

dryer bags Kavon pro-

vides custom

replacement

fluid-bed dryer

bags for US

and European

equipment models. The bags are appropriate

for wet granulation, dry filtration, and wet

and dry coating applications. The company

offers flexible 1–4-bag systems in various

fabrics choices and also repairs bags.

Kavon Filter Products, Wall Township, NJ •

www.kavonfilter.com • tel. 732.938.3135

Quality-

control

system The FS-80 IP

system reliably

detects improp-

erly sealed cans

and twist-off

bottle caps. The

system improves

final-product quality on assembly lines that

fill containers under vacuum or pressure,

including nitrogen-dosed cans, and it reliably

detects low vacuum or pressure at speeds as

high as 1300 bottles/min or 2000 cans/min.

Industrial Dynamics/filtec, Torrance, CA •

www.filtec.com • tel. 888.434.5832

INDUSTRY PIPELINE





INDUSTRY PIPELINEINDU STR Y PIPELIN EY INDUSTRY PIPELINE

Handheld capsule-filling systemThe ProFill 3006 300-hole handheld capsule-

filling system is the newest addition to the

established ProFill line. The small stainless-

steel filler can be used under a powder hood

and is suitable for research and development

laboratories and compounding pharmacies.

The unit can fill 6900 capsules/h. Capsugel,

Greenwood, SC • www.capsugel.com •

tel. 800.845.6973

Powder-

induction systemRoss’s In-line SLIM

system is designed

to improve powder

induction in a liquid

stream. The system’s

rotor–stator gen-

erator includes progressive spiral porting,

which produces high flow, high shear, and

a high level of vacuum. This feature enables

the system to operate without a pump and

induct powders quickly. Charles Ross and Son,

Hauppauge, NY • www.highshearmixers.com

• tel. 800.243.ROSS

Tablet pressThe new model of

the Hata CVX Core

Press enables preci-

sion core alignment

and multilayer core

tableting. The custom

mechanical assembly,

an addition to Hata’s

Three-Layer Tablet-

ing Press, is specific to customers’ core tablet

sizes and shapes. The CVX-Series is suitable

for multilayer and custom core-tableting

technology. Elizabeth-Hata, McKeesport, PA •

www.eliz.com • tel. 412.751.3000

Sterile

disconnectors Kleenpak sterile

disconnectors from

Pall Life Sciences are

intended to enable

users to disconnect

sterile single-use

systems in seconds.

The products are

easy to operate and

validated to ensure

that the discon-

nected systems remain closed and sterile,

inside or outside a controlled-air environ-

ment. Pall Life Sciences, Port Washington, NY •

www.pall.com • tel. 800.521.1520

Filter-

integrity

tester Thirty years of

design refine-

ments have

resulted in the

Sartocheck 4 plus advanced filter-integrity

tester. The unit incorporates productivity-

enhancing features and is built to be du-

rable. The device also was designed for the

operator’s ease of use. Sartorius Stedim North

America, Bohemia, NY • www.sartorius.com •

tel. 631.254.4249

Turnkey vial line Optima Group Pharma offers a turnkey

processing line for vials that comprises an

integrated freeze-drying system. Designed

to be flexible and operator-friendly, the

line processes liquids, freeze-dried phar-

maceuticals, and biopharmaceuticals.

Optima Group Pharma, Green Bay, WI •

www.optima-pharma.com •

tel. 920.339.2222

Dry-

material

feederThe PureFeed

AP-300 dry-

material feeder

was designed

specifically for

pharmaceutical

processes. Users can disassemble the device

quickly and easily. The machine includes a

dual-arm agitation system for versatility in

material handling. Its disposable and recy-

clable EPDM feed hopper complies with US

Food and Drug Administration regulations.

Schenck AccuRate, Whitewater, WI • www.

accuratefeeders.com • tel. 888.232.4828

Tablet-

coating

platformThe Accela-

Cota FLEX 500

tablet-coating

platform

features six

exchangeable

drums and pro-

vides an overall batch-size range of 50–820

L. Innovative gun positioning, a segmented

exhaust plenum, and interchangeable mix-

ing baffles configure the coater according

to the requirements of the batch size and

coating processes. Thomas Engineering, Hoff-

man Estates, IL • www.thomaseng.com •

tel. 800.634.9910

DetergentsAlconox detergents

are designed to handle

tough crucial cleaning

jobs from tablet presses

to mixing tanks. The

Alconox product is a

concentrated, anionic

detergent for manual

and ultrasonic clean-

ing. It is suitable for

cleaning contaminants

from glassware, met-

als, plastic, ceramic, porcelain, rubber, and

fiberglass. The solution is intended to replace

corrosive acids and hazardous solvents.

Alconox, White Plains, NY • www.alconox.com •

tel. 914.948.4040

INDUSTRY PIPELINE




MANUFACTURING

EQUIPMENT & SUPPLIES

IN U T Y PIPELIN EY INDUSTRY PIPELINE

OUTSOURCING & CONSULTING SERVICES

Development serviceDow’s Feasibility Assessment for dermatolog-

ical product development helps clients make

a decision about whether to pursue potential

topical drug candidates. The service includes

an evaluation of candidates’ physiochemi-

cal properties as they relate to penetration.

The service also encompasses solubility and

stability studies in solution, in vitro skin irrita-

tion, and in vitro skin penetration testing.

Dow Pharmaceutical Sciences, Petaluma, CA •

www.dowpharmsci.com • tel. 707.793.2600

Lyophilization servicesHospira’s One 2 One business is a leading

contract manufacturing organization special-

izing in injectable fill–finish services. The

company meets clients’ global manufactur-

ing and supply demands with lyophilization

capabilities at its three facilities located in

Kansas, Milan, and Melbourne. Hospira One 2

One, Lake Forest, IL • www.one2onecmo.com •

tel. 224.212.2267

Tablet pressSpecialty Mea-

surement 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

Dual-shaft

change-can

mixersRoss‘s dual-shaft

change-can mixers

each include an

anchor and a high-

speed disperser.

Each agitator is

driven indepen-

dently by an

inverter-duty, explosion-proof motor to

enable variable-speed operation. Mixers

are available in 2-, 10-, 50-, 100-, and 200-

gal sizes. Change-can models are available

in 2–1000-gal sizes. Charles Ross and Son,

Hauppauge, NY • http://mixers.com •

tel. 800.243.ROSS

Photoelectric

communica-

tion sensorA high-perfor-

mance, photoelec-

tric communication

sensor provides

users with remote control from an onboard

interface or from a central plant-control sta-

tion. The SmartEye X-PRO Model XPC unit

was designed for monitoring and configuring

machines for local or plantwide automation.

It provides multidrop sensor feedback for

overall process control. Tri-Tronics Company,

Tampa, FL • www.ttco.com • tel. 800.237.0946

Capsule fillerThe Adapta

machine is de-

signed to adapt

to customers’

requirements. Two

of the device’s

dosing units are

reversible and

interchangeable,

thus allowing a plug-and-play shift between

various configurations and filling combina-

tions. The machine can dose three products

into the same capsule at a speed of 100,000

capsules/h. Total production control is avail-

able. IMA North America, Leominster, MA •

www.ima.it • tel. 978.537.8534

Filter cartridgesMeissner’s hydro-

phobic Steridyne

polyvinylidene

difluoride mem-

brane filter car-

tridges are available

in absolute-rated

0.2 µm for the sterile filtration of air and

gases. The Steridyne brochure features a

typical airflow rate chart per 10-in. cartridge

to provide sizing guidelines for flow require-

ments. It also highlights applications, such as

the filtration of pharmaceutical and biologi-

cal process gases. Meissner, Camarillo, CA •

www.meissner.com • tel. 805.388.9911

Custom metallic

filtersW.S. Tyler specializes

in the design, service,

and fabrication of

custom metallic fil-

ters for prototyping

and small-production

needs. These prod-

ucts are constructed in stainless steel, Hastel-

loy, and other metallic filter mesh or metal-

sintered laminates. They allow migration-free

filtration from 1 to 200 µm. W.S. Tyler, Mentor,

OH • www.wstyler.com • tel. 800.321.6188

Weigh panThe SmartGrid

weigh pan

is designed

for Mettler

Toledo’s Excel-

lence balances.

The weigh pan

is designed to minimize the effects of air

turbulence for faster stabilization. Users can

secure fastening and direct weighing into

tare containers with Ergoclips. The unit is

intended to provide quality and durability.

Mettler Toledo, Columbus, OH • www.mt.com •

tel. 800.METTLER

INDUSTRY PIPELINE





INDU STR Y PIPELIN EY INDUSTRY PIPELINE

Contract

manufacturingA brochure from Ben

Venue Laboratories

describes the com-

pany’s contract man-

ufacturing services.

Capabilities include

the development and

production of dosage

forms such as sterile suspension, emulsion,

liposome, microsphere, lyophilized, and

liquid injectables in aqueous or nonaqueous

solvent systems. The company produces

batch sizes from clinical to commercial scale.

Ben Venue Laboratories, Bedford, OH •

www.benvenue.com • tel. 440.232.3320

Contract manufacturingSAFC is ready to meet clients’ contract-man-

ufacturing needs with high-quality products,

helpful ideas, and excellent service. The

company works with its customers every stop

of the way and attempts to anticipate their

needs and offer keen insight. SAFC, St. Louis,

MO • www.safcglobal.com • tel. 314.771.5765

Contract

servicesPatheon is a leading

provider of contract

development and

manufacturing ser-

vices to the global

pharmaceutical

industry. The company supplies products and

services to approximately 300 of the world’s

leading pharmaceutical and biotechnical

companies. Patheon’s fully integrated world-

wide 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

Contract

manufacturing

servicesTapemark is regis-

tered with the US

Drug Enforcement

Administration as

a Schedule III–V manufacturer of controlled

substances. As a contract manufacturer,

Tapemark serves the pharmaceutical market

with active and passive transdermal patches,

topical patches and pads, soluble film, hy-

drogel, and proprietary Snap! packaging.

Tapemark, West St. Paul, MN • www.tapemark.

com • tel. 800.535.1998

Contract

servicesMetrics is a

respected

contract

pharmaceu-

tical research, formulation, development,

and manufacturing company. Offering first-

in-man (FTIM) development and Phase I–III

clinical-trial materials (CTM), Metrics has

conducted more than 120 FTIM studies for

various chemical entities in the past five years

while producing more than 700 batches of

CTM. Metrics, Greenville, NC • www.metricsinc.

com • tel. 252.752.3800

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

servicesPfizer CentreSource

provides solutions

for sterile manufac-

turing, high-con-

tainment manufac-

turing, and oral and

solid dosage forms.

Its capabilities draw

upon Pfizer’s global

network of facili-

ties, technologies, and expertise to fulfill a

broad range of sourcing and outsourcing re-

quirements, regardless of dosage form, batch

size, or the complexity of the process. Pfizer

CentreSource (PCS), Kalamazoo, MI • www.

pfizercentresource.com • tel. 269.833.5844

Job-focused

trainingPDA’s Training and

Research Institute

provides inten-

sive, job-focused

training that clients can apply immediately.

The curriculum is designed to foster profes-

sional development in areas such as aseptic

processing, biotechnology, environmental

monitoring, filtration, microbiology, quality,

regulatory affairs, training, and validation.

Courses can be customized and provided at

the client’s location. Parenteral Drug

Association, Bethesda, MD • www.pda.org •

tel. 301.656.5900

CLEANROOM EQUIPMENT & SUPPLIES

Cleanroom

pass-through

chambersTerra’s BioSafe pass-

through chambers

incorporate coved

corners and ul-

trasmooth 304 or

316 stainless-steel

surfaces to simplify cleaning and sterilization

in aseptic applications. No-lip edges elimi-

nate clearance obstructions and facilitate

material transfer. A rugged mechanical inter-

lock, mounted outside of the pass-through

chamber, prevents cross-contamination. Terra

Universal, Fullerton, CA • www.terrauniversal.

com • tel. 714.578.6000

INDUSTRY PIPELINE


CLEANROOM EQUIPMENT & SUPPLIES

IN U T Y P EY INDUSTRY PIPELINE

PACKAGING EQUIPMENT & SUPPLIES

PACKAGING EQUIPMENT & SUPPLIES

LABORATORY EQUIPMENT & SUPPLIES


Sterile

wipesVeltek offers

sodium-

hypochlorite

and hydrogen-

peroxide

wipes that

are Class 10

laundered, filtered at 0.2 µm, and formulated

with US Pharmacopeia water-for-injection.

The products have laser-cut edges and

are guaranteed sterile with lot-specific

documentation. Veltek, Malvern, PA •

www.sterile.com • tel. 610.644.8335

Transfer

packaging for

prefillable syringesBD TSCF packaging en-

sures the secure transfer

of sterile prefillable

syringe components

into the pharmaceutical filling environment.

The packaging is compatible with IDC Biosafe

doors for aseptic filling machines within isola-

tor or barrier systems. This packaging is part

of the BD SCF global offer, which features

expertise in sterile processing of preserva-

tive-free drugs; secure, reliable, easy-to-use

systems; and drug master files and technical

dossiers. BD Medical–Pharmaceutical Systems,

Franklin Lakes, NJ • www.bdpharma.com •

tel. 800.225.3310

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

Analytical

systemThe amaZon

PowerPack liquid

chromatography–

mass spectrom-

etry system combines the performance and

reliability of the amaZon SL ion-trap mass

spectrometer with a state-of-the-art Dionex

UltiMate 3000 ultrahigh-performance liquid

chromatography system. The instrument is

designed to enhance the analytical capabili-

ties and productivity of laboratories that ana-

lyze the structure of various molecules.

Bruker Daltonics, Billerica, MA • www.bdal.com •

tel. 978.663.3660

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

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

Total-organic-carbon analyzerThe Anatel TOC600 on-line total-organic-

carbon analyzer is designed for pharmaceuti-

cal water measurement. Its patented stop-

flow oxidation technology provides complete

oxidation of an aliquot of water and fully

complies with USP <643> and EP 2.2.44. The

Anatel TOC600 unit’s wide dynamic range al-

lows for monitoring an array of water-system

applications. Hach Ultra Analytics, Grants Pass,

OR • www.hachultra.com • tel. 541.472.6500

On-line TOC analysisTo help pharmaceutical companies improve

quality and reduce costs, GE Analytical

Instruments offers a science- and risk-based

program for achieving real-time release of

pharmaceutical water. The program 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

Process-

analysis systemThe ProFoss process-

analysis system

is based on high-

resolution diode-array

technology. It provides

nondestructive analy-

sis of pharmaceutical

and chemical products

directly in the process

line without bypass. The solution helps to

optimize the use of raw materials and to

consistently run production closer to target

specifications. FOSS NIRSystems, Laurel, MD •

www.foss-nirsystems.com • tel. 301.680.9600

INDUSTRY PIPELINE


INDU STR Y PIPELIN EY INDUSTRY PIPELINE


CHEMICALS, RAW MATERIALS,

INTERMEDIATES, & EXCIPIENTS

CHEMICALS, RAW MATERIALS, INTERMEDIATES, & EXCIPIENTS

INFORMATION TECHNOLOGY

Fluid

chromatographyRegis Technologies

offers RegisSEP

supercritical-fluid

chromatography

(SFC) services for chi-

ral separations. The

services comply with

good manufacturing

practices. The services help determine the

best stationary phase and aid scale-up from

small-scale to kilogram separations. The

company’s RegisSEP SFC Services brochure is

available for download on its website. Regis

Technologies, Morton Grove, IL • www.reg-

istech.com • tel. 800.323.8144

Total organic

carbon analyzersSuitable for managing ul-

trapure and pharmaceutical

water, and for evaluating

cleaning efficiency, Shimad-

zu’s TOC-L series features a

wide sample range (4 μg/L

to 30,000 mg/L), a 680 °C

combustion catalytic-oxidation method,

automatic sample acidification and sparging,

and automatic dilution. New functions and

options improve the instrument’s ease of

operation. Shimadzu Scientific Instruments,

Columbia, MD, • www.ssi.shimadzu.com •

tel. 800.477.1227

Ergonomic pipettorsThe Ovation line of ergonomic pipettors is

designed to offers relief from repetitive stress

injuries caused or exacerbated by traditional

pipetting. The pipettors keep the hand in

a neutral position recommended by ergo-

nomic experts and encourage correct pos-

ture. In addition, the pipettors stand upright,

thus removing the need for racks or stands.

Cole-Parmer, Vernon Hills, IL • www.

coleparmer.com • tel. 800.323.4340

Performance

excipientAvantor Perfor-

mance Materi-

als, formerly

Mallinckrodt

Baker, offers the

J.T. Baker PanEx-

cea MC200G performance excipient for oral

disintegrating tablet applications. The excipi-

ent combines two ingredients for rapid tablet

disintegration and dispersion with good

taste and texture. It is designed to increase

drug-loading capacity and reduce tableting,

licensing, and equipment expenses. Avantor

Performance Materials, Phillipsburg, NJ •

www.mallbaker.com • tel. 855.AVANTOR

ChemicalsMore than 15,000 of Spectrum Chemical’s

products are available through Lab Safety

Supply, a leading provider of laboratory,

safety, and other industrial products to more

than 800,000 customers in North America.

Spectrum Chemical Manufacturing, Gardena,

CA • www.spectrumchemical.com • tel.

800.901.5516

Microcrystal-

line celluloseCeolus UF-711

is a highly

compactible

micro-crystalline

cellulose with

excellent pow-

der flow. It comprises comparatively round

and porous particles that contribute to high

flow and compactibility. The product enables

the creation of small tablets and challenging

formulations. The ingredient is designed for

direct compression using a gravity feeder.

AsahiKASEI America, New York, NY •

www.ceolus.com • tel. 212.371.9900

Pharmaceutical

polymersEUDRAGIT acrylic

polymers are

designed for enteric,

sustained-release,

and immediate-

release drug-delivery

formulations of solid

oral dosage forms.

Evonik’s portfolio of

development services ranges from formula-

tion support to individually designed drug-

delivery technologies. Evonik Degussa Corp.,

Pharma Polymers, Piscataway, NJ •

www.eudragit.com • tel. 732.981.5383

Compliance

softwareEtQ’s FDA Compli-

ance Management

software is an

integrated quality-

and compliance-

management

system designed to

maintain compli-

ance to various regulatory requirements and

adapt to business processes. EtQ’s modules

are tightly integrated to deliver a high-quality

FDA-compliance solution and include Med-

Watch Plus, Complaint Handling, Corrective

And Preventive Action, Document Control,

and Change Management. EtQ, Farmingdale,

NY • www.etq.com • tel. 800.354.4476

Software updateSparta Systems offers an enhanced training-

management functionality for its TrackWise

software. The TrainingManager function-

ality adds automation and configurable

business-rules capabilities to supplement the

software’s existing training-management ca-

pabilities. Sparta Systems, Holmdel, NJ • www.

sparta-systems.com • tel. 888.261.5948

PharmTech .com

PRODUCTS AND SERVICES SHOWCASE

94 Pharmaceutical Technology APRIL 2011

CLEAN ROOM SUPPLIES

Disinfecting

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Certified by ACM

Cleaning

www.advcleanroom.com - 800/649/4625

Since 1983. Nationwide.

Janitorial, Disinfecting, Certification, Microbial Monitoring, Training, Audits

EQUIPMENT & SUPPLIES

Punches & Dies

Turrets

Tablet Presses

Replacement Parts

Accessories

Tool Management Software

Technical Training Courses

636.926.8900 • natoli.com • [email protected]

EQUIPMENT

PharmTech .com

MANUFACTURING EQUIPMENT

MANUFACTURING/PROCESSING EQUIPMENT

Kalish Label-It Wraparound Labeler Model 72000 Vanguard Single Station Tablet Press CP-501Dott. Bonapace Blister Packager Model In-Pack 3 Cu Ft PK Stainless Steel Twin Shell Blender w/Bar Kikusui 55 Stn Gemini Double Sided Tablet PressQty. 2 48” Thomas Accela Coaters 48-M-111 Manesty Express - 20 Stn “D” Tablet PressManesty BB4-27 Station Tablet PressNew 48” S/S Feed & Accumulating Tables Brunner Horizontal Cartoner CMI-11Tisma Cartoner, Model TC-50E BLMatrix 337 Vertical Form Fill Sealer

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Complete Packaging Lines for Tablets, Capsules, Liquids, and Powders Process Equipment: Mixers, Tanks/Kettles, Granulators, & Coating Pans

Kalish Label-It Pressure Sensitive Wraparound Labeler

3 Cu Ft Stainless Steel Twin Shell Blender

New Semi-Automatic Capsule 8 Capsule Filler

New Table Top Single Station Tablet Presses, Model TDP5N

PRODUCTS AND SERVICES SHOWCASE


SEAL MASTER CORPORATIONInflatable seals and other custom rubber products

368 MARTINEL DRIVE, KENT, OH 44240-4368 USA 800.477.8436 • 330.673.8410 • FAX 330.673.8242

E-mail: [email protected] • www.sealmaster.com

Ask about our RSVP Design Assistance Program.

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Sealing is just one of many tasks for custom-built, fabric-reinforced, elastomeric inflat-able seals. Simple, versatile with close tolerancecapability, they’re widely used in mixing, drying,

cooling, granulating, coating, conveying and otherprocessing applications. Freedom of design per-

mits odd and unusual shapes. Compounds in foodgrade white, gray and black are certified to be in

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SEALS

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Natrium® Granular Baking Soda

Natrium Products HIGH PURITYSodium Bicarbonate has WELL-FORMED

CRYSTALS that are free-flowing.

800-962-4203

www.natrium.com

CHEMICALS/EXCIPIENTS/API’S

Bulk Oils

Jedwards International, Inc.

www.bulknaturaloils.com [email protected] | 617-472-9300

Suppliers of Natural Plant and Marine OilsLeading Supplier of Omega-3 ( EPA and DHA )

CENTRIFUGES

Centrifuges

Horizontal Peeler Centrifuges

Vertical Basket Centrifuges

856-467-3399www.heinkelusa.com

Inverting Filter Centrifuges

Newly acquired Comber Nutsche Filter-Dryers available

High Purity Soda Ash IPH and BICAR® Sodium Bicarbonate

For the excipient and API market

Solvay Chemicals, Inc. www.solvaychemicals.us 1-800-SOLVAY-C

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PharmTech .com

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96 Pharmaceutical Technology APRIL 2011

OUTSOURCING RESOURCES

Analytical Testing

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PLANT MANAGERPLANT MANAGERDayton, NJ: Aurolife Pharma LLC a pharmaceutical companyneeds experienced professional to coordinate development ofpre/final formulation, analytical methods, process techniques &optimization of analytical method validation/equipment qualifi-cation program. Responsible to maintain QC & manufacturingfacilities in cGMP compliance for completion of process/clean-ing validation of new & existing drug products. Design pharma-ceutical manufacturing facility. Responsible for documentationrequired for regulatory filing/inspections. Review/approveChange Control Requests, Drug Product Specifications, Stabil-ity protocols. Supervise 5 Chemist. We offer competitivesalaries. Send resume to: Attn-HRPM, Aurolife Pharma LLC,2400 Route 130 North, Dayton, NJ 08810.

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Ad IndexCOMPANY PAGE COMPANY PAGE COMPANY PAGE

Viewpoint


AMRI (Albany Molecular Research, Inc) .......56

Alconox Inc ................................................71

Atlantic Scale ..............................................4

BD Medical-Pharmaceutical Systems .......... 13

BASF Corporation ....................................... 51

Ben Venue Laboratories ...............................7

Bruker daltonics ........................................29

Catalent Pharma Solutions ...................... 100

Cole Parmer Instrument Co ........................60

Compliance Insight, Inc ..............................86

Cook Pharmica ...........................................45

DPT laboratories ........................................85

Dow Pharmaceutical Sciences, Inc ................4

Emerson Process Management .................. 31

ETQ, Inc ...................................................... 21

Excipient Fest ............................................77

Fette America Inc .......................................43

Global Biopharmaceutical .........................58

HollisterStier Contract Manufacturing .........9

Hospira One 2 One ...................................... 11

International Specialty Products ...............99

JHP Pharmaceuticals LLC ............................65

Lonza Inc ................................................... 53

Meggle USA, Inc ......................................... 61

Meissner Filtration Products ........................2

Mettler Toledo ........................................... 17

MG America ............................................... 15

Natoli Engineering Company, inc ............... 19

OPTIMA Machinery Corporation .................49

PDA ........................................................... 37

Pall Life Sciences ........................................39

Patheon ....................................................23

Pfizer CentreSource ................................... 47

Pyramid Laboratories ................................ 35

Regis Technologies Inc ...............................57

rommelag USA, Inc .................................... 41

SAFC Pharma ............................................. 55

Sartorius Stedim Biotech ........................... 33

Schenck AccuRate ...................................... 10

Schott AG ...................................................73

SciLog Inc...................................................27

Spectrum Chemical Mfg Corp .....14, 42, 58A-D

Suheung Capsule .........................................6

Terra Universal ...................................... 6, 86

Thomas Engineering Inc.............................25

Vac-U-Max .................................................36

Veltek Associates, Inc ...................................5

Vetter Pharma - Fertingung GmBH .............63

Weiler Engineering Inc .................................3

Wheaton Science Products .........................32

contin. from page 98

researchers were exploring the theory that patients with diabetes could con-trol glucose in their blood by inhibiting the action of an enzyme called DPP-4.

In addition to in-house efforts, Merck also acquired a compound from a small biotechnology company that showed promise for inhibiting DPP-4. Unfortunately, preclinical safety trials showed that the compound wasn’t well tolerated, and it had to be abandoned.

Their work eventually proved that inhibiting DPP-4 was the right idea. To find a DPP-4 inhibitor that was well tolerated, they tested more than 800,000 compounds. From those they found two with promise. Mak-ing variations of those two, they cre-ated more than 2000 new molecules. Of those, one turned out to be the compound that became JANUVIA.

Today, it has been prescribed to mil-lions of patients with diabetes.

Our industry exists to reduce human suffering, but the ancillary benefits deserve recognition as well. Medicines help the entire healthcare system by reducing hospital and nurs-ing home admissions and by keeping people productive.

And in a competitive world where innovation is the key to economic sur-vival, our industry invests more than 10 times more in R&D than manufac-turing industries overall and supports 3.1 million jobs in the US.

Weber and Thornberry are part of a grand enterprise. As we honor them, we acknowledge the importance of an entire industry. PT

CALL FOR PAPERSPharmaceutical Technology is seeking paper submissions for peer review (research must be novel and data-based) as well as papers for its upcoming special issues on Outsourcing, Pharmaceutical Ingredients, and Analytical Technology. Send submissions and paper topic ideas to adrakulich@ advanstar.com.


PharmTech.com/view

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John Castellani

When chemist Ann Weber saw data from the first clinical trial of a molecule she’d helped de-

velop, she was so excited that she wor-ried about herself.

“For four days,” she says, “I felt like I was flying.”

She had good reason for feeling emo-tional. She’d earned a PhD because she dreamed that education could lead to her finding new medicines that could help people. The data she saw was pre-liminary, but provided evidence that maybe, just maybe, this molecule could be a new weapon in the battle against diabetes —a devastating disease of epi-demic proportions.

When I hear of our industry being criticized, I think of people like Ann Weber. Our industry is filled with bril-liant researchers who have dedicated their lives to seeking new medicines. If you’ve ever questioned the motivation of people working for biopharmaceuti-cal companies, you need only talk to someone who has worked on a success-ful medicine.

Nancy Thornberry, who worked with Weber on the diabetes project, says she cannot begin to describe the “absolute thrill, the incredibly satisfy-ing feeling” of learning that the first new oral medication for diabetes in a

decade had been approved by FDA.Thornberry and Weber are winners

of this year’s annual Discoverers Award in recognition of their leadership in the development of JANUVIA at Merck. For the first time in the award’s 24-year history, two women have won the com-petition which recognizes researchers whose work has been of special benefit to mankind. The award is the highest

honor presented by the Pharmaceu-tcial Research and Manufacturers of America (PhRMA) to biopharmaceu-tical scientists.

To those who perpetuate the myth that our industry focuses on me-too and lifestyle drugs, I offer Weber and Thornberry as an example of the drive and enthusiasm of thousands of bio-pharmaceutical scientists.

Last year, nearly 3000 medicines were in development in the US, either in clinical trials or awaiting FDA re-view. That figure includes 235 medi-cines to treat diabetes and related conditions, more than 400 for rare diseases, more than 800 for cancers, and about 250 each for cardiovascular diseases and mental disorders.

Our successes save and enhance the

lives of millions. Thanks in large mea-sure to new medicines, for example, AIDS deaths in the US have dropped more than 70% since 1995. From 1995 to 2005, heart-disease death rates in the US dropped more than 34%.

These achievements come despite the tremendous difficulty of discover-ing new medicines. Weber and Thorn-berry, in fact, represent not only the successes of researchers in our indus-try, but also their dogged determina-tion in the face of failure.

Woody Allen once said, “If you’re not failing every now and again, it’s a sign you’re not doing anything very in-novative.”

By that measure, among others, America’s biopharmaceutical compa-nies are incredibly innovative. On aver-age, of 250 drugs tested in preclinical trials, one becomes an FDA-approved drug.

Just before she started on the JANU-VIA project, Weber had spent 10 years working on a weight-loss drug. She and her colleagues felt hopeful when preclinical data showed that the com-pound slimmed down fat rats, fat dogs and fat monkeys. Only problem was, it simply didn’t work on people.

Although JANUVIA was developed in record time, by no means did this diabetes program sail through re-search and development (R&D). The

contin. on page 97

PhRMA acknowledges the persistent

efforts of industry’s R&D scientists.

When Patience Pays Off

John Castellani is

president and CEO of the

Pharmaceutical Research

and Manufacturers of

America (PhRMA).

Our industry

exists to reduce

human suffering,

but the ancillary

benefits deserve

recognition as well.

Your opinion matters.To contribute to this column,

send your proposal to

[email protected].

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