Untitled - PharmTech

Jim Miller’s Outsourcing Outlook: Waiting for the Pipeline

November 2009

Volume 33 Number 11

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The Industry’s Authoritative Source

Sharing Supply-Chain Security

PEER-REVIEWED

A Robust, Automated Karl Fischer Titration System

Moisture-Activated Dry Granulation

Novel Excipient Evaluation

AUDITORS •

IN

SPEC

TORS • MANUFACTURERS • SUPPLIER

S • DISTR

IBUTORS

James P. Agalloco

President,

Agalloco & Associates

Michael J. Akers, PhD

Senior Director,

Pharmaceutical R&D,

Baxter BioPharma Solutions

Larry L. Augsburger, PhD

Professor, Department of

Pharmaceutics,

University of Maryland

Patrick F. Belcastro, PhD

Professor Emeritus,

School of Pharmacy,

Purdue University

David H. Bergstrom, PhD

COO, NovaDel Pharma Inc.

Rory Budihandojo

Computer Validation

Manager,

Boehringer-Ingelheim

Todd L. Cecil

Vice-President

Compendial Science

United States Pharmacopeia

Metin Çelik, PhD

President,

Pharmaceutical Technologies

International (PTI)

Zak T. Chowhan, PhD

Consultant, Pharmaceutical

Development

Suggy S. Chrai, PhD

President and CEO,

Chrai Associates, Inc.

Roger Dabbah, PhD

Principal Consultant,

Tri-Intersect Solutions

Sanjay Garg, PhD

Associate Professor and

Deputy Head,

School of Pharmacy,

University of Auckland

George Grigonis, Jr.

Consultant

R. Gary Hollenbeck, PhD

Chief Scientific Officer,

UPM Pharmaceuticals

Ruey-ching (Richard) Hwang, PhD

Senior Director,

Pharmaceutical Sciences,

Pfizer Global R&D

Mansoor A. Khan, PhD

Director, FDA/CDER/DPQR

Russell E. Madsen

President, The Williamsburg

Group, LLC

Heidi M. Mansour, PhD

Assistant Professor,

College of Pharmacy,

University of Kentucky

Theodore Meltzer, PhD

Principal, Capitola Consulting Co.

Jim Miller

President,

PharmSource Information

Services Bio/Pharmaceutical

Outsourcing Report

R. Christian Moreton, PhD

Vice-President,

Pharmaceutical Sciences,

Finnbrit Consulting

Ram Murty, PhD

President and CEO,

Murty Pharmaceuticals

Fernando J. Muzzio, PhD

Director, NSF Engineering

Research Center on Structured

Organic Particulate Systems,

Dept. of Chemical and

Biochemical Engineering,

Rutgers University

Moheb M. Nasr, PhD

Director,

Office of New Drug Quality

Assessment, CDER, FDA

Garnet E. Peck, PhD

Professor Emeritus of Industrial

Pharmacy,

Purdue University

James Polli, PhD

Associate Professor and

Director of Graduate Studies,

School of Pharmacy,

University of Maryland

Gurvinder Singh Rekhi, PhD

Director,

Research and Development,

Elan Drug Delivery Inc.

Susan J. Schniepp

Vice-President, Quality Assurance,

Javelin Pharmaceuticals

David R. Schoneker

Director of Global Regulatory Affairs,

Colorcon

Eric B. Sheinin, PhD

President,

Sheinin and Associates

Charles A. Signorino, PhD

CEO, Emerson Resources, Inc.

Alan J. Smith, PhD

President,

Pharmaceutical Quality &

Technology Consulting

Heinz Sucker, PhD

Professor Emeritus,

Pharmaceutical Institute,

University of Bern

Mr. Lynn D. Torbeck

Principal Statistician,

Torbeck & Associates

Editor-in-Chief Michelle Hoffman

[email protected]

Managing Editor Angie Drakulich

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4 Pharmaceutical Technology NOVEMBER 2009 PharmTech .com

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November 2009 Volume 33 Number 11

Pharmaceutical Technology is the authoritative source of peer-reviewed research

and expert analyses for scientists, engineers, and managers engaged in process development,

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

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

and biotechnology industries.

Features

PHARMA INGREDIENTS

44 Advancing Chiral Chemistry in API SynthesisPatricia Van Arnum

Recent developments in catalysis in

asymmetric synthesis.

POSITION PAPER

72 Regulatory Update: The IPEC Novel Excipient Safety Evaluation Procedure

Christopher DeMerlis, Jay Goldring,

Ranga Velagaleti, William Brock,

and Robert OsterbergThe authors propose a new

evaluation procedure that may

change the way manufacturers look

at drug-product development.

Peer-reviewed research

ANALYTICAL TESTING

52 A Robust, Automated Karl Fischer Titration System

Philippe Lam and Mike Nariman

The authors developed a system to

conduct Karl Fischer moisture assays

for lyophilized products.

FORMULATION

62 Moisture-Activated Dry Granulation, Part 1

Ismat Ullah, Jennifer Wang, Shih-Ying

Chang, Gary J. Wiley, Nemichand B. Jain,

and San Kiang

The authors provide guidance

for the selection of excipients and

equipment to formulate a moisture-

activated dry-granulation process.

Issue extras➲ As part of this issue’s

cover story, an online sidebar

addresses at-the-border

proposals, including the Qualified

Trusted Importer Program

and FDA’s Secure Supply

Chain Pilot Program. Also, a

table outlines legislation and

programs targeting the global

pharmaceutical supply chain.

Angie Drakulich

➲ A full position paper based

on this issue’s Viewpoint

column on IQ and OQ

Louis A. Angelucci

Special podcast series on supply-chain security

Listen to the individual audio

transcripts from the “Sharing Supply-

Chain Security” roundtable,

featuring Susan J. Schniepp of Javelin

Pharmaceuticals, Martin Van Trieste of

Rx–360, Janeen Skutnik of IPEC, Tom

Buggy of DSM Anti-Infectives, and

Susanne Keitel of EDQM.

eNewsletters Visit PharmTech.com/enews to

read or subscribe to our weekly

eNewsletter ePT, our monthly

Sourcing and Management

publication, and our monthly

Equipment & Processing Report.

Blog Visit blog.PharmTech.com

to read the editors’ latest

posts on topics such as FDA’s

widgets, Merck’s Gardasil

vaccine, the CPhI Worldwide

conference held in Madrid, and

anticounterfeiting technology.

Composite concept image and background image by Don Fraser

Lauren Nicole & Bluemoon Stock: Getty ImagesOn

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Cover story

36 Sharing Supply-Chain SecurityAngie Drakulich

A panel of industry and regulatory experts,

including FDA, discuss efforts to secure the

global supply chain.

➲ On PharmTech.com

Departments 18 In the Field 90 Pharma Capsules 103 Career Opportunities 105 Ad Index

Products 28 In the Spotlight 92 Industry Pipeline100 Product and Services

Showcase/Marketplace Continued on page 10

Columns

FROM THE EDITOR

12 DIY Healthcare Reform

Michelle HoffmanWhile Congress debates hundreds of

healthcare plan proposals, perhaps we, the

public, can get in the game too.

PHARMTECH TALK

14 Stay Afloat with Lessons Learned

Angie Drakulich

FDA’s Edwin Rivera-Martinez on

dodging supply-chain challenges.

AGENTINPLACE

16 Changes for Better or Worse

Control, a Senior Compliance Officer

New tests solve one issue, but

cheaper plastic and new stoppers

cause problems.

WASHINGTON REPORT

30 Safety versus Speed in Drug Development

Jill Wechsler

The heightened focus on risk raises

concerns about delays in approving

new drugs.

INSIDER SOLUTIONS

84 A New Direction for USP?

Susan J. Schniepp

With a five-year revision cycle around

the corner, USP will hit or miss the col-

laboration mark.

OUTSOURCING OUTLOOK

86 Facing Reality

Jim Miller

Contract organizations waiting for

the pipeline to come roaring back

are kidding themselves.

VIEWPOINT

106 Are We Abandoning IQ and OQ?

Louis A. Angelucci

New standards may overlook critical

qualification needs.

Pharmaceutical Technology is selectively

abstracted or indexed in:

- Biological Sciences Database

(Cambridge Scientific Abstracts)

- Biotechnology and Bioengineering Data-

base (Cambridge Scientific Abstracts)

- Business and Management Practices (RDSI)

-Chemical Abstracts (CAS)

-Current Packaging Abstracts

-DECHEMA

- Derwent Biotechnology Abstracts

(Derwent Information, Ltd.)

-Excerpta Medica (Elsevier)

-International Pharmaceutical Abstracts

(ASHP)

-Science Citation Index (Thomson)

Pharmaceutical Technology is proud to be a

member of DCAT, IPEC, and PDA.

Continued from page 8

PHARMACEUTICAL TECHNOLOGY (ISSN 1543-2521) is published

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pharmtech .com

Correction: 1. The phrase “doctor of pharmacy

degree” should have read “PhD” in the Oct.

2009 issue’s Guest Editorial by Patrick P.

DeLuca. 2. The references numbered “5” on

pages s14 and s15 of Raul Soikes’ “Moving from

Vials to Prefilled Syringes” article in the Sept.

2009 API Synthesis and Formulation issue should

have been numbered Ref 6.

FROM THE EDITOR

The healthcare reform debate rages on, with more opinions than opinion-makers it seems, and more variations

than there are members of Congress to introduce bills. So if you’re confused about the options—and let’s face it, who’s not?—I propose a different approach. Why not do it yourself? What follows is a handy worksheet to help you formulate your own healthcare proposal—just circle your preferred options.

A comprehensive reform bill (should; should not; should with an exemption for people who can’t afford it; should with an exemption for people with religious or moral objections; should with exemptions for people with incomes lower than 133% of the poverty level or for those individuals who would have to pay more than 8% of their income to buy the lowest cost plan available to them) mandate that all (US citizens; citi-zens and legal US residents; legal and illegal residents) carry health insurance. Individu-als who violate the mandate (would; would not) be assessed a penalty of (0; 2.5% of ad-justed gross income; up to $750 a person per year) that will be phased in gradually over the next eight years.

Employers (should; should not) be re-quired to contribute (100%; 50%; 25%; 8%; 0%) of the cost of coverage (under all circumstances; under no circumstances; if their annual payroll exceeds $250,000;

under all circumstances unless the com-pany can demonstrate that paying for health insurance would lead to job losses or have other negative effects; if they employ more than 25 people). Employers who fail to comply (should; should not) be assessed a penalty of (0; $750 for each full-time em-ployee, and half that for each part-time employee) not covered.

Health insurance (should; should not) be brokered through a (national; exchange; state-based exchange; private insurers). In addition, a (government-run insurance plan; nonprofit cooperative) (should; should not) be set up to compete with private plans.

Employers (should; should not) be eligi-ble for tax credits (under no circumstances; if they have fewer than [25; 50; 100)] work-ers; on a sliding scale based on the size of the company and the level of worker pay, with larger companies and better-paid workers receiving few or no credits; if they are con-sidered a small business).

Health insurance (should; should not) include (a basic package of preventive ser-vices, mental health, dental, and vision benefits; at least ambulatory patient ser-vices, emergency services, hospitalization, maternity and newborn care, mental health and substance-abuse services, rehabilita-tion services as well as devices, laboratory tests, preventive and wellness services, and pediatric services; four levels of coverage, with an escalating number of services and increasing percentage of costs covered as one ascends the levels). In addition, insurers (should; should not) be prevented from de-nying coverage to individuals with pre-ex-ising conditions. Plans (should; should not) include prescription drug coverage, and if a public plan is put into effect, the govern-

ment (should; should not) use its purchas-ing power to negotiate lower drug costs. In addition (government; private; no; all) plan(s) (should; should not) take into ac-count comparative-effectiveness research when constructing their formularies. The plan (should; should not) also take into account follow-on biologics and (should; should not) provide (0; 10; 12; 14) years of data exclusivity for innovator drugs.

This plan will cost ($1 trillion; $829 bil-lion; not so much as to add to the federal debt) over the next 10 years. The plan will be paid for by (slowing the growth of health spending in the long term; income surtaxes on families earning over $350,000 and in-dividuals earning more than $280,000; surtaxes on families earning over $1 mil-lion and individuals earning more than $500,000; fees on insurance companies, medical-device manufacturers, and drug-makers; limiting tax deductions on chari-table contributions; mortgage interest for families earning more than $250,000; tax-ing money spent by drugmakers on adver-tising; tax money for direct-to-consumer advertising; raising taxes). Additional funds (can; cannot) be raised by trim-ming Medicare payments to hospitals and subsidies through Medicare Advan-tage. Hospital associations (should; should not) give up some proportion of Medicare and Medicaid payments to offset the cost of insurance, and drugmakers (should; should not) reduce the costs of drugs for individuals who fall into the Medicare “doughnut hole.”

Now wasn’t that was easy? Next month, we’ll tackle the economy. (For more information, the New York Times website has an interactive graphic on healthcare proposal comparisons.) PT

DIY Healthcare Reform

Michelle Hoffman

While Congress debates hundreds

of healthcare plan proposals, perhaps we,

the public, can get in on the game too.

PharmTech.com/forum

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Michelle Hoffman

is editor-in-chief of

Pharmaceutical Technology.

Send your thoughts

and story ideas to

[email protected].


Stay Afloat with Lessons LearnedAngie Drakulich

Angie Drakulich is the managing editor of

Pharmaceutical Technology.

»Read Angie’s blogs at blog.PharmTech.com.

PharmTech.com/forum

FDA’s Edwin Rivera-Martinez used an example of the Titanic to explain how pharmaceutical manufacturers need

to dodge supply-chain challenges. Think of

your company as a ship approaching mul-tiple icebergs (i.e., economically motivated adulteration, contamination, shadow fac-tories), some of them invisible underneath

the water, and figure out how you can avoid hitting them and should you hit one, have a strategy for staying afloat, he said. Acting Associate Director for Drug Quality Assur-

ance in the Center for Drug Evaluation and Research’s Office of Compliance at FDA, Rivera-Martinez was speaking at the International Pharmaceutical Ex-cipients Council regulatory conference in Washington, DC, early last month.

He went on to say that manufactur-ers can’t rely on FDA to handle all their supplier audits. The agency doesn’t have the resources to perform frequent audits or to inspect all the processes and equip-ment that a particular company may need to know about in detail.

Rivera-Martinez suggested industry and regulators get back to basics. He offered the 1950 Deming model that focuses on aligning processes within a system by sharing continuous feedback with suppliers, distributors, internal staff, consumers, and all parties in-volved in the manufacture and use of a drug product. Constant communication about where things are and how they are being affected is critical.

He pushed industry to look forward as well. “We need new ideas beyond testing,” he said, referring specifically to diethylene glycol (DEG) and contami-nation incidents with glycerin. After a series of catastrophes, the natural gas industry figured out how to add a harm-less “rotten egg” odorant to its product to alert people when a leak may be pres-ent. The pharma industry needs to come up with something similar—something as simple as an odor—to make the presence of DEG in a medical product known, Rivera-Martinez suggested. Now there’s an idea to help the industry stay afloat. PT

PHARMTECH TALK

PharmTech .com

AGENT-IN-PLACEAGENT-IN-PLACE

Off the charts“We had an endotoxin control chart that showed a trend,” recounted our GMP Agent-in-Place. “There was one result out of limits, but when we checked the data, we realized that there were 20 consecutive batches that were higher than the normal “non-detect-able” results. This was clearly a time-based phenomenon, so we did the obvi-ous checks for time-related changes.

“The only item we found we dis-counted, as it was an excipient lot number change that is used in 1 part per million. The quantity used was why we discounted it, as the 6-log di-lution alone should result in no detect-able endotoxin. In the end, the suspect lot was tested. It took some doing as we had to run numerous dilutions to get it into a readable range, and found it to be over 2 x 106. Therefore, even with the 6-log dilution, there was plenty of endotoxin left to make the test read high. Endotoxin hadn’t been a release test for that excipient, but it was after that,” our agent reported.

Holey water“We had a lyophilized product that is typically self-administered and needed reconstitution before use,” explained our GMP Agent-in-Place. “In the package, we included a double-ended transfer needle for the patient to use to transfer the sterile water diluent to the product. The transfer needle is packed in a plastic pouch that is ster-ilized. When we found holes in the plastic pouch on some samples from the contract sterilizer, we initiated

an investigation. We found holes in pouches in retain samples of the prod-uct, which immediately led to a recall. This product is sold in more than 30 countries and we recalled all in-date batches to replace the transfer needle. It turned out that someone had made a change to the plastic years ago to make it less expensive, but our recall cost hundreds of times more than the cost savings totaled.”

Hazy weather ahead“We had a sterile liquid-protein prod-uct that we made for more than 20 years with no problems and no for-mulation change,” noted our GMP Agent-in-Place. “The annual inspec-tion of retain samples also showed no problems, until recently. For some reason, on a few batches, we found a slight sediment in the bottom of the bottle. In fact, the sediment could not be seen until an undisturbed bottle was carefully picked up and tipped over, whereupon a haze could be seen drifting along the bottom. Our inves-tigation gave a possible cause of a small change in the stopper that roughly correlated with the appearance of the haze. When we investigated the ma-

terial, the quantities were nearly too small to measure, and were evaluated as medically inert, although we did correct the stopper problem.”

We’re green (with envy)“We ship and receive products from around the world,” bragged our GMP Agent-in-Place. “One refrigerated product came from Europe in a ro-bust, double-pallet-sized package that was stacked on a full sheet of plywood and covered by another to protect the product and the 4 in of expanded poly-styrene insulation that was used. The plywood was very high quality (eight layers and about 5/8 in thick.) Instead of recycling it, one employee took it home all year claiming that he was in-sulating his barn with it. We got one to two such shipments a week; that must have been a huge barn.” PT

Changes for Better or Worse

Cautionary Tales from the Files of “Control,”

a Senior Compliance Officer

New tests solve one issue, but cheaper plastic

and new stoppers cause problems.

PharmTech.com/aip

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Pharmaceutical Technology’s month-

ly “Agent-in-Place” column distills

true-life cautionary tales from the

secret files of Control, a senior com-

pliance officer. If you have a story

of clueless operators, oblivious

management, inopportune lapses

of judgment, or Murphy’s Law in

action, please send it to Control at

[email protected]. We

won’t use any names, but if we do

use your tale of disaster, courage,

or just plain weirdness, Control will

send you a coveted Pharmaceutical

Technology t-shirt.

Our recall cost

hundreds of times

more than the cost

savings totaled.

16 Pharmaceutical Technology NOVEMBER 2009 PharmTech .comPharmTech .com

New pricing controls and healthcare reforms may be pushing the pharmaceutical market out of this southeast Asian country.

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Report from:

Philippines Jane Wan

In the Field

The Philippine pharmaceutical industry is taking a beating from the govern-ment’s decision to impose a 50% price cut on certain drugs. For the first time in the country’s history, 21 molecules or medicines were forced to comply with the Maximum Drug Retail Price (MDRP) system that was implemented last September. These are medicines used to treat hypertension, diabetes, common infections, amoebiasis (a leading cause for diarrhea), and some cancers such as leukemia. The cut went into effect Aug. 15, 2009. In addition, pharmaceutical companies are committed to reduce by approximately 10–50% the prices of 22 other products (a table identifying these 22 products is available in the online version of this article at PharmTech.com).

The price controls system is part of the government’s Cheaper Medicine Bill, which was passed in late 2008. The system will be reviewed after three to six months by the Department of Health. To help enforce the price cuts, the government has lobbied the public to report noncompliant drugstores and has taken action against four such stores that violated the new ruling.

continued on page 20

18 .....Market Report

from the Philippines

22 .....FDA Draft REMS Guidance

24 .....Pfizer and Wyeth as One

26 .....USP’s New Heparin

Quality Standards

PharmTech .com18 Pharmaceutical Technology NOVEMBER 2009

continued from page 18The system is meant to provide affordable and easy access

to healthcare to citizens, especially the poor, but industry players remain skeptical that the program will provide such a solution. According to a statement released by the Phar-maceutical and Healthcare Association of the Philippines (PHAP), the price controls policy “is not the best approach as most medicines will remain inaccessible to the poor who live on an income of less than PHP100 ($2) a day.”

To worsen the situation, taxation on medicines comprises approximately 20% of the retail price of drugs in the country. This explains why medications (both over the counter and prescription) in the Philippines are typically priced 40–70% higher than those sold in nearby Asian countries, according to 2008 figures cited by the Philippine International Trading Corporation.

Private hospitals have already upped prices for their services to offset the reduced drug prices. Other related problems such as delays in obtaining rebates from drug companies by drugstore representatives have also started to surface.

Over the years, the government has implemented healthcare policies to alleviate the problem of accessibility and affordability, only some of which have been effective. For example, a generic-drug law expanded the amount of generic drugs and manu-facturers in the country. On the other hand, the government-run PhilHealth insurance package is unable to cover the pro-jected 77.4 million beneficiaries (84% of the 92 million Filipi-nos) because it has only 13.85 million paying members. Simi-larly, the Drug Price Reference Index, which is meant to inform consumers of prices, provides only retail-drug pricing and is unable to address the high drug-pricing problem.

Healthcare policies aside, industry’s primary concern about the MDRP system is that it may turn the tables on domestic firms. Nonoy Oplas, president of the Minimal Government Thinkers, a group of professionals and small entrepreneurs, says, “Local firms who are producing drugs under the 21 mol-ecules will become more expensive sellers now. To remain competitive, the natural response is for them to slash prices between 10–20%, which will reduce their profits.”

He adds, “Domestic firms do not enjoy economies of scale due to high production costs. Eventually, many will be forced out of business. Unlike multinational companies (MNCs) who can divert their attention to other markets, home-grown companies have fewer product offerings and do not have other market avenues.”

On the other hand, it appears that foreign firms are likely to grow in the long run. Although their product prices are affected as well, the Philippine market is considerably small (about 5% of the global sales of multninational corporations) and, these companies can afford to divert their attention to other markets. They already hold a lead in manufacturing and retail revenue, according to 2008 PHAP figures. For-

eign firms garnered total sales of PHP71.12 billion ($1.46 billion) compared to local ones at PHP32.46 billion ($0.69 million).

Oplas believes that foreign drug manufacturers should feel encouraged to remain on Filipino soil to help develop the local pharmaceutical industry. The majority of MNCs in the country are focused on drug discovery, which can, in turn, create opportunities for local firms to produce generic versions when innovator-drug patents expire.

That said, there’s nothing to stop foreign firms from ex-ploring the development and manufacturing of generic drugs for the Philippines market. Louis D. Payet, senior consultant of the healthcare division at Frost and Sullivan Asia– Pacific says, “Several MNCs have acquired generic-drug manufac-turing capabilities in recent years. If they produce and sell them in the domestic market, local companies will lose mar-ket share and suffer reduced profitability as competition in the branded generic-drug market increases.”

In light of the current situation, some MNCs such as Bris-tol Myers Squibb (New York) may adopt business approaches such as engaging external sales personnel to continue un-disrupted supply to the market or out-license their products to local players while maintaining control over profitable product lines, according to Payet.

Ultimately, patients are the losers. “We are likely to expect a fall in the number of generics companies and medicines in the country, which in turn, limits treatment options for doctors and patients,” says Oplas. “Also, it is also possible that a black market emerges when storage, dispensation, and sale of essential medicines are no longer transparent [or competitive]. This paves the way for the entry of coun-terfeit drugs that are perfect substitutes for effective and expensive medicines.”

Payet is trying to stay positive. “The bill has to be more expansive in the number of drugs covered. Currently, there are more than 80 price-control candidates under review. The implementation of the price-controls system is just one aspect of the Cheaper Medicines Bill and may not have a big impact on the market.” Jane Wan is a freelance writer based in Singapore.

IN THE FIELD

Healthcare policies aside,

industry’s primary concern

about the MDRP system is

that it may turn the tables on

domestic firms.


Zone in on: RegulationFDA Releases Draft

Guidance for REMS

Erik Greb

The US Food and Drug Administration

published its first draft guidance for indus-

try about Risk Evaluation and Mitigation

Strategies (REMS) on Sept. 30, 2009. The

document describes the format and content

of a proposed REMS, including supporting

documentation, the content of assessments

and proposed modifications of an approved

REMS, which identifiers should be used on

REMS documents, and how to communicate

with FDA about a REMS. The guidance also

provides an example of what an approved

REMS might look like.

“With this new guidance, manufactur-

ers will have a useful blueprint for how to

develop these important safety strategies,”

said Janet Woodcock, director of the FDA’s

Center for Drug Evaluation and Research, in a

press release.

According to the draft guidance, a pro-

posed REMS submission to FDA should

include a proposed REMS, which concisely

describes the proposed goals and elements

of the REMS, and a REMS supporting docu-

ment that provides additional information

such as a thorough explanation of the

rationale for, and supporting information

about, the content of the proposed REMS.

All proposed materials that are included in

the REMS (e.g., proposed communication

and education materials, Medication Guide,

elements to assure safe use, patient package

insert, enrollment forms, and prescriber and

patient agreements) should be appended to

the proposed REMS. A template for the pro-

posed REMS is available on FDA’s website.

The REMS supporting document should

thoroughly explain the rationale for and sup-

porting information about the content of the

proposed REMS, according to the draft guid-

ance. The REMS supporting document should

describe how and when each REMS element

will be implemented and specify the ratio-

nale for the timelines and milestones. If any

REMS activity will not be implemented at the

time of REMS approval, the REMS supporting

document should describe the reason for

the implementation schedule. “For example,

the document should address the rationale

for whether a communication plan would be

implemented before, or concurrently with,

other elements,” the draft guidance says. A

template for the REMS supporting document

can also be found on FDA’s website.

In addition, the draft guidance describes

REMS policies for certain regulatory situations.

The draft lists FDA websites where documents

about approved REMS will be posted.

The FDA Amendments Act of 2007

granted FDA the authority to require the

submission and implementation of a REMS

if the agency determines that it is necessary

to ensure that a drug’s benefits outweigh

its risks. Future draft guidances will address

additional REMS topics, according to an

agency press release.

IN THE FIELD

PharmTech .com22 Pharmaceutical Technology NOVEMBER 2009 PharmTech .com

Following the completion of its $68-billion acquisition of Wyeth (Madison, NJ), Pfizer (New York) began joint opera-tions of the combined company Oct. 16, 2009. Pfizer said in a company press release that in-tegration teams at Pfizer and Wyeth have been working since the announcement of the acquisition agreement in Janu-ary to ensure that the combined company would be fully opera-tional at the time of closing. In achieving that objective, Pfizer outlined its executive leader-ship team and organizational structures for its commercial operations and research and development (R&D).

Pfizer will operate through what it calls “patient-centric” business units in two major areas: biopharmaceuticals and diversified businesses. Its bio-pharmaceutical business units are emerging markets, established prod-ucts, oncology, primary care, and specialty care, which includes vaccines. The units in its diversified businesses are animal health, Capsugel, consumer healthcare, and nutrition.

Pfizer now has two R&D groups in bi-opharmaceuticals, one focused on small molecules and related modalities (the PharmaTherapeutics Research Group) and one on larger molecules and vaccines (the BioTherapeutics Research Group). The individual units within these two re-search organizations are led by chief scien-tific officers, who will act as single points of accountability for delivering proofs-of-concept for development.

Pfizer’s executive leadership team con-sists of senior management from both Pfizer and Wyeth as follows:

• Jeffrey B. Kindler, chairman and chief executive officer

• Frank D’Amelio, chief financial officer and senior vice-president of business operations

• Mikael Dolsten, president of BioTher-apeutics Research & Development

• Freda Lewis-Hall, senior vice-president and chief medical officer

• Martin Mackay, president of PharmaTherapeutics Research & De-velopment

• Mary McLeod, senior vice-president of human resources

• Ian Read, group presi-dent of worldwide bio-pharmaceutical busi-nesses

• Cavan Redmond, group president of diversified businesses

• Nat Ricciardi, president of manufacturing

• Bill Ringo, senior vice- president of business de-velopment, strategy and innovation

• Amy Schulman, senior vice-president and gen-eral counsel

• Sally Susman, senior vice-president and chief communications officer.

In addition to the execu-tive leadership team, Kindler has established the execu-tive compliance committee, which he will chair. It will include Doug Lankler, who as chief compliance officer

reports directly to Kindler, and chief inter-nal auditor Hugh Donnelly, who reports both to the audit committee of the board of directors and to the chief financial offi-cer Frank D’Amelio. Also on the executive compliance committee will be D’Amelio, Freda Lewis-Hall, Ian Read, Cavan Red-mond, and Amy Schulman.

Further changes and cost synergies.

Pfizer is now in the process of finalizing decisions relating to talent and site matters. The company says it “will work quickly to effectively implement those decisions,” adding that such decisions are subject to work councils and/or union consultations and other legal requirements as applicable. continued on page 26

Pfizer and Wyeth Begin Operations as a Combined CompanyThe companies’ $68-billion merger is completed

Patricia Van Arnum

IMAGEZOO / IMAGES.COM, GETTY IMAGES

IN THE FIELD


continued from page 24

Pfizer expects the Wyeth acquisition to be accretive to adjusted diluted earn-ings per share in the second full year after closing. Pfizer hopes to achieve synergies of $4 billion by the end of 2012 in selling, informational and adminis-trative functions, R&D, and manufac-turing. The $4 billion in cost synergies is in addition to another $2 billion in cost savings that Pfizer plans to achieve by the end of 2011.

Financial performance. Pfizer an-nounced Oct. 20, 2009 its third-quarter and nine-month financial results for 2009. Global third-quarter 2009 revenues were $11.6 billion, down 3% from $12 bil-lion in the third quarter of 2008. US rev-enues were $4.8 billion, a decrease of 2% compared with the same period last year. International revenues were $6.8 billion, a decrease of 4% year over year.

For the first nine months of 2009, global revenues were $33.5 billion, a de-

cline of 7% from $36 billion in the same period in 2008. International revenues, which accounted for 57% of Pfizer’s total revenues, were $19.2 billion. This level was a decrease of 8% compared with the same period last year, reflecting 3% op-erational growth and an 11% unfavorable impact of foreign exchange. US revenues were $14.3 billion, a 6% decline from the year-ago period.

Effective Jan. 1, 2009, Pfizer expanded its operating model within its pharmaceu-tical business to include the five customer-centric focused units (primary care, spe-cialty care, oncology, established products, and emerging markets) that are now part of its new organizational structure post the integration with Wyeth. Primary-care revenues for the third quarter 2009 were $5.5 billion, a decline of 4% com-pared with the year-ago period, primarily due to declining sales of Lipitor (atorv-astatin), Pfizer’s top-selling drug. Global sales of Lipitor were $2.85 billion in the

third quarter of 2009, down 9% com-pared with sales in the third quarter of 2008. For the first nine months of 2009, Lipitor sales declined 11% year over year to $8.26 billion.

For the third quarter 2009, specialty-care revenues were up 3% from the year-ago period to $1.6 billion. Oncology rev-enues fell 5% to $371 million. Revenues in established products declined 12% to $1.6 billion, and revenues from its emerging markets unit declined 4% to $1.6 billion.

Pfizer is also continuing its cost-cutting efforts. At the end of the third-quarter 2009, the company had reduced its workforce to 75,400, a decline of 1100 positions compared with the second-quarter of 2009, and a decline of 11,200 since the beginning of 2008.

Pfizer expects stable short- and long-term earnings growth. The company expects that no single drug will account from more than 10% of the combined company’s revenue in 2012.

Zone in on: TestingUSP Issues New Quality Standards for HeparinPatricia Van Arnum

Last month, the US Food and Drug

Administration issued an alert to healthcare

professionals of a change in heparin

manufacturing that is expected to decrease

the drug’s potency. The change is a result of

a second round of revised quality standards

and controls for manufacturing heparin

issued by the United States Pharmacopeia

(USP), effective Oct. 1, 2009.

USP started initial revisions for quality

standards for heparin in 2008 after adverse

reactions and deaths resulted from heparin

intentionally adulterated with oversulfated

chondroitin sulfate. The first stage of the

quality revisions were released by USP

in June 2008. The second-stage tests

and accompanying reference materials

that enable manufacturers to compare

their products to a proven standard were

announced by USP in February 2009.

Following a period of public comment, the

standards are now enforceable in the US by

FDA, according to a USP press release.

As part of the second-stage revisions,

USP harmonized dosage measurement units

with those established by the World Health

Organization (WHO). The changes adopted

by USP for the heparin unit dose match

WHO’s International Standard (IS) unit dose

definition that has been in use in Europe for

many years, according to FDA. The revised

USP reference standard and unit definition

for heparin is about 10% less potent than

the former USP unit, according to FDA.

Manufacturers in the US label the amount

of heparin included in their products based

on USP standards. A unit is the measure of

a drug’s activity in the body. For heparin,

a unit dose is the measure of the drug’s

ability to block the blood’s natural clotting

ability (anticoagulation). Heparin’s potency is

determined by the dose of the drug required

to produce a specific level of anticoagulation.

Although the USP manufacturing

controls took effect Oct. 1 for production,

FDA asked manufacturers to not ship this

new product to customers until Oct. 8,

2009, or later. The delay was intended to

give healthcare providers and facilities time

to learn about the changes and to make

adjustments to their pharmacy procedures

and dosing practices, according to John

Jenkins, director of the Office of New Drugs

in FDA’s Center for Drug Evaluation and

Research, in an FDA release.

“Although the FDA-approved labeling

for heparin has not changed, including the

recommended doses, it is essential that

healthcare professionals be aware of the

potential difference in potency between

the old and new vials of heparin when

administering the drug,” said Jenkins in

the release.

USP and FDA are starting work on a third

stage of revisions to the heparin standards,

which will involve laboratory research

designed to provide greater sensitivity and

precision to the tests and standards used to

help ensure drug quality, according to the

USP release.

IN THE FIELD


IN THE SPOTLIGHT: AUTOMATION

Syringe-testing systemoffers high throughputAstech Projects (Runcorn, England)

has introduced its Syringe-Pro fully

automated solution for prefilled-

syringe sample preparation and

testing. Software enables the sys-

tem to perform functions such as

sample preparation and analysis

simultaneously, thereby enabling

greater throughput than conven-

tional automated systems achieve.

The Syringe-Pro system’s modular

software solution is designed to

run test methods specific to users’

requirements. Operators load the

system with a batch of prefilled sy-

ringes and select the required test

protocol for each syringe through

the user interface. The system aspi-

rates samples from their glass vessels

and injects them directly into a high-

performance liquid chromatography

instrument, thus reducing manual

handling and increasing throughput.

To ensure sterility, the Syringe-

Pro system is fully enclosed, and

environmental control or extrac-

tion features can be incorporated

into the unit. The system minimizes

operator hazards compared with

manual testing.

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].

Robotic packager brings flexibilityThe Solo Packer Cell from QComp Technologies (Greenville, WI) is de-signed to offer production flexibility. Users can select a program from a touch-screen interface to change products. The cell also can receive signals about prod-uct changeover from upstream devices. A standalone programmable logic con-trol (PLC) stores product specifications in memory and interfaces with up- and downstream equipment easily.

The PLC directs the robot’s motion and contributes to its 0.5-mm position repeatability. A safe-move function tightens the robot’s range of motion, which reduces the cell’s footprint.

Software mergesscheduling and planningWAM Systems (Plymouth Meeting,

PA) and ORTEMS (Lyon, France) have

integrated their supply-chain plan-

ning solutions for the pharmaceuti-

cal industry to create the Advanced

Planning System (APS). Because the

software is targeted to the industry,

it is easier to configure and support

and takes less time to implement

than nonspecific planning solutions.

After users enter variables such as

sales history, current inventories, capacity, and capabilities, the APS’s algorithms

automatically create a production schedule at each plant and at all manufactur-

ing stages. The schedules are downloaded into manufacturing execution sys-

tems (MESs) for implementation, and the MESs send updates to the APS about

whether work orders are being executed promptly.

Syringe-Pro system

Astech Projects

www.astechprojects.co.uk

Solo Packer Cell

QComp Technologies

www.qcomptech.com

Advanced Planning System

WAM Systems

www.wamsystems.com

Editor’s Picks of Pharmaceutical Science & Technology InnovationsPharmaceutical ingredients, manufacturing equipment, and regular mainte-

nance contribute to the industry’s high capital costs. Drugmakers’ tolerance

for wasted time and materials has decreased as the pressures on the market-

place have grown. Automation and computer systems can improve process

speed and reduce errors and waste. This month’s products are designed to

aid operations at various levels within a pharmaceutical company. A new

system from Astech helps ensure the quality of prefilled syringes. A robotic

packaging cell from QComp can ease product changeover. Software devel-

oped by WAM and ORTEMS automatically creates production schedules and

facilitates supply-chain planning.


The unstated tradeoff for drugmak-ers’ increased investment in post-approval drug-safety monitoring

is supposed to be greater US Food and Drug Administration flexibility in ap-proving new drugs for market. In real-ity, the agency’s burden of implementing a host of new drug-safety policies and programs has overtaxed staffers and slowed the new-drug review process. Outside criticism and internal dissent have heightened reviewers’ fears about approving new products that raise safety concerns, thus exacerbating FDA’s struggle to fulfill its many new statu-tory requirements and to meet review goals set by the Prescription Drug User Fee Act (PDUFA).

Janet Woodcock, director of the Cen-ter for Drug Evaluation and Research (CDER), acknowledges these chal-lenges. Drugs are getting approved, but more slowly, she explained at the FDA Regulatory Symposium in September 2009. The problem is that the FDA Amendments Act of 2007 (FDAAA) added new requirements for assessing postmarketing studies and determin-ing the need for Risk Evaluation and Mitigation Strategies (REMS) at the time of approval, but with no exten-

sion in review times. CDER has hired more staff and is implementing new procedures to make the review process more efficient. Electronic submission and review systems for drug applica-tions would help, Woodcock noted. But these innovations remain far from reality, and many applications take much more than one review cycle to gain market approval.

As a result, the US may be falling behind Europe in approving innova-tive therapies for patients. At a meet-ing in September 2009 sponsored by the Institute of Medicine (IOM) to evaluate safety initiatives established by FDAAA, Peter Honig, executive vice-president of Merck (Whitehouse Station, NJ), noted that first-cycle ap-provals are down and that user-fee approval dates are “routinely missed” because of increased scrutiny of safety issues. FDA is “clearly struggling” with postmarket safety demands, he said, adding that “drug lag” may be rearing up once more as European regulators approve some new drugs for market faster than US regulators.

The approval slowdown is noticeably affecting drugs to which the agency has granted priority-review status, a designation traditionally reserved for the most innovative and important new therapies. In the past, about 70% of priority-review applications gained first-cycle approval, but this proportion dropped to 50% in 2008, according to a recent report from Parexel Consulting. User-fee approval targets are 10 months for new drug applications (NDAs) and

six months for priority applications. It is particularly difficult for reviewers to accelerate the latter review goal.

The good news is that signs indicate a surge in NDAs filed with FDA and a more robust pipeline for new drugs. Parexel cited 147 NDAs pending at FDA at the beginning of 2009, a notable in-crease from the 86 under review one year earlier. The number of applications for new molecular entities (NMEs) ap-pears to be holding steady, but the per-centage enjoying first-cycle reviews has been dropping slightly, but steadily.

Safety firstThe main culprit in the NDA-review slowdown is pressure on FDA to imple-ment FDAAA postmarketing safety re-quirements, which is an enormous task for the agency and a growing burden on manufacturers. CDER’s Safety First initiative aims to meet the challenge by integrating drug-safety activities and establishing a broader approach to en-suring appropriate drug use through-

Safety versus Speed in Drug Development Jill Wechsler

The heightened focus on risk raises

concerns about delays in approving new drugs.

Jill Wechsler

is Pharmaceutical

Technology’s Washington

editor, 7715 Rocton Ave.,

Chevy Chase, MD 20815,

tel. 301.656.4634,

[email protected].

WASHINGTON REPORT

PharmTech.com/washrep

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In Washington this month

Pipelines are swelling, but

new-drug approvals are

slowing

FDA REMS guidance spells out

content, format, and future

assessments

Manufacturers are fulfilling

postmarketing study obliga-

tions on schedule

•

•

•


out the product life cycle. The REMS program is the most vis-

ible new assignment. CDER has ap-proved 63 new REMS in the past two years, 47 of which only require phar-macists to hand Medication Guides to patients filling new prescriptions. Ten of the REMS have additional commu-nication plans that usually involve let-ters to healthcare professionals about product risks and how to prevent them, and six REMS include Elements to As-sure Safe Use, which may impose re-strictions on prescribers or patients, limit drug distribution, or require special monitoring.

CDER’s Office of Surveillance and Epidemiology has expanded its staff to assess REMS plans, among its other assignments, but the backlog of REMS evaluations is growing, and more work is on the way as requests for periodic assessments emerge. The process of devising, proposing, and negotiating a REMS with FDA is complex and time-consuming, as seen in the long-awaited draft guidance on REMS content and format for drugs and biologics, which FDA issued on Sept. 30, 2009. Even a Medication Guide-only REMS re-quires a manufacturer to explain why a moderate postmarketing strategy is sufficient to ensure safe product use, and to allow FDA to determine that patient information or more detailed directions for use could prevent serious adverse events.

The need for a restricted REMS program, which requires considerable analysis to develop and implement, will be determined based on the size of the patient population, the seriousness of the disease, the drug’s benefits, the duration of treatment, and the known adverse-event profile. The REMS rules for generic drugs are even more complex and will be addressed in further guidance.

The draft guidance describes how manufacturers should submit a REMS proposal to FDA to appropriately ex-plain the risks addressed, program goals and elements, materials involved, and how and when the plan will be implemented. A REMS supporting document should provide a thorough

explanation of the rationale for the program and give details about how the elements or tools in the REMS are expected to mitigate risks without dis-rupting established drug distribution and dispensing systems.

An important REMS component is a timetable for assessing the program after 18 months, three years, and seven years, or more often if warranted. The policy spells out detailed procedures for modifying a REMS after it is ap-proved and adopted if goals are not met or circumstances change. FDA also may unilaterally modify a REMS if new safety or effectiveness informa-tion emerges.

A major challenge for sponsors and for FDA is to determine how best to measure whether a REMS is effective. FDA suggests that sponsors conduct surveys, collect prescriber informa-tion, or establish active systems to assess these programs. Although it’s

fairly straightforward to verify that pieces of paper have been handed out as part of a Medication Guide distri-bution program, it’s much trickier to determine whether risk information inf luences prescribers’ and patients’ behavior. And manufacturers cannot do much to compel practitioners to re-port adverse events or to limit inappro-priate prescribing if physicians ignore advisories and restrictions.

The pages of the detailed guidance on REMS submissions plainly show why FDA’s review of these plans takes so much time. Manufacturers report that information requests and nego-tiations with FDA on REMS can go on for months. If FDA determines late in the review process that a product re-quires a more comprehensive REMS program than that initially expected by the sponsor, it’s unlikely that the appli-cation will be approved in one review cycle, explained John Jenkins, director

FDA to revise approval process for combination products and medical devicesIn addition to modernizing the approval process for new drugs, the US Food and Drug Administration

seeks to clarify procedures and requirements for developing and reviewing new medical devices and

combination medical products. For combination products, a key issue is which manufacturing standards

should be followed for products with both drug and medical-device components. FDA’s Office of

Combination Products (OCP) designates whether a combination product should be reviewed as a drug,

device, or biologic product based on the product’s primary mode of action and its proposed use. OCP is

seeking comments on ways to make the designation process transparent and on how manufacturers

should meet good manufacturing practice (GMP) requirements.

A new proposal [Current Good Manufacturing Practice Requirements for Combination Products,

posted Sep. 23, 2009 at FDA.gov.] explains how manufacturers should select either the drug or the

device as the primary operating system for the product and fully comply with manufacturing and

quality standards for that component. A streamlined approach is permitted for meeting manufacturing

standards for the other component. Compliance with quality requirements, however, will be based on

the total combination product, and not on each part.

FDA also has embarked on a major reassessment of its medical-device approval process in the wake of

complaints that the agency has become too lax and has approved risky products without sufficient testing.

In an unusual move, FDA leaders unveiled an internal report of the controversy surrounding the approval

of ReGen Biologics’s (Hackensack, NJ) Menaflex knee-repair product in September 2009. The scathing

analysis described procedural irregularities within FDA and inappropriate outside pressure on the agency

and advisory committees. In response, the Institute of Medicine (IOM) will examine the fast-track premarket

notification or 510(k) program, which permits manufacturers to notify FDA that a low-risk device is

equivalent to a similar approved product and does not require extensive preapproval clinical trials.

The Center for Devices and Radiological Health also has established an internal task force to evaluate

the use of science in regulatory decision-making. The IOM report, which is due in early 2011, will assess

whether the 510(k) process needs to be changed and whether change would require legislation. FDA

also is reviewing whether the ReGen product should stay on the market. One consequence of this

scrutiny of device-safety issues is that manufacturers are detecting delays in approvals for new medical

devices and fear a cautious approach to 510(k) reviews while the IOM assessment proceeds.

Washington Report


of CDER’s Office of New Drugs, at the IOM workshop.

An important decision for manu-facturers is whether it’s better to pro-pose a REMS voluntarily before filing an NDA, or to wait and see whether FDA reviewers determine that such a program is necessary. No one wants to implement a REMS if it’s not required, because the process consumes con-siderable resources and elevates the risk associated with the product. But FDA seems to be requiring REMS for most NMEs, and developing a REMS during the application review period will slow the approval process. More drugmakers are talking about bring-ing up REMS issues at end-of-Phase-II meetings with FDA to avoid surprises later on.

Whatever tack a company takes, it’s important to get the details of a REMS right and to establish reasonable and practical goals and timetables. Manu-facturers that violate a REMS require-ment face fines as high as $10 million and the possibility that FDA will pull the product off the market.

Timely postmarketing studiesPeriodic REMS assessments also in-clude updated information about postapproval studies or clinical trials undertaken by the sponsor, including study status, expected completion date, and whether difficulties have been en-countered in meeting set goals. Simi-larly, this information is provided in annual reports on postapproval stud-ies, as required by FDAAA to address complaints that pharmaceutical com-panies have failed to complete agreed-on postmarketing studies in a timely manner. Congress authorized FDA to mandate postapproval studies that achieve specific objectives and to levy fines on companies that miss agreed-on deadlines.

The result is that FDA reviewers now have to determine the scope and timing of postmarketing studies as part of the complex application-review process. Instead of merely vetting manufac-

turers’ study proposals, agency staff-ers must examine what scientific data can best assess known and unknown serious risks and set appropriate time-frames for the completion of postmar-ket studies and trials.

This scrutiny of postmarketing studies seems to be having a notable effect. FDA’s latest annual report on the program showed considerable industry progress in achieving “on schedule” status for fulfilling post-marketing study obligations. About 20% of studies are ongoing (i.e., were started on schedule) or submitted to FDA, and most are “pending” (i.e., not yet started, but not delayed). This cat-egory includes many studies involving pediatric populations, which have to wait until all other safety information is submitted and reviewed.

FDA should improve its ability to track and review postmarketing stud-ies following Booz Allen Hamilton’s analysis of these obligations. The con-tracted analysts cleaned up FDA’s con-fusing database of about 1531 postmar-keting studies, identifying many that have been submitted to FDA or that the agency no longer considers neces-sary, and determining that more than 80% are proceeding according to estab-lished timelines.

FDAAA also authorizes FDA to re-quire additional postmarket studies for approved drugs and to require changes in labeling when new safety informa-tion emerges. The agency sent 14 letters requiring additional studies from mid-2008 to mid-2009 and issued 18 safety-labeling notification letters during that period. These additional tasks tap the agency’s resources.

Because some postmarketing stud-ies are likely to involve thousands of patients, CDER plans to ask advisory committees to weigh in on acceptable trial designs, numbers of patients, and endpoints. These committee sessions will address study designs for classes of drugs—rather than for each individual product, which would only extend ap-proval times even more. And broader

public buy-in for innovative studies may

help FDA parry second-guessing later

on if research is delayed or changed.

Streamlining reviewsWoodcock hopes that CDER’s 21st Cen-

tury Review initiative will deal with these

new challenges by better managing the

application-review process. The aim is to

compress review times up front to pro-

vide more leeway at the end of the review

period to address safety issues and re-

solve internal and external disputes. But

streamlining reviews is a considerable

challenge, Woodcock explained at the

symposium, because the average NDA

consists of 10 gigabytes of material. The

data may no longer come in truckloads,

but CDER reviewers still have to digest a

massive amount of information.

CDER conducted a pilot program

last year that reviewed 17 applica-

tions for NMEs under the new review

process. This approach now is being

extended to most NMEs and new bio-

logics license applications and is slated

to affect all applications and supple-

ments by 2012. The streamlined sys-

tem involves meeting in advance with

manufacturers to identify key issues

and ensure that applications are com-

plete when submitted. Earlier internal

deadlines have been set for establish-

ing multidisciplinary review teams,

for identifying application deficien-

cies, and for reviewing product label-

ing. FDA will assess up front whether

an advisory committee meeting will

be needed, what potential postmarket

safety requirements might apply, and

other possible “showstoppers” that

could delay the approval process.

The agency and industry are opti-

mistic that these efforts, along with

staff expansion and training, will get

CDER back on track with review goals

and deadlines. But any changes must

support FDA’s capability for assessing

and preventing drug-safety problems

and ensuring safe drug use throughout

the product life cycle. PT

Washington Report


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Cover Story: Supply Chain

In late September,

Pharmaceutical Technology

hosted a roundtable featuring

representatives from industry,

standard-setting bodies, and

regulatory organizations to

discuss growing concerns

over the security of the global

pharmaceutical supply chain.

A condensed transcript of that

roundtable follows, including

each speaker’s thoughts on

supply-chain solutions such as

shared or third-party audits,

joint inspections, and increased

international collaboration.

*Susan J. Schniepp, vice-president of quality for Javelin Pharmaceuticals and a member of Pharmaceutical Technology’s Editorial Advisory Board, moderatedthe discussion.

Martin Van Trieste

on Rx–360 and shared audits

Van Trieste is vice-president of quality at Amgen (Thou-sand Oaks, CA) and interim direc-tor of Rx-360, the recently established international phar-maceutical supply-chain consortium.We have learned some recent lessons the hard way. The tragedies related to econom-ically motivated adulteration of glycerin in Haiti, Panama, and Nigeria as well as hepa-rin used in the United States and Europe, and melamine found in various products throughout the world, have taught us that unethical individuals and criminals have entered the pharmaceutical supply chain with tragic consequences. The US Food and Drug Administration estimates that at least 800 individuals have died throughout the world [because of] adulterated glycerin. The number of deaths and serious injuries related to the other events mentioned is in the thousands.

As regulators and industry profession-als, we wake up every morning and decide how our ideas and work will help patients. This is all undermined by another group of individuals that wakes up every morning to develop methods to pass off cheap sub-standard materials to make a quick profit.

About a year ago, FDA and PDA, the Parenteral Drug Association, collaborated to develop a conference series to increase awareness of this problem and to solicit ideas from industry about how to fight back. Several quality leaders from within our industry quickly realized that the problem was not due to a failure of good manufacturing practices (GMPs) but was a result of criminal activity. We also recognized that this problem was global and very complex, requiring a big bold re-sponse that no one company could solve on its own. At the second conference, in December 2008, we decided the best re-sponse would come if the industry joined forces. We decided to form a consortium, which grew into Rx–360 .

Rx–360 now has more than 25 members representing pharmaceutical and biotech-nology companies, their suppliers, and

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various professional organizations. Rx-360 does not intend to compete or duplicate the efforts of other organizations such as the International Pharmaceutical Excipients Council (IPEC), but rather to collaborate with these organizations to reduce patient risk as quickly as possible.

There are four functions of Rx–360. First, we are adopting standards and best practices. The consortium will scan exter-nal sources for the best available standards today that will assist in improving the performance of the supply chain. After implementation, the consortium will look to identify any gaps in the standards aimed at improving these standards

Second, Rx–360 will conduct supply-chain surveillance. The consortium will act as a clearinghouse for vital market supplier and supply-chain information. Consor-tium members will report suspicious and pertinent events to the consortium, which will disseminate the initial information, evaluate the impact of the information on its members, and develop potential proac-tive solutions for its members to consider adopting. By creating an effective surveil-lance system, we will know about short-ages and other critical events earlier than the criminals.

Third, we will develop technology to prevent or detect adulteration. The con-sortium will work with research organiza-tions to develop new technologies that will ... detect if there has been tampering within the supply chain. Finally, we are developing a process for sharing audit information. We are working on the standards we should adopt, what those standards are, and how to qualify our auditors. Our goal is to begin sharing audit data between member com-panies by year’s end.

It is important to remember that it is still the responsibility of each member company to make its own decision on a supplier’s acceptability based on its indi-vidual product requirements and its own company policies and procedures.

The shared-audit program should re-duce the number of audits at common suppliers, eliminating what is known as “audit fatigue.” What we will ask for in re-turn from the suppliers is to allow Rx–360 to conduct longer, more thorough audits that not only cover GMP but that also look

at environmental health and safety, risk management, supply-chain security, and other activities.

Janeen Skutnik on IPEC guidelines and IPEA’s third-party audits Skutnik is director of quality and regula-tory policy at Pfizer (New York) and chair of the International Pharmaceutical Ex-cipients Council of the Americas (IPEC-Americas). IPEC, which rep-resents pharma-ceutical manu-facturers, excipient suppliers, and distrib-utors, has been focusing on developing vol-untary guidances for excipients and white-papers for the past 15 years, all focusing on the safety and security of pharmaceutical supply chains. We believe that to ensure the security and integrity of the pharmaceuti-cal ingredient supply chain, we must have a comprehensive, multifaceted, risk-based approach to this issue.

[One growing approach is] geopolitical environmental scanning, which focuses on what is going on globally from an eco-nomic perspective, a political perspective, and [within] other industries so that we can be better prepared to look at poten-tial vulnerabilities. If we look at the case study of heparin, we know that heparin is (sourced) from pigs and that the majority of the world’s pig population happens to be in China. We also know that it takes about 50 million pigs to supply the US market for a single year. Prior to the heparin incident, we had several years where the price of pigs was increasing due to demand as well as a disease that ransacked the pig population. Had we, as industry, been more in tune to those changes—economic changes—we may have been better able to predict po-tential issues.

Solely focusing on GMPs is not going to solve the [problems we face.] IPEC is working to convert our GMP and good distribution practice (GDP) standard into ANSI standards, which would make them voluntary consensus-based standards in lieu of government-unique standards. This way, they can serve as a tool for industry ... that FDA would find acceptable.

We need to make sure we have proce-dures for the good distribution of excipi-ents and how they’re received. We need to make sure that we have a periodic audit. From IPEC’s perspective, it is no longer acceptable to accept your excipient sup-pliers based on paper audit. Anyone can tell you anything on a piece of paper. You need to have first-hand knowledge ... from either your individual company or from a third party.

We should make sure that we’re aware whether any of our contractors subcon-tract out work. We need to confirm that the agreed-upon supply chain is being used. And we need to start thinking dif-ferently about how can we ensure the integrity of packaging and seals and also work with our distributors and excipient suppliers so we know how things are sup-posed to be received.

A quality agreement is something that we need to think about a little bit more for excipients. Quality agreements for excipi-ents in the past have not been an item of focus for most pharmaceutical manufac-turers. [But they provide a very] important way to delineate what is important, what expectations [of the supplier] are, and how the two parties can work together. IPEC has developed [free quality agreement] templates for use with excipient suppliers and distributors.

IPEC [also has] an excipient qualifica-tion guidance, which lays out what is im-portant from the perspective of the excipi-ent manufacturer as well as the excipient user. It focuses on things like only using excipients from high-quality suppliers and ensuring that you have a [comprehensive] vendor/supplier qualification program. It’s no longer acceptable just to look at a vendor qualification program for the top 10% of your suppliers.

We need to make sure that we have im-proved communications between users, makers, and distributors. If we, as phar-maceutical manufacturers are more open and transparent with excipient suppliers, they can better help meet our needs.

Another piece of ... supply chain se-curity for excipients is the importance of the audit. It is critical to have audit information for all of your excipients. And we have seen that the expectations

Supply Chain


Although the US Food and Drug Administration was unable to participate in

Pharmaceutical Technology’s September roundtable, the Division of Manufacturing

and Product Quality (DMPQ), which falls under the Center for Drug Evaluation and

Research’s Office of Compliance, provided some input to the issues discussed.

Q: Does FDA support the Rx–360 consortium’s overall efforts? More specifically, is

the agency likely to accept shared audit reports in the future, and if so, will certain

criteria be necessary to do so?

A: FDA is in favor of industry cooperative efforts, such as Rx–360, which aim

to improve quality assurance and secure the pharmaceutical ingredient supply

chain. We believe site audits are an integral part of assuring ingredient quality and

supply-chain integrity. Recent tragedies involving ingredients have indicated that

the entire supply chain needs to be appropriately scrutinized. Users of ingredients

are innovating cooperative approaches to leverage resources and thereby,

[ensuring] that they can audit all suppliers around the globe at an appropriate

frequency, including the distribution network. FDA agrees that qualified third

parties can be used by manufacturers to support their audit programs. FDA is

considering the possibility of recognizing third-party auditing bodies and the

standards used by such parties to conduct audits.

—Steven Wolfgang, Consumer Safety Officer

Q: Will FDA also support and accept third-party audit reports (e.g., those conducted by

International Pharmaceutical Excipients Auditing), or does the agency prefer a company

do its own audit? What general criteria does a company need for its audits of active

pharmaceutical ingredient (API) and excipient suppliers to meet FDA expectations?

A: A manufacturer can opt to rely on a qualified third-party auditing body to

be a provider of an audit report to replace or supplement its own audit. Generally

speaking, a manufacturer would want to consider the scope of the audit, its own

internal procedural requirements (e.g., frequency of audits), and its own quality

requirements for the supplied ingredient(s) in determining whether or not the

audit performed by the third party is adequate. Other considerations such as

functionality of the ingredient or intended use of the finished product are also

important factors to consider in determining whether or not a third-party audit

of an ingredient manufacturer provided the relevant scope, focus, and depth to

fully meet user expectations. —Rick Friedman, Director of DMPQ

Q: What is the status of the pilot project being conducted with the European

Medicinces Agency (EMEA) and Australia’s Therapeutic Goods Administration (TGA),

aimed at sharing inspection information about API and excipient manufacturers and

conducting joint inspections?

A: Starting in late 2008, the three regulatory authorities (EMEA, FDA, and

TGA) began to use a template to share their inspection plans (see www.

emea.europa.eu/Inspections/docs/41432308en.pdf ). Through this process,

we identified sites of common interest with TGA and EMEA. Since that time,

FDA and its regulatory partners have shared numerous inspectional reports.

Each report is evaluated for content, currency, relevance of coverage and, in a

number of cases, FDA has chosen to use these reports in lieu of doing an FDA

inspection. We have also built relationships by doing joint drug inspections. So,

the project continues to gain momentum, and we are now meeting with TGA

and EMEA on a routine basis (monthly). —R. Friedman

Q: The agency’s Safer Medical Products initiative, announced in May 2009, also aims

to improve the supply chain through inspections, field exams, and greater access to

international regulatory authorities’ inspection data and results. How will sharing

information benefit the global pharmaceutical industry?

A: We believe FDA’s information-sharing will benefit consumers and the

industry, and yield major benefits for public health protection. In this new

regulatory paradigm, we are leveraging information from various sources to

monitor and control the expanding globalized network of pharmaceutical

ingredient suppliers. And it appears to us that industry is largely on a similar

path toward leveraging resources and sharing information. We think ethical

suppliers of pharmaceutical ingredients should readily realize the importance

of cooperating to secure the supply chain since it would seem in everyone’s best

interests to provide safe and secure ingredients. Assuring the sharing of certain

technical information among users and manufacturers of ingredients is essential

to a robust supply-chain quality management system. So success in securing

the supply chain through improved traceability of pharmaceutical ingredients

will depend upon cooperation among ingredient users and all members of the

ingredient supply chain. FDA also foresees significant opportunities to build on

recent developments in the use of analytical technology to identify ingredients

that come from qualified trusted suppliers and also to screen for adulterants.

These emerging technological approaches can make a profound difference, and

we believe these innovations will ultimately be found to be very beneficial to

both FDA and industry in combating supply-chain risks. —S. Wolfgang

US Food and Drug Administration responds to supply-chain security concerns and proposals.

Supply Chain

of regulators are changing. We need to reassess our audit programs, our priori-ties, and how we define risk. We may want to consider that the risk is not nec-essarily the highest with the companies with the highest volume that you’ve been working with for 10 or 20 years. Perhaps there’s a higher risk with some of the smaller companies that you’ve never actually visited.

We need to rethink our audit questions

as well. Inquire about your subcontractors, and make sure that your suppliers have their own qualification systems.

International Pharmaceutical Excipi-ents Auditing (IPEA) is one tool. A sub-sidiary of IPEC, its mission is to facili-tate site assessment for the qualification of excipient suppliers with [the goal of] reducing cost for makers and users. The report provides you with the full details of an audit so, as a company, you can

decide, does this meet my needs? The audits are done [under] the GMP guide for pharmaceutical excipients developed by IPEC.

Overall, IPEC has numerous initiatives driving at excipient and pharmaceutical in-gredient supply-chain security and safety. We really are trying to work together with the key parties to ensure the safety and se-curity of excipients.

continued on

PharmTech .com40 Pharmaceutical Technology NOVEMBER 2009 PharmTech .com40 Pharmaceutical Technology NOVEMBER 2009 PharmTech .com

Tom Buggy on Europe’s audit program

Buggy is inter-national quality manager of DSM Anti-Infectives in The Netherlands and part of the Quality Working Group of the Eu-ropean Chemical Industry Council’s Active Pharma-ceutical Ingredients Commit tee (APIC). He is also a key member of the APIC Audit Program Task Force. As the European API manufacturers asso-ciation, APIC fully understands the risks to patients if non-GMP or counterfeit APIs are used as starting materials in the manufac-ture of medicinal products. We recognize the importance of supplier qualification as an effective quality system to approve new suppliers and to periodically evaluate suppliers and manufacturers for ongoing

manufacture. In fact, APIC is preparing a supplier-qualification guidance that should be published in November 2009.

One key element we’ve been dealing with at APIC in terms of supplier qualifica-tions is the on-site audit. When you look at the overall audit requirements in the phar-maceutical industry and the international requirements ... the audit burden on the industry is overpowering. APIC has devel-oped a third-party audit program ... that is available for the pharmaceutical industry to use whenever they see the need for a third-party audit that can be shared with many medicinal-product manufacturers (see Figure 1). The option of a credible inde-pendent third-party audit is acceptable to the European authorities as long as certain principles are followed. Key elements of the APIC audit program are:

Coordination of the audits by the API •

Compliance Institute to avoid any po-tential conflict of interest with APIC members A standardized six-step procedure for performing the third-party audit A standard approach for an audit of an API manufacturer, which involves two days with two auditors to make sure there is an effective assessment of GMP compliance Most importantly, only APIC-certi-fied auditors are involved.

With regard to auditors, they must have a good background in terms of qualifica-tion in chemistry or a related science and appropriate experience in the pharma-ceutical industry. To become an APIC-certified auditor, the individual must pass a five-day course covering the GMP requirements for APIs, including a work-shop on auditing techniques related to APIs. The API Compliance Institute en-sures that the auditors chosen to perform the audit are independent of the customer and the auditee to avoid potential conflicts of interest. Auditors must also sign a con-fidentiality agreement.

Auditors [assess] GMP compliance based on the International Conference on Harmonization Q7 Good Manufacturing Practice for Active Pharmaceutical Ingre-dients guideline. Any findings that come out of the audit are explained in full in the closing meeting with the auditee. The au-ditors classify the findings using a similar classification system used by the European member-state inspectors and include de-tailed evidence for their findings in the audit reports. At the end of the audit, there will be a clear indication whether the GMP-compliance level has been assessed as sat-isfactory by the auditors. The APIC audit report can also be shared with other me-dicinal-product manufacturers.

The key advantage of the APIC audit program is that it is based on the guid-ances of the European authorities relating to third-party audits. We think this audit program can contribute significantly to assessing overall supply-chain security of medicines for the protection of patients. We also agree that the program provides only one option for effective audits. If the industry as a whole can work together, we can do more to ensure the safety and integ-

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rity of the medicines used worldwide.

Susanne Keitel on certification standards and sharing inspection informationKeitel is director of the European Director-ate for the Quality of Medicines and Health-care (EDQM) of the Council of Eu-rope in Strasbourg, France. EDQM is also responsible for the European Pharmacopoeia (PhEur). EDQM devel-oped a program to certify suitability of the monographs of PhEur to adequately control the quality of a substance from a specific source (i.e., cer-tification of suitability [CEP]), which has been running since 1994. This procedure provides active substance manufacturers as well as brokers and distributors with the option of filing their quality documenta-tion for the active substance with EDQM for a centralized assessment, rather than filing individual drug master files in dif-ferent European Union member states or including the information in individual marketing authorization applications.

The focus of the procedure is to ensure that impurities are adequately controlled. Hence, a certificate will often include ad-ditional tests and specifications to be con-ducted for a given active substance from a specific source in addition to the manda-tory pharmacopeial tests.

In 1997, it was decided that it would be prudent not only to rely on paper assess-ment, but also to include inspections of manufacturing sites and processes. Based on a mandate from the European Com-mission, EDQM is now running GMP inspections for APIs—these inspections also assess compliance with the dossier. Inspections are normally conducted by a team of inspectors from EDQM and European national competent authori-ties. These inspections completely follow EU rules. This means that inspections of API manufacturing sites are not done rou-tinely, but following a risk-based selection of sites according to the triggers identified at a European level and published ... on the EMEA website.

Supply Chain

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EDQM today faces a situation where the vast majority of inspections are con-ducted outside of Europe, predominantly in India and China, reflecting the global shift in API production. The outcome of the inspections indicates the need for closer surveillance. In 2008, EDQM conducted 28 on-site inspections, leading to 16 cer-tificates (CEPs) being suspended. Between January 209 and June 2009, EDQM per-formed 17 inspections, leading to 8 cer-tificate suspensions. This means that 35% of the sites covered were found to be non-GMP compliant. It is important to stress that this is not representative of the entire API market. In contrast, it does indicate that the triggers used in the risk-based ap-proach in the selection of inspection sites are the right ones.

In the case of a negative inspection outcome, European competent authori-ties and the local competent authority of the country where the inspection took place are informed (local inspectorates are routinely invited to participate in any inspection performed in their respective

country). The competent authorities then take appropriate action.

As demonstrated by the number of suspended CEPs, there is a clear need for a broader coverage of inspection sites. EDQM therefore welcomes EMEA’s pilot project to exchange information on API inspections with the FDA and Australia’s Therapeutic Goods Administration. In fact, EDQM participates in this exercise on the European side.... Due to the absence of mutual recognition agreements, it will not be possible to take action based on infor-mation received from the partners in this pilot project. However, the information re-ceived from the partners will be very useful when applying risk-based selection of sites for inspection. For example, why should a site already covered by a partner and found to be GMP-compliant be high on the prior-ity list of another partner?

Current EU pharmaceutical legislation requires the qualified person (QP) of the holder of the manufacturing authorization certify that all API used in the product has been manufactured according to GMP.

This has to be certified in every single mar-keting authorization application or subse-quent variation. Based on the outcome of inspections carried out in the framework of EDQM’s certification scheme, I have the impression that not all QPs really take their responsibility serious enough to ensure an audit—else it would be difficult to explain why we still see so many deficiencies. The planned revision of the pharmaceutical legislation, the EU Pharmaceutical Pack-age, is [expected] to explicitly require the performance of audits. The draft legisla-tion requires that any contracted auditor be accredited by the national competent authority of a member state. Hence, the draft legislation foresees more stringent requirements for the future. Based on our experience in conducting inspections of API manufacturing site, we consider this a move into the right direction. PT

Listen to the complete transcript of this roundtable

on PharmTech.com. Also online, sidebars address security

solutions for pharmaceutical imports and legislative programs

targeting the pharmaceutical supply chain.

PharmTech .comPharmaceutical Technology NOVEMBER 2009 43

The goal of reaching desired enanti-oselectivity of active pharmaceutical ingredients (APIs) is an ongoing chal-lenge for process chemists. Chemo-catalysis and biocatalysis play an im-

portant role in asymmetric synthesis, and there have been several interesting developments in these areas.

Supramolecular catalystsResearchers at the Graduate School of Engineering at Nagoya University in Nagoya, Japan, recently reported that they developed an asymmetric catalyst that assembles spontaneously, a devel-opment that lays the groundwork for further designing functional supramo-lecular catalysts. Their work involved using chiral organic ion-pair catalysts assembled through a hydrogen-bonding

network (1). The researchers pointed out that overall development of structurally discrete, chiral supramolecular catalysts for asymmetric organic transformations has been met with limited success. In their work, however, the researchers reported that a chiral tetraaminophos-phonium cation, two phenols, and a phenoxide anion appeared to have self-assembled into a catalytically active supramolecular architecture through intermolecular hydrogen bonding. The researchers developed the catalyst for the highly enantioselective conjugate addition of acyl anion equivalents to α-, β-unsaturated ester surrogates (1).

Catalytic asymmetric synthesis for nonnatural amino acidsEric Jacobsen, professor of chemistry at Harvard University, and his research team detailed an improved method for making bulky nonnatural amino acids, which are used as building blocks for APIs and in chiral catalysts (2). The re-searchers point out that although there are efficient chemo–enzymatic methods for producing enantioenriched α-amino acids, obtaining nonnatural amino acids has been more difficult. The researchers explained that although alkene hydroge-nation is useful for the enantioselective catalytic synthesis of many amino acids, it is not possible to obtain α-amino acids with aryl or quarternary alkyl α-substituents with this approach (2).

The researchers addressed this prob-lem by developing a scaleable catalytic asymmetric Strecker synthesis of un-natural α-amino acids. The Strecker syn-thesis is an approach to produce racemic α-amino acids, but catalytic asymmet-ric methods have been limited to small scales. The Strecker synthesis involves the reaction of an imine or imine equivalent with hydrogen cyanide followed by nitrile hydrolysis. Existing catalytic methods

Advancing Chiral Chemistry in API SynthesisPatricia Van Arnum

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485 Route One South,

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Functionalized supramolecular catalysts and an enantioselective route to unnatural amino acids are some recent developments.

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and the use of hazardous cyanide mate-rials in the asymmetric Strecker reaction however, limits its application in large-scale reactions (2).

To resolve that issue, Jacobsen and his team developed a new catalytic asym-metric method for producing enantio-merically rich nonnatural amino acids using a chiral amidothiourea catalyst to control the hydrocyanation step. The researchers report that this approach is compatible with aqueous cyanide salts, which are safer than other cyanide sources, which allows the process to be run at larger scales (2).

Ligand selection in asymmetric transition-metal catalysisResearchers at McGill University in Montreal reported on an approach for ligand selection in asymmetric transition-metal catalysis. The ap-

proach in chiral catalyst formation involved coupling a pool of Brønsted acids, specifically amino-acid de-rivatives, with adjustable ligands on copper catalysts. The researchers re-ported that the system can be used to generate various chiral environments by changing the amino acid or ligand and therefore is a suitable approach for screening and identification of possible combinations to achieve high enantioselectivity. An example of this approach is shown with the copper-catalyzed alkynylation of imines in enantiomeric excess of up to 99% (3).

Enantioselectivity innatural product synthesis Natural products offer a source for bioactive molecules, but developing a synthetic route to such compounds can be challenging. Dennis G. Hall,

professor of chemistry at the Uni-versity of Alberta in Edmonton, Al-berta, Canada, and his team recently reported on the catalytic asymmet-ric synthesis of palmerolide A using organoboron chemistry (4). Palmero-lide A is a marine natural product that is being developed as a potential drug to treat melanoma. The researchers re-ported on a catalytic enantioselective synthesis of palmerolide A without using stoichemetric chiral auxiliaries or a chiral pool (4).

Instead, the researchers produced the right half of the molecule by using a variant of the Claisen–Ireland rear-rangement using alkenylboronate as a masked hydroxyl. To produce the left half of the molecule, the research-ers used a diol–tin (IV) chloride-catalyzed enantioselective crotylbora-tion. The researchers said that this ap-proach may offer a easy way to design simplified analogs of palmerolide (4).

Jacobsen et al. recently reported on a general approach for producing the polycyclic carbon framework shared by terpene natural products (5, 6). Specifi-cally, Jacobsen reported on a catalytic transannular asymmetric Diels–Alder (TADA) reaction for producing poly-cyclic products in high enantiomeric excess. The catalyst system (deriva-tives of oxazaborolidine-based Lewis-acid compounds) were used to alter the diastereoselectivity of cyclizations with substrates containing chiral centers. The catalytic enantioselective TADA was used as the key step in synthesizing sesquiterpene 11, 12-diacetoxydrimane. This route may provide a strategy to the polycyclic carbon framework shared by other terpene natural products (5, 6).

Mohammad Movassaghi, associate professor of chemistry at the Massa-chusetts Institute of Technology (MIT) in Cambridge, recently reported on an 11-step synthesis for producing (+)-11, 11’-dideoxyverticillin A, a naturally oc-curring alkaloid with anticancer activ-ity. (+)-11, 11’-Dideoxyverticillin A is a densely functionalized, stereochemi-

Chiral separations.Although asymmetric synthesis may be a preferred method for producing a single enantiomer,

methods for chiral separations of racemic mixtures is also used to produce a given enantiomer.

Researchers at the Massachusetts Institute of Technology (MIT) in Cambridge, and Brown

University in Providence, Rhode Island, recently reported on their work using microfluidics as a

potential tool in chiral separations.

Specifically, the researchers showed that a plane parabolic flow in a microfluidic channel causes

nommotile, helically shaped bacteria to draft perpendicular to the shear plane. They assert that

the net drift results from the preferential alignment of helices with streamlines with a direction

that depends of the chirality of the helix and the sign of the shear rate (1).

“This discovery could impact our understanding of how water currents affect ocean microbes,

particularly with respect to their ability to forage for food since chiral effects make them drift off-

course,” said Roman Stocker, the Doherty assistant professor of ocean utilization in MIT’s Department

of Civil and Environmental Engineering, in a Apr. 17, 2009 MIT press release. “But it is also important

for several industries that rely upon the ability to separate two-handed molecules.”

The researchers designed a microfluidic environment with channels containing water and

bacteria to create a shear flow of adjacent layers of water moving at different speeds. They

used a nonmotile mutant of the bacterium Leptospira biflexa and injected it into the center of

the microfluid device and showed that bacteria drift off-course in a direction directed by their

chirality. The researchers developed a mathematical mode for the process and are implementing

the approach to separate objects at molecular scales.

“The methods currently used to separate chiral molecules are far more expensive and far slower

than the microfluidic option,” said the researchers in the MIT press release. “While we still have

some way to go to separate actual chiral molecules, we think our work is very promising for the

agriculture, food, and pharmaceutical industries.”

Source 1. R. Stocker et al., Phys. Rev. Lett 102 (15), 158103–158107 (2009).

46 Pharmaceutical Technology NOVEMBER 200846 Pharmaceutical Technology NOVEMBER 2009 PharmTech .com46 Pharmaceutical Technology NOVEMBER 2009 PharmTech .com

cally complex and dimeric epidithio-diketopiperazine natural product, and the synthesis of epidithiodiketopipera-zines represented a challenge (7). The researchers developed an approach for the enantioselective total synthesis of the compound through a biosynthetic route that used stereo- and chemose-lective advanced-stage tetrahydroxyl-

ation and tetrathiolation reactions and the introduction of the epidithiodi-ketopiperazine core (7).

Other approaches in asymmetric synthesisResearchers at Princeton University reported on β-aminocarbonyl syn-thesis using oxidative organocatalysis.

β-aminocarbonyl moities are impor-tant to many bioactive molecules such as paclitaxel, β-peptides, and β-lactam antibiotics (8).

Enantioselective catalytic routes to β-aminocarbonyl-containing com-pounds have involved several differ-ent approaches. These approaches in-clude Mannich couplings, enamine hydrogenation, conjugate additions, and Staudinger reactions (8). The research-ers developed another strategy based on singly occupied molecular orbital (SOMO) catalysis, by which a three-π electron radical cation species undergoes enantioselective bond formation with π-SOMO to produce α-functional-ized aldehyde adducts. The research-ers applied the fundamentals of this approach by using silyl nitronates as SOMOphiles to provide enantioselective β-nitroaldehydes. The researchers re-ported on their strategy for producing β-aminocarbonyl synthesis using oxida-tive organocatalysis. The approach is im-portant because it achieves enantioselec-tivity to the syn or anti diastereomers of β-amino acids or 1,3-aminoalcohols (8).

T.V. RajanBabu, professor in the chem-istry department at Ohio State University, and his team discovered a new codimer-ization of ethylene and various func-tionalized vinylarenes, 1,3-dienes, and strained alkenes (i.e., asymmetric hy-drovinylation). This chemistry has appli-cations in the enantioselective synthesis of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, and fenoprofen from the corresponding styrenes and ethylene (9, 10). Specifically, the group developed highly catalytic pro-tocols to allow for the codimerization of ethylene and various functionalized vi-nylarenes, 1,3-dienes, and strained al-kenes under mild reactions conditions to produce 3-arylbutenes. Such chemistry can be applied to the synthesis of select NSAIDs (9, 10).

His work has further application in the synthesis of steroid deriva-tives. Cyclic and acylic 1,3-dienes can also undergo efficient heterodimer-

PharmTech .comPharmTech .com48 Pharmaceutical Technology NOVEMBER 2009

ization with ethylene with yields up to 99% for several 1-vinylcycloalkenes and 1-substituted 1,3-butadienes (9, 10). Phospholanes and phosphoramidites can be used for ligands for an asymmetric variation of this reaction with yields up to 99% and enantiomeric excess of 95% for select substrates. An exocyclic chiral center can be used to install other stereo-centers in the ring. His work also has involved the synthesis of several new ligands for improving enantioselectivity and the use of hemilabile ligands and their synergy with highly dissociated counterions to enhance selectivity (9, 10).

The very nature of asymmetric synthesis, which lends itself to more efficient transformations, can support the broader goal of applying green chemistry in pharmaceutical applications. A recent review article by the American Chemical Society’s Green Chemis-try Institute Pharmaceutical Roundtable reported that more than 150 articles relating to asymmetric hydrogenation were published in 2008, with the majority of articles relating to the modification of the catalyst and ligands (11, 12). An important development that may lead to improving reaction conditions for asymmetric hydro-genation was the use of an iron-catalyst system for asymmetric hydrogenation at 50 °C and asymmetric transfer hydrogenation at room temperature that offered transfer hydrogenation activity similar to that of ruthenium-based catalysts (11, 12).

Biocatalysis at work An example of a successful process substitution using biocataly-sis was recently reported for producing an intermediate used in the synthesis of aliskiren, a renin inhibitor used to treat hyper-tension. A key step in the synthesis of aliskiren is an enzymatic resolution catalyzed by pig-liver esterase (PLE). PLE is a versa-tile biocatalyst because it has a broad substrate spectrum and excellent enantio- and regio-selectivity. Commercially avail-able PLE is animal derived, which can result in variability. To address this problem, DSM (Heerleen, The Netherlands) and its collaboration partner, the Graz University of Technology in Austria, identified different isoforms of PLE. Using capabilities in enzyme development and production, a highly efficient and patented microbial expression system and fermentation pro-cess was developed for different isoforms of PLE that runs at a 25,000-L scale at DSM. This system delivers nonanimal-derived PLE isoforms (PharmaPLEs, DSM) at a large scale for pharma-

ceutical applications (13).In another development, researchers at Merck & Co.

(Whitehouse Station, NJ) reported on the pilot-scale asymmetric synthesis of 4,4-dimethoxytetrahydro-2H-pyran-3-ol with a ketone reductase and in situ cofactor recycling using glucose dehydrogenase in high yield and enantiomeric excess (11, 12).

References 1. D. Uraguchi, Y. Ueki, and T. Ooi, Science 326 (5949), 120–123 (2009). 2. S.J. Zuend et al., Nature 461 (7266), 968–970 (2009). 3. Y. Lu, T.C. Johnstone, and B.A. Arndtsen, J. Am. Chem. Soc. 131 (32), 11284–11285 (2009). 4. M. Penner et al., J. Am. Chem. Soc. 131 (40), 14216–14217 (2009). 5. P. Van Arnum, Pharm. Technol. 32 (9), 60–64 (2008). 6. E. Balskus and E. Jacobsen, Science 317 (5845), 1736–1740 (2007.) 7. J. Kim, J.A. Ashenhurst, and M. Movassaghi, Science 324 (5950), 238–241 (2009).

8. J. E. Wilson, A.D. Caserez, and D.W.C. MacMillan, J. Am. Chem. Soc. 131 (32), 113332–11334 (2009). 9. P. Van Arnum, Sourcing and Management, July 8, 2009, PharmTech.com/ptsm. 10. T.V. RajanBabu et al., J. Am. Chem. Soc., 130 (25), 7845–7847 (2008). 11. P. Van Arnum, Sourcing and Management, Sept. 1, 2009, PharmTech.com/ptsm. 12. I. Andrews et al., Org. Process Res. Dev. 13 (3), 397–408 (2009). 13. P. Van Arnum, Pharm. Technol. 33 (9) API Synthesis and Formulation suppl. s34–s38 (2009). PT

Biocatalysis plays an important role in asymmetric synthesis.


Analytical Testing

arl Fischer titration is one of the few assay tech-niques recognized by the US Food and Drug Ad-ministration for the determination of residual moisture in lyophilized pharmaceutical prod-

ucts (1). Because the iodine–water reaction is specific and quantitative, this technique provides high accuracy and precision. However, conventional Karl Fischer titration is not considered a high-throughput assay and requires sig-nificant manual intervention. This test can present a chal-lenge when many samples must be analyzed in a short time. Furthermore, most lyophilized products are hygroscopic and must be processed promptly after removal from the primary container.

The few off-the-shelf automated setups offered by Karl Fischer titrator vendors use a carousel onto which sev-eral samples, preweighed in individual containers, can be loaded. The titration is performed directly in these contain-ers as the carousel rotates each sample through the titration station. Unfortunately, no satisfactory means has been de-vised for sealing the samples from the environment while they await analysis. Hence, hygroscopic lyophilizates can-not be processed on these types of automated titrators.

This article describes the authors’ development of a reliable system for performing Karl Fischer titration automatically on numerous samples. It explains the rationale for selecting instrumentation and discusses sample-preparation strategies that affect the overall design of the automated system.

Titration-instrument selectionThe Karl Fischer titrator is the heart of an automated moisture-analysis system. First, a sample is loaded into a conditioned water-free titration cell. Iodine (I

2) from the titrant is then

metered in and reacts with water present in the sample. The titration end point occurs when all the water in the sample has reacted away. The end point is determined by detecting free iodine at a double-pin platinum electrode. Because this reaction is quantitative, the amount of water can be obtained by measuring the amount of titrant required to return the titration cell to an anhydrous state. The literature contains

A Robust, Automated Karl Fischer Titration SystemPhilippe Lam and Mike Nariman

The authors developed a robust, automated

system to conduct Karl Fischer moisture assays

for lyophilized products. Although sample

preparation is required, the instrument allows

several samples to be tested in a timely manner.

The tool is validated for use in the authors’

manufacturing operation and has provided

significant time and labor savings over the manual

assay method.

Philippe Lam* is a senior engineer for pharmaceutical

process research and development at Genentech,

1 DNA Way, South San Francisco, CA 94080,

tel. 650.225.7002, fax 650.225.3616, [email protected].

Mike Nariman is a senior systems architect at AB

Controls.

*To whom all correspondence should be addressed.

Submitted: Dec. 4, 2008. Accepted: Feb. 19, 2009.

K

52 Pharmaceutical Technology NOVEMBER 2009 PharmTech .compharmtech .comPharmTech .comPharmTech .com

a comprehensive treatise about Karl Fischer titration (2). Two types of instruments are available to perform titration: coulometric titrators and volumetric titrators.

Coulometric titrators. Coulometric titrators generate io-dine by the in situ electrochemical oxidation of iodide (I−) contained in the reagents. The total amount of iodine generated is proportional to the total charge passed in the electrochemical cell. This allows for sensitive detection of water: from ~1 to ~50,000 ppm (5% w/w).

Volumetric titrator. In a volumetric titrator, the iodine is already present in the titrant, and the titrator simply measures the volume of reagent dispensed into the cell from a precision burette. Sacrificing sensitivity for range, volumetric titrators can measure water content from ~0.1 to 100 % (w/w).

For the current application, the high sensitivity of Cou-lometric titration was not necessary, but it was desirable to be able to analyze samples with high moisture content (>5 wt %). Hence, the authors decided that a volumetric Karl Fischer titrator was more suitable.

Any titrator that allows operations to be controlled from an RS-232 interface could have been selected. The authors con-sidered only Metrohm (Herisau, Switzerland) and Mettler–Toledo (Greifensee, Switzerland) instruments, however, be-cause these two companies’ titrators were already used and supported at their site. When the project began, Metrohm offered the 700 series of titrators, which included models 784, 787, and 795. The models had similar capabilities, but the 784 and 795 provided more f lexible interconnectivity with optional accessories and additional internal memory for method storage. Mettler–Toledo offered the DL31 and DL38 titrators; the latter model had more internal mem-ory and slightly more data-processing functionality. No significant operational differences existed between these five instruments for the authors’ application because all data treatment was intended to be performed on a sepa-rate computer. Ultimately, the authors selected the Mettler DL31 because its setup included a higher-volume titration cell with a larger sample port than the Metrohm models. In addition, the Mettler titrator’s stir-bar driver could be controlled remotely.

Sample-preparation techniquesAll of Genentech’s (South San Francisco, CA) lyophilized products are packaged in glass vials. Many configurations, spanning various compositions, fill volumes, and vial sizes, exist, however. The authors considered the techniques as outlined below for preparing samples.

Method A: extraction in the product vial. Mettler-Toledo rec-ommends this technique for handling freeze-dried sub-stances (3). The procedure calls for injecting a known amount of anhydrous solvent (e.g., methanol or other pri-mary alcohols) directly into the unopened sample vial and allowing time for water to be extracted into the solvent. Agitation or sonication can expedite the extraction. An

aliquot of the extract is then withdrawn from the sample vial and introduced into the titration cell for analysis.

Method B: drying oven. In this technique, the sample vial is placed into a small oven and heated to desorb the mois-ture from the contents. An inert, dry carrier gas is fed into the vial, and the eff luent is introduced into the titration cell for analysis. The oven temperature setting and total desorption time often depend on the sample. Higher tem-peratures allow for faster water desorption but can cause the decomposition of certain substances such as sugars, which can yield erroneous moisture results (2).

Method C: direct extraction of crushed sample in titration cell. Genentech has traditionally used this technique. The prod-uct vial is uncapped, and the contents are crushed inside the vial using a smooth metal rod. A known amount of powdered sample is then transferred directly into the titra-tion vessel for analysis.

All of the authors’ historical data were collected using Method C. The following study was undertaken to deter-mine the comparability between Method A and Method C only. The experimental setup for Method B was not avail-able. Furthermore, many of Genentech’s lyophilized prod-ucts are formulated with large amounts (e.g., as high as 85% wt.) of sugars, which limits drying ovens to low tem-peratures. Other products contain high amounts of salts and require high oven temperature for efficient moisture desorption. Because it was undesirable to develop a sepa-rate method for each product, the authors did not use the moisture-analysis technique that relies on drying ovens.

A Mettler-Toledo DL31 volumetric Karl Fischer titra-tor with a one-component Hydranal Composite 2 titrant was used in all cases. Sodium tartrate dihydrate was used as the standard to determine the reagent titer at the be-ginning of each day, as recommended by the instrument manufacturer.

The authors used active lyophilized product configured as a 0.88-mL fill volume in 5-cm3 vials in the study. Two sets of samples, spanning the typical range of moisture normally observed for this product (i.e., 0.5–5% wt.), were tested.

The authors investigated the following two extraction schemes for Method A:

Introduction of anhydrous methanol into the product vial, 5-min sonication, withdrawal of an aliquot and analysis. This is the instrument manufacturer’s rec-ommended procedure.

. Introduction of anhydrous methanol into the prod-uct vial, 5-min sonication, 5-min standing, an ad-ditional 5-min sonication, withdrawal of an aliquot, and analysis.

Figure 1 summarizes the results for these experiments. For consistency with historical data, water content is reported as weight percent moisture of the lyophilized product cake. To calculate weight percent moisture values for Method A, the sample vials had to be weighed before extraction, emptied after extraction, cleaned, dried, and

I.

II.

Analytical Testing


reweighed to obtain the actual freeze-dried cake’s mass. These extra steps added complexity and lengthened the overall analysis time. Method B would also require follow-ing the same procedure.

Comparing results from the two methods, it is clear that Scheme II of Method A extracted more water than the rec-ommended Scheme I, suggesting that Scheme I was not able to fully extract the water from the sample. Yet it is unclear whether Scheme II achieved complete extraction.

Neither scheme of Method A extracted as much water from the samples as Method C. The difference is more pronounced for high-moisture samples (see the circles in Figure 1), where Method C also yielded less scatter in the data. However, Method C may be influenced by the level of relative humidity in the room because the crushed lyophi-lized cake is briefly exposed to ambient conditions. Hence, the true moisture content of a sample may lie between the values given by Methods A and C.

The authors attempted to estimate the tendency for mois-ture uptake during sample preparation for Method C by leaving uncapped vials on the bench for 2–3 min after the contents were crushed. The difference in moisture content between these dwelled samples and ones that were analyzed immediately after pulverization was typically less than 0.1% (w/w). It is not possible to know the absolute amount of envi-ronmental moisture introduced during the entire sequence of operation, but Method C tends to err on the safer side because it may overestimate samples’ water content.

Although Method A offers the advantage of protecting the sample from direct handling and exposure to ambient conditions, the additional steps required after extraction are undesirable. Furthermore, products contained in large containers such as 50–100-cm3 vials will require longer ex-traction time because the water has a longer diffusion path.

Method A also requires large volumes of solvent for the ex-traction, thus compounding waste-disposal problems. For these reasons, the authors decided to implement Method C in the automated system.

The authors also considered fully automating sample preparation, including uncapping, crushing, and dispensing of the lyophilized cake. Such a system, however, would need to handle vials sizes from 5 to 100 cm3 and to consistently pulverize lyophilized product cake of various consistencies and various heights. These capabilities would entail a com-plex and cost-prohibitive setup for sample preparation alone. Hence, the authors simply elected to prepare samples manu-ally, as is current practice. A trained analyst can perform these operations in less than 2 min per sample.

Automated-system design and constructionSequence of operation. Given the requirements discussed above, the automated system should operate according to the following sequence:

The analyst prepares the sample according to Method C. An amount (e.g., 50–150 mg) of crushed lyophi-lizate is dispensed into a standard centrifuge tube, which is then tightly capped. The tube is placed into a sample rack. Several samples can be prepared and loaded into the system.

The automated system retrieves a sample tube from the rack and transfers it to a balance that records the weight.

The sample tube is placed in a decapping station, and the tube cap is removed.

The sample is dispensed into the titration cell. Titra-tion is initiated.

The sample tube is recapped and reweighed. The ac-tual sample mass delivered to the titration cell is de-termined, and the sample tube is discarded.

The titration result is returned, and the titration cell is cleaned if necessary after a prespecified number of titrations.

The cycle repeats from step 2.This sequence is basically the same as that of the manual

technique. A robotic system is needed to shuttle the sample between the rack, balance, and titrator. The titration of the sample remains the rate-limiting step, so the total analysis time is comparable to that of a fully manual operation. Titration times typically range from a few minutes to more than 10 min, depending on the composition and moisture level of the sample. The benefit of an automated setup, however, is the ability to perform unattended analysis once the samples have been loaded into the system.

System construction. To minimize costs, the authors incor-porated as many off-the-shelf components as possible. A Mettler-Toledo XP 204 balance was selected because this model offers RS-232 serial connectivity, motorized draft doors, and a removable front control panel. The latter feature is important because removing the front panel

1.

2.

3.

4.

5.

6.

7.

Figure 1: Comparison between extraction methods. Squares

represent low-moisture samples, and circles represent high-

moisture samples.

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2

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Method A2

Method C

Analytical Testing

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prevents the accidental activation of a balance operation during a run.

The DL31 titrator includes a small vacuum pump for withdrawing and dispensing solvent from the titration cell. However, that setup is not sufficiently powerful to ensure the full removal of the cell contents and accurate dispens-ing of solvent. Hence, the automated system performs the f luid handling (e.g., waste removal and solvent dispens-ing) with a pair of Masterf lex L/S computer-compatible peristaltic pumps that also offer RS-232 serial connec-tivity. The f luid-path contact surface includes PTFE and chemical-resistant Masterflex Tygon Chemical tubing.

The samples are shuttled between the various stations by a Mitsubishi RV-2AJ-511 five-axis industrial robot arm

equipped with a set of custom triposition grippers. This robot has a proven track record in industrial settings, is reliable, is widely used, and also is controlled through RS-232 serial communication. Furthermore, the robot arm controller provides several digital input–output lines that can power solenoid valves, thus permitting the actuation of pneumatic cylinders for the decapping station and the titration cell cap.

AB Controls (Irvine, CA) integrated all the components and placed them aboard a compact, custom-fabricated alu-minum frame. The Focus software, AB Controls’s automa-tion and robotics application, was customized to control all operations from a standard computer equipped with the Windows operating system and a multiport serial-com-munication card.

Figure 2 shows the entire setup, including the sample rack, which holds a total of 105 samples contained in stan-dard 15-cm3 screw-cap polypropylene centrifuge tubes. The system was designed primarily for robustness and reduces the potential for operator and hardware errors by minimizing the number and complexity of operational steps. In addition, numerous step-completion verification and safety checks are included in the run sequence. For example, before starting a run, the system verifies that the balance chamber is empty to prevent placing a sample tube in a location that is already occupied. At the decapping station, the system ensures that the cap has been removed from the sample tube before attempting to dispense the sample into the titration cell.

The instrument control software offers the users a lim-ited number of choices. The manual “Control” screen al-lows the operator to activate certain functions such as the titration-cell wash routine, open and close the titration-cell cap, move the robot arm grippers, control the balance door, and operate the decapping station gripper. The operator thus has sufficient control to handle routine maintenance such as cleaning the titration cell and removing sample tubes that were left in the system after a critical error or an emergency stop. Advanced functions such as control of the robot-arm movements are disabled for safety reasons and can only be accessed through a password-protected administrator login.

The “Run Standards” screen allows the operator to per-form titer determination using sodium tartrate. The raw data (volume of titrant dispensed) is obtained from the titrator, the sample mass is obtained from the balance and the titer (mg H

2O/mL KF reagent) is calculated and stored

by the Focus software. Here, a minimum of three replicates are required. The average value is used for all subsequent sample moisture determination.

The “Run Sample” screen allow users to enter the total number of samples to be analyzed and the number of titra-tions to be performed before the titration cell is washed. These two user-input parameters are the only ones that directly affect system operation. No product-specific

Figure 2: Automated Karl Fischer titration system components.

Side view (a) and top view (b) of the titration deck. The footprint

is approximately 95 x 110 cm. Components include the result

line printer (1), UPS for entire robotic system (2), Windows XP

computer (3), Mitsubishi robot controller (4), sample tube rack

that includes 105 positions (5), titration-cell pneumatic sealing

mechanism assembly (6), Mitsubishi robot arm (7), Mettler–Toledo

XP analytical balance (8), Mettler–Toledo DL 31 volumetric Karl

Fischer titrator (9), solvent-delivery and waste-removal peristaltic

pumps (10) and (11), waste bottle (12), solvent bottle (13),

pneumatic decapping station (14), cap holder (15), spent-sample

tube chute to trash bin (16), hydranal reagent bottle and holder

(17), and ionizer for static charge control (18).

Analytical Testing


methods exist. All samples are handled and analyzed in the same manner. After each moisture determination, the result is sent to the computer and immediately printed on the attached line printer. To simplify system validation, the authors decided not to include the optional 21 CFR Part 11: Electronic Records, Electronic Signature feature, but this functionality could be added in a future software revision if needed.

The “Mock Run” screen is identical to the “Run Sample” screen, with exception that no titration is performed. This mode is used for system demonstration and training purposes.

System testingThe system was subjected to comprehensive tests, includ-ing hardware error checking and recovery. No major dif-ficulties were encountered. Operational testing was simpli-fied by the limited number of user input parameters. This section presents the results from the most relevant studies: the moisture determination of active hygroscopic freeze-dried product from a fully loaded sample rack.

For these studies, the sample queue times (i.e., the time the samples were on the rack awaiting analysis) were re-corded. Figure 3 summarizes the results for two sets of sam-ples consisting of two batches of active material lyophilized in 50-cm3 vials. For the second set, analysis was paused after 4.5 h and resumed 17 h later to increase the queue time.

The data show that, for this product, the sample moisture increases in a linear way as a function of queue time. The in-crease suggests that the samples absorb environmental mois-ture, most likely from diffusion though the centrifuge tube wall or the cap closure seal. The absolute overhead moisture present in a 15-mL sample tube under typical laboratory ambient conditions of 21 ∘C and 50 ± 15% relative humid-ity is approximately 1.4 × 10-4 mg, an insignificant amount. The moisture-ingress rates for the two sets of samples are 0.018 wt%/h and 0.0095 wt %/h, respectively. This behavior is expected and results from the sample-preparation method selected. Although this small amount of moisture ingress seems to be a shortfall, in practice, analysts prepare 10–20 samples at a time, and samples are added only after most of the initial samples have been tested. Hence, the queue time is typically only a few hours. This minor limitation was deemed an acceptable tradeoff for the convenience afforded by an automated system.

ConclusionThe authors have demonstrated a system that can perform Karl Fischer titration unattended. This instrument is fully validated for use in activities such as lyophilization-cycle de-velopment, technology transfer between various manufactur-ing sites, and manufacturing-discrepancy investigations.

Although the platform upon which this system is based is highly customizable and versatile, the authors decided to sacrifice functionality in favor of robustness. As a re-sult, this instrument requires minimal training for op-erator proficiency, requires little maintenance, and has seen heavy use. Overall, the instrument it has been a cost-effective tool that saved labor, time, and money.

AcknowledgmentsThe authors would like to thank M. Joyce, D. Lawrence, D. Mehrwein, C. Buruel, K. Kif le, A. Gonzales, and P. Hearne for suggestions and help with system validation.

References 1. FDA, Guideline for the Determination of Residual Moisture in

Dried Biological Products (Rockville, MD, Jan. 1990). 2. E. Scholz, Karl Fischer Titration, (Springer-Verlag, Berlin,

1984). 3. Mettler–Toledo, “Fundamentals of the Volumetric Karl Fischer

Titration,” (Mettler–Toledo, Columbus, OH, 1999), p. 42. PT

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

Figure 3: The effect of queue time on sample moisture. The

squares and dashed line represent Sample Set 1. The circles and

solid line represent Sample Set 2.

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Analytical Testing


n the pharmaceutical industry, the three most common granulation processes for solid dosage form production are wet granulation, dry granulation (i.e., roller compaction), and direct blending. In spite of their popularity, each of the

processes raise concerns as they are currently practiced.The obligatory use of a granulating liquid during wet gran-

ulation generates large granules during the wet massing and kneading stages. The typical amount of water used in the for-mulation is 20–50% of the weight of the dry powder mixture. After granulation, most of the added water usually is removed by drying, followed by a granule-sizing step. In a way, the drying process cancels the water-addition step, and the sizing step shrinks the large granules formed during the process. One vexing, but thankfully infrequent, problem with the wet-granulation process is that it produces a bimodal particle-size distribution of the final granulation that may result in unsatisfactory granulation flow and compactability.

In the dry-granulation process, the powder mixture is roller compacted into ribbons that are milled into granules. Unlike the wet-granulation process, the roller-compaction process commonly obtains a final granulation with a bi-modal particle-size distribution. Roller-compaction pro-cesses have the added problem of yielding material with low compactability during ribbon formation, thus resulting in soft and friable tablets.

The direct-blending process, followed by tablet compres-sion or other downstream actions, often depends on the batch-to-batch and vendor-to-vendor consistency of drugs and excipients. The potential for segregation and inadequate material flow are risks often associated with this process.

In what is arguably the seminal paper on the moisture-activated dry-granulation (MADG) process, the authors proposed a simple, economical, and novel granulation pro-cess that uses a small amount (1–4%) of water to cause ag-glomeration without subsequently requiring a drying step (1). Few studies of this process appear in the literature (2–3).

Moisture-ActivatedDry GranulationPart I: A Guide to Excipient and Equipment Selection and Formulation DevelopmentIsmat Ullah, Jennifer Wang, Shih-Ying Chang,

Gary J. Wiley, Nemichand B. Jain, and San Kiang

Wet granulation, dry granulation, and direct

blending are the most popular granulation

processes in the pharmaceutical industry, but

they each have distinct drawbacks. A moisture-

activated dry granulation (MADG) process was

described more than 20 years ago, but has not

found widespread acceptance. The authors

explain this process in detail, provide guidance

for the selection of excipients and equipment, and

give instructions for the development of MADG-

based formulations.

Ismat Ullah is president of Simple Pharma Solutions

(Cranbury, NJ). Jennifer Wang* is a senior research

investigator, Shih-Ying Chang is a principal

scientist, Gary J. Wiley is a retired research

scientist, Nemichand B. Jain is a director of

biopharmaceutics research and development, and San

Kiang is a research fellow, all at Bristol–Myers Squibb,

1 Squibb Dr., New Brunswick, NJ 08903,

tel. 732.227.5684, [email protected].


Submitted: Jan. 15, 2009. Accepted: Feb. 23, 2009.

I

Formulation

62 Pharmaceutical Technology NOVEMBER 2009 PharmTech .compharmtech .comPharmTech .comPharmTech .comPharmTech .comPharmTech .com

Given its simplicity and cost-saving poten-tial, the authors expected that the MADG process would have been widely adopted in the pharmaceutical industry by this time. The MADG process has not caught on, how-ever, perhaps because of its unusual simplic-ity coupled with uncertainty about equip-ment specifications and ambiguity about the manufacturing process.

This paper will explain the MADG process further and provide guidance for the selec-tion of the excipients and equipment neces-sary for its successful implementation. The authors will also give instructions for the de-velopment of MADG-based formulations.

The MADG process As its name implies, MADG is a process in which moisture is used to activate granule formation (i.e., agglomeration) without the need for applying heat to dry the granules. The formation of the moist agglomerates is followed by the stepwise addition and blend-ing of common pharmaceutical ingredients that absorb and distribute the moisture, thereby resulting in a uniform, free-flowing, and compactible granulation. This process enables the drug to bind with the excipients after the agglomeration phase, thus resulting in small, almost spherical granules with low potential for segregation of the drug in the formulation. The intent of the MADG process is not to make large particles, but rather to agglomerate the fines and bind the drug with excipients to create free flowing, compactible, and nonag-gregating granules.

The essence of the MADG process is to add enough water to achieve agglomeration without adding excess water that would require a drying step. It is equally important that only enough particle-size enlargement be achieved to ensure satisfactory granulation f low and compactability without segregation. The MADG process has the advantages of not generally requiring further size reduction and avoiding the regeneration of fines as a result of milling. And, unlike the conventional wet- and dry-granulation processes, MADG does not overdo and then undo what has been overdone.

The MADG process includes two major stages, the agglom-eration stage, and the moisture distribution and absorption stage. Figure 1 shows a flow diagram of the MADG process.

Agglomeration stage. In this stage, all or part of the drug is mixed with filler(s) and an agglomerating binder to obtain a uniform mixture. During mixing, a small amount of water (1–4%) is sprayed onto the powder blend, thus moistening the binder and making it tacky. The binder functions as the drug and excipients move in the circular motion caused by the mixer impellers or blades. The resulting agglomerates

are small and spherical because the amount of water used in the MADG process is much lower than that in conventional wet granulation. The agglomerates therefore cannot grow into large, wet lumps. The particle size of the agglomerates generally is in the range of 150–500 µm.

It is possible, based on the drug loading technique, to add only part of the drug to the formulation during the ag-glomeration stage. The remaining drug can be added after the moist agglomerates have been formed. The added drug particles adhere to the wet agglomerates and become incor-porated into them.

Moisture-distribution and absorption stage. In this stage, mois-ture absorbents such as microcrystalline cellulose or silicon dioxide are added as mixing continues. When these agents come into contact with the moist agglomerates, they pick up moisture from the agglomerates and redistribute moisture within the mixture. The entire mixture thus becomes rela-tively dry. Although some of the moisture is removed from the wet agglomerates, some of these agglomerates remain almost intact, and some, usually the larger particles, may break up. This process results in a granulation with uniform particle-size distribution. The process continues with the ad-dition of a disintegrant to the mixture, followed by blending for a few minutes. Then, during mixing, lubricant is added and blended for sufficient time to achieve adequate lubricity.

Figure 1: Flow diagram of the moisture-activated dry-granulation process.

Blending in granulator

Mixing for 2–5 min

Premixing in granulator


Wet granulation in granulator

Water spraying while mixing for 1–5 min

Blending in granulator


Water

Moisture absorbingagent(s)

Disintegrant(s)

Lubricant(s)

DrugFiller(s)Binder(s)

Moisture absorption–

distribution stage

Agglomeration

stage

Lubricating in granulator

Mixing for 0.5–2 min

Final bend sift sizing

(if necessary)

Formulation

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RS


This step completes the MADG granulation process. Excluding material loading, the actual processing time

for the MADG process is only 10–20 min. Even for a commercial-scale batch, the processing time is essentially the same as it would be for a laboratory- or pilot-scale batch. Beginning with the premixing of the drug and excipients, the final granulation could be ready for tablet compression, encapsulation, or powder filling in about an hour.

Excipients for the MADG processFillers for the MADG process during agglomeration. It is critical to select suitable excipients for a successful MADG process. Unlike the conventional wet-granulation process, which often employs microcrystalline cellulose or starch as fill-ers, MADG process uses nonabsorbent, easy-to-wet fillers such as lactose monohydrate and mannitol. The main rea-son for this selection is that microcrystalline cellulose and starch-based excipients absorb and retain a considerable amount of moisture during agglomeration. Because of this characteristic, more than the desired amount of water must be used during processing to form proper wet agglomerates. To ensure proper agglomeration, filler particles must not be too coarse or too fine. In general, coarse particles do not agglomerate easily, and fine particles require more moisture for agglomeration.

In rare cases, the drug itself could be soluble and become tacky upon moistening. Such drugs are classified as self-granulating. For these types of drugs, it is beneficial to in-clude moisture absorbents during the agglomeration stage if a high drug-load formulation is desired in the MADG. Microcrystalline cellulose or starch products can help avoid overwetting and overgranulation of the product even when little moisture is used.

Agglomerating binders for the MADG process. The binders used in the agglomeration stage should be easily wettable and become tacky with the addition of a small amount of water. Previous studies indicate that low-viscosity polyvinylpyrrol-idones (PVPs) such as PVP K-12 are ideal for this purpose. If PVP is not an acceptable choice because of formulation concerns such as chemical compatibility, binders such as hydroxypropyl cellulose (HPC), copovidone, maltodextrins, sodium carboxymethylcellulose (Na CMC), or hydroxypro-pyl methylcellulose (HPMC) can be used instead. The bind-ers can be used singly or in multiple combinations to achieve the desired effects or address specific concerns.

If binders are available in various viscosity grades, it is de-sirable to use the ones with low viscosity because they tend not to retard tablet or capsule dissolution. However, binders with very low viscosity may not provide enough tackiness for agglomeration. In general, high-viscosity binders are often required in small amounts. The amount of binder needed does not depend on the viscosity alone; other factors such as binder mass must be considered. For example, if 5% of PVP K-12 is sufficient for one formulation, 2% of PVP K-30 may not be the correct proportion for the same formulation.

Experiments have shown that about 3% or more of PVP K-30 would be required for proper agglomeration. This difference results from the fact that, in addition to binder viscosity and tackiness, the mass of the binder also plays an important role in covering and coating the blend particles that are to be agglomerated. The binders with small particle size and great surface area would be advantageous as well.

Generally, binders such as HPC, Na CMC, and HPMC require more water and longer hydration time compared with PVP or maltodextrin. On the other hand, binders such as Starch 1500 would not be suitable for the MADG process because this binder has a significant percentage of unhy-drolyzed starch components that could absorb considerable amounts of water. As a result, the amount of water needed to effect agglomeration when using Starch 1500 would not be practical for the development of a typical MADG formu-lation. Completely hydrolyzed starch is not recommended because it does not have sufficient tackiness to cause ag-glomeration. In all cases, the binder chosen should have fine particles and sufficient tackiness upon moistening to cause adequate agglomeration.

Moisture absorbents for the MADG process. About 70–95% of any MADG formulation is agglomerated, and the remaining portion of excipients is added as is. In general, the nonag-glomerated portion consists of moisture absorbents, disin-tegrants, and lubricants. It is desirable that nonagglomer-ated excipients be closer in particle-size distribution to the agglomerated portion of the formulation to minimize the potential for segregation.

Microcrystalline cellulose, which doubles as a filler and mois-ture absorbent, is available in the approximate particle size of 200 µm. Low moisture grades are also available. Avicel PH 200 LM (FMC, Philadelphia) is an excipient with low moisture content (< 1.5% by weight, as determined by loss on drying). Aeroperl 300, a moisture absorbent in the form of a non-lumpy, free-flowing granulated silica consisting of ~30-µm spherical particles is also available from Evonik Industries (Essen, Germany). Granular Aeroperl 300 has excellent moisture-absorbing capacity, and its surface area is much lower than that of the colloidal silica used as a glidant for granulation. The amount of Aeroperl 300 typically needed for the MADG formulation is small, which is advantageous from the standpoint of preventing tablet-ejection problems.

The disintegrant crospovidone is available in coarse particle-size grade from either ISP (Wayne, NJ) and BASF (Ludwig-shafen, Germany). This material is not only a superdisintegrant, but is also compactible and acts as a moisture absorbent.

Overall, excipients such as Avicel PH 200 LM, Aeroperl 300, and the coarse grade of crospovidone for the nonag-glomerated portion of the MADG process can significantly improve the quality of the formulation and facilitate the pro-cess. If the recommended excipients are not available, reg-ular microcrystalline cellulose (e.g., Avicel PH101, PH102, and PH200), regular silicone dioxide, and crospovidone can be used as substitutes.

Formulation


MADG formulation developmentAssessment of API wettability. Drug solubility, particle-size dis-tribution, and desired drug loading in the formulation are the primary factors to be considered for an MADG-based development. In general, a great amount of agglomerating binder and water are needed to create the agglomerates when a high drug load is desired for a drug with low solu-bility and small particle size. The converse is also true. Less agglomerating binder and water is required if the drug is water-soluble, the particle size is not small (e.g., > 10 µm), and the drug loading is low (e.g., < 25%). Self-granulating drugs sometimes do not require any binder and need less water to granulate.

Drug attributes such as wettability and agglomeration characteristics should be determined experimentally if they are not already known. Scientists can add water to the drug in a vial or in a small beaker using a syringe and stir the mixture with a small spatula. Generally, the drug is a suitable candidate for an MADG process if it can be wetted with 1–2% of water. If, on the other hand, the drug does not easily wet with 1–2% water, the formulation likely needs more binding material and water. Therefore, the higher the percentage of water needed to wet the drug, the more water or binder is needed for the agglomeration stage. As previously mentioned, it is difficult to develop an MADG process if a high amount of water or binder is required for the formulation.

Formulation assessment. Assessment of the formulation it-self is the next task to be completed once the wettability of the drug has been established. For most drugs, a preliminary formulation-development evaluation can be initiated with a small batch. Using the starting formulation scheme pro-vided in Table I, a 5–10-g batch can be prepared in a 20-mL scintillation vial.

For nonwettable drugs or high drug-loading formula-tions, additional agglomerating binder (e.g., PVP) and more water during the agglomeration stage might be required. In addition, for drugs that are more difficult to granulate, man-nitol (e.g., Perlitol 160 C, Roquette, France) or other wet-table fillers can be used in place of lactose monohydrate to achieve the desired granulation. Conversely, small amounts of binder and water are needed if the drug is easily wettable and self-granulating. The ratio of Aeroperl 300 or other sili-con-dioxide-type excipients to water should be kept to at least 1:1 by weight in the formulation. If PVP is not desirable in a given formulation, other agglomerating binders can be used, as described above.

Final formulation and optimization. Using the knowledge gained from the formulation-screening experiments de-scribed above, a large batch of several hundred grams can be manufactured with a high-shear granulator. The authors’ experience has shown, however, that slightly more water is required for the experiments when a granulator is used in-stead of a vial. The preliminary studies enable adjustments to be made to improve formulation characteristics such as granulation and tableting, which can be further optimized

as needed. Upon the successful completion of optimization exercises, the accelerated stability of the formulation can be evaluated. The scale-up and design-space studies can be conducted as needed.

Mechanism of the MADG process. The granule-formation mechanism in the MADG process is the same as that in conventional wet granulation. In both cases, it is a process of powder particle-size enlargement, often in the presence of water and binders, through wet massing and kneading. The main differences between these two granulation processes are the amount of granulating liquid used and the level of agglomeration achieved. In conventional wet granulation, substantially more water is used to create large and wet gran-ules, and heat drying removes the excess water. This step is followed by milling to reduce the granule size. In the MADG process, only a small amount of water is used to create ag-glomeration. Moisture distribution and absorption steps follow, and neither heat drying nor milling is needed.

Additional considerations for the MADG processMoisture in the MADG formulation. The amount of water used in the MADG process is part of the formula composition. This amount is a fixed value in the formula and is determined during formulation development. For example, if 2.0% (w/w) water is used, the rest of the ingredients should make up the 98.0% (w/w) of the formula. Because the MADG process does not include a heat-drying step, the water added would not be intentionally removed from the formulation.

Because moisture is added but not removed in the MADG process, what happens to the moisture and how it affects product quality might be causes for concern. To answer these questions, an MADG formulation that uses 1.5% water, 20% Avicel PH 200 LM, 1.5% Aeroperl 300, and other ingredients for a total weight of 100 g can be considered. First, 1.5 g of water is used in the agglomeration stage. Dur-ing the moisture-absorbing and -distribution stage, 20.0 g of Avicel PH200 LM (with an inherent moisture level of 1.5%) can take 0.7 g of moisture, while 1.5 g of Aeroperl 300 can absorb 2.25 g of moisture from the wet agglomerates. As a result, the final granulation reaches its equilibrium moisture level, and neither Avicel PH200 LM nor Aeroperl 300 ap-

Table I: MADG formulation for preliminary screening.Ingredients Percent (%) Per 5.0 g (g)

Lactose monohydrate and API 65.0 3.25

PVP K-12 (to be adjusted) 5.0 0.25

Water (to be adjusted) 1.4 0.07

Avicel PH 200 LM 21.6 1.08

Aeroperl 300 1.5 0.075

Crospovidone 5.0 0.25

Magnesium stearate 0.5 0.025

Total 100.0 5.0 g

Note: API is active pharmaceutical ingredient.

Formulation


pears damp or lumpy. Such a MADG formulation would not have much more free water than that produced by a typical conventional granulation process. Even if only regular Avi-cel PH200 (with a moisture content of ~5%) is used without Aeroperl 300 in the same formulation, the amount of the remaining moisture (0.8 g) would be well distributed in the other formulation excipients, thus resulting in a free-flowing final granulation. Silicone dioxide in an MADG formulation sometimes may be preferred to minimize the risk of granu-lation caking during storage, to avoid flowability problems, and to reduce the chance of moisture-induced chemical in-stability. In general, unless the drug in the MADG formu-lation is moisture-sensitive, additional stability risks of the finished product would not be expected.

Water-delivery system. The agglomeration stage is critical in the MADG process and depends on the characteristics of the drug, type and amount of binders and fillers, and the addition of water. Because the amount of water used in the MADG process is small (e.g., 1–4%), it is important that the water be delivered accurately and distributed uniformly dur-ing the agglomeration stage. The selection of a spray system that provides accurate delivery and a well-defined spray pat-tern is important. A suitable spray system, Schlick MADG Spray Kit, is available for laboratory use from Orthos Liquid Systems (Buffton, SC).

The preferred mechanism to deliver water spray consis-tently would be an airless spray system, which enables the water to be directed onto the powder bed in a high-shear granulator. Any airless spray nozzle with a gear pump or pressure vessel, where the spray pattern can be reproduced and the exact amount of water delivered, would be adequate. Spray nozzles with an orifice of 0.1 mm or 0.15 mm can be attached to a syringe to deliver a low (5–10 mL) volume of water for small experiments.

Selection of the granulator for the MADG process. Although it has been reported that a simple planetary blender can be used for the MADG process, the authors believe that a high-shear granulator would be more suitable for the process (1). An ideal high-shear granulator has efficient impellers or blades and

choppers to allow good mass movement and proper mixing. It also allows water to be sprayed only on the powder bed and not on the blades, choppers, or granulator wall. Also, the blades and bowl configuration should be such that they would not allow wet pockets or dead spots to remain after the moisture-distribution or absorption stages. Additional sifting or sizing of the granulation is required if such pockets or spots form. In other words, if good water distribution is achieved, further granulation sifting or sizing is unnecessary. Using this approach, the authors have successfully manufac-tured various products at batch sizes ranging from 100 g to 30 kg using equipment such as Bohle, Diosna, Fuji, Collette, or PMA Aeromatic-Fielder high-shear granulators.

Granulation sizing and milling. An optimized MADG formula-tion and process should not produce large lumps in the gran-ulation that require sizing or milling. Therefore, once lubri-cant is blended in with the granulation, the result may be the final blend that can be directly used for tablet compression, encapsulation, or powder filling. At times, small amounts of lumps in the granulation may stem from material buildup on the blades, choppers, walls, or the bottom of the granulator during agglomeration. In such situations, it may be necessary to pass the granulation through a screen such as 10 mesh or any other suitable size. Often, sizing or sifting is needed only if the formulation or process contains imperfections.

NoteMADG process-based formulation-development studies carried out with various pharmaceutical compounds will be described in Part II of this article, which will appear in the December 2009 issue of Pharmaceutical Technology.

References 1. I. Ullah et al., Pharm. Technol. 11 (9), 48–54 (1987). 2. C. Chen et al., Drug Dev. Ind. Pharm. 16 (3), 379–394 (1990). 3. L.H. Christensen, H.E. Johansen, and T. Schaefer, Drug. Dev. Ind.

Pharm. 20 (14), 2195–2213 (1994). PT


Formulation


he US Food and Drug Administration has approved a substantially lower number of drug formulations con-taining new molecular entities (NMEs) in the past decade (1). In 2008, the agency approved formulations contain-ing 21 NMEs and four biologics, slightly higher than the

2007 total of 17 NMEs and two biologics. The growth between 2007 and 2008, however, was not enough to counter the marked downward spiral of drug approvals during the past 10 years (1). Behind the trend may be tightening safety standards, the com-plexity of clinical trials that have escalated drug-development costs, and even perhaps a shift in emphasis as pharmaceutical companies move away from truly innovative solutions toward more complex therapeutic profiles.

An additional barrier to the development of new drug formu-lations is that, in some cases, active pharmaceutical ingredients (APIs) that show promising activity in animals or in vitro biologic systems fail to show sufficient efficacy in human clinical trials. In some cases, this discrepancy may be due to a lack of bioavailability and desired effect at the target site in the human body—properties potentially linked to the specifics of the formulation.

The choice of excipients also can be a critical factor for de-veloping clinically efficacious drug formulations. The current regulatory environment both inside and outside the United States, however, strongly discourages development of new ex-cipients, limiting the choices to those already approved. The In-ternational Pharmaceutical Excipients Council of the Americas (IPEC–Americas) has proposed specific regulatory changes to encourage new excipient development which, if adopted, could expand options for API formulation, potentially removing this formidable barrier to drug development. IPEC–Americas also developed an independent excipient review procedure, the IPEC Novel Excipient Safety Evaluation Procedure, which can serve as a temporary solution to this issue until the council’s proposals are implemented. These efforts resulted in the evalu-ation of at least one novel excipient, Solutol HS 15 [Polyoxyl (Macrogol) 15 hydroxystearate manufactured by BASF, Lud-wigshafen, Germany). The development of procedures for in-dependent safety evaluation and its application to Solutol HS 15 are described in subsequent sections of this article.

Regulatory Update: The IPEC Novel Excipient Safety Evaluation ProcedureChristopher DeMerlis, Jay Goldring, Ranga Velagaleti, William Brock, and Robert Osterberg

The lack of a pathway for regulatory approval of

novel excipients outside a new drug application

has stifled innovation in drug development.

The authors, representing the International

Pharmaceutical Excipients Council, propose a new

evaluation procedure, including tiered toxicology

testing that may change the way pharmaceutical

and biopharmaceutical manufacturers look at

drug-product development.

Christopher DeMerlis, M.S.,* is a manager of

regulatory affairs at Colorcon, Inc., 415 Moyer Blvd.,

West Point, PA 19486, [email protected]. Jay

Goldring, PhD, is prior director of toxicology at Wyeth

Consumer Healthcare, Ranga Velagaleti, PhD, is

a manager of regulatory affairs at BASF Corporation,

William Brock, PhD, is principal of Brock Scientific

Consulting, and Robert Osterberg, PhD, is a senior

consultant of pharmacology/toxicology at Aclairo PDG.

For specific information about IPEC’s procedure, contact

Dr. Osterberg, tel. 703.506.6760, ext. 302, ROsterberg@

aclairo.com.


T

Position Paper

72 Pharmaceutical Technology NOVEMBER 2009 PharmTech .compharmtech .comPharmTech .comPharmTech .comPharmTech .com

Position Paper

There is considerable activity in the development of new and innovative excipients (2, 3), including excipients for orally disintegrating tablets and controlled-release formulations. In the future, the application of nanotechnology may be evalu-ated for developing novel excipients for new therapeutic solu-tions. In many cases, these excipients will never be included in drug products under development because the regulatory risks under the current system are simply too great.

In the long term, new paradigms are needed to evaluate excipi-ent safety. The FDA guidance on the safety evaluation of excipi-ents details safety tests generally required to establish safety of a novel excipient, which are strikingly similar to those required for a new drug (4). However, unlike drugs, excipients are designed to be pharmacologically inactive and these tests may be excessive for safety evaluation, thereby representing a potential barrier to innovative development of new excipients.

Current regulatory status of new excipientsUnder the current paradigm, even though excipient innovators are able to adapt to new procedures and are willing to invest in development and safety-evaluation costs, novel excipients are not finding their way into drug products. Understandably, drug-product manufacturers are risk-averse because of the large investments required for drug development. Despite these challenges, the expanding FDA Inactive Ingredient Database (IID) suggests that the demand for new excipients is strong. The IID lists excipients used in approved drug products, their route of administration, and their maximum dosage (i.e., maxi-mum potency per dosage unit). A regulatory system with a strong, predictable excipient safety and efficacy evaluation could potentially lead to an explosion of new choices for drug formulators.

Under current drug approval processes, novel excipients are not independently evaluated; they are only reviewed in the context of the first drug application containing the excipient. There is no regulatory approval process specifi-cally for a new excipient as a unique molecule. Globally, the International Conference on Harmonization (ICH) does not have specific excipient safety evaluation guidelines, but FDA guidance on excipient safety evaluation cites several ICH safety-testing guidelines (e.g., ICH S1A, S2B, S3A, S5A, S7A and M3) as reference materials for the conduct of safety tests (4).

According to FDA and ICH definitions, an excipient is con-sidered “novel” if it is used for the first time in a human drug product. Although FDA maintains the IID, none of the US nor ICH standards distinguish between new chemical entities and minor modifications of approved excipients, coprocessed mix-tures of existing excipients, approved excipients proposed for a new route of administration, or excipients approved for use in foods or cosmetics. Some of these excipients may not require the full battery of tests listed in the FDA guidance on excipient safety evaluation (4). In these cases, excipient and pharmaceu-tical manufacturers must predict what the reviewing agency will require upon review of the drug application. If the manu-

factuer is wrong, the consequence could be significant delays in drug approvals or rejection of the drug application. Most drug manufacturers are wary of this process and therefore rely on excipients already used in approved drug products for their formulation needs.

In 2007, the IPEC–Americas Safety Committee proposed and developed the IPEC Novel Excipient Safety Evaluation Proce-dure, which is an independent excipient review procedure. This process was anticipated to reduce the cost and uncertainty related to the use of novel excipients in pharmaceutical formulations, thereby encouraging their use in drug-development programs and providing a needed boost to drug formulation innovation.

The Aclairo Pharmaceutical Development Group (Aclairo PDG, Vienna, VA) manages the Novel Excipient Evaluation Committee (NEEC), an independent expert group of IPEC charged with conducting the safety evaluations of new excipi-ents. The committee has successfully evaluated one excipient, Solutol HS 15, and is in the process of reviewing others. Two authors of this paper (R. Osterberg and W. Brock) serve on this expert committee.

The IPEC–Americas procedureHistory. The development of a regulatory strategy for novel ex-cipient review has been an IPEC–Americas priority since the organization’s inception in the early 1990s. At that time, the IPEC–Americas Safety Committee held a series of meetings that culminated in a publication of recommendations for excipient-safety testing based on route of administration (5). In 2002, the chairman and deputy chairman of FDA’s Center for Drug

Table I: Estimated costs of a typical toxicology program. Toxicology study Estimated cost ($)

90-day repeat dose toxicity (two species)* 250,000-400,000

Developmental and reproductive toxicity

Fertility/early prenatal development (Seg. I) 150,000

Developmental toxicity (Seg. II) 125,000

Postnatal development (Seg. III) 175,000

Genotoxicity

Bacterial reverse mutation 8000

In vitro chromosomal aberration 28,000

In vivo micronucleus 25,000

Safety pharmacology

Central nervous system 20,000

Respiratory 25,000

Cardiovascular 60,000

Carcinogenicity (two species)* 900,000-

1,500,000

Absorption, distribution, metabolism,

excretion (ADME)

250,000

Costs reflect 2009 estimates.

*For repeat dose toxicity studies, the species would be rodent and

non-rodent; for carcinogenicity studies, the species would be rat and

mouse.


Position Paper

Evaluation and Research (CDER) Inactive Ingredients Subcom-mittee published a proposal for excipient safety review largely based on the IPEC recommendations (6). The agency proposal was finalized in 2005. The ICH M3 document on nonclinical safety studies for conducting human clinical trials is also rel-evant in this context (7).

In August 2005, IPEC–Americas presented a proposal for an independent excipient evaluation procedure to FDA staff. FDA agreed to review the first excipient-safety evaluation expert com-mittee submission for consistency with FDA procedures. Over the next two years, the IPEC Safety Committee convened the expert committee, developed procedures, and solicited the first submission. In September 2007, the expert committee reviewed the safety package for Solutol HS 15 and submitted their con-clusions to the sponsor. In May 2008, in a letter to IPEC, FDA concluded that, “The issues considered by the expert committee reviewers in the weight-of-evidence determination on the safety of Solutol HS 15 are the same as would be considered by a re-viewing division,” indicating that the IPEC process provides a reasonable proxy for FDA review.

Review procedure. NEEC’s primary function is to evalu-ate compliance of excipient data with the FDA guidance on safety evaluation and to make recommendations to the excipi-ent manufacturer if data gaps are noted in the excipient dos-sier. The expert committee acts independently of the IPEC-Americas Safety Committee and its members must have con-

fidentiality agreements in place. NEEC is comprised of three experts in general toxicology and, ideally, members have expe-rience in industrial, academic, or regulatory toxicology, includ-ing experience in toxicology laboratories. Committee members may rotate off the committee every two to three years to pro-vide new expertise to the process. If the committee decides that an expert in one facet of toxicology is needed to help in decision-making, a request to the excipient manufacturer will be made for permission to include the expert in the delibera-tions. This expert must also sign a confidentiality agreement. Aclairo PDG administers this review procedure.

An excipient safety dossier in common technical document (CTD) format (to facilitate subsequent FDA review) is submit-ted to Aclairo PDG who sends it to the expert committee chair-person, who in turn distributes it to other committee members. Review times will depend upon the quantity of the information within or absent from the dossiers but are anticipated to take one to three months; in most cases, costs will not exceed a total of 50 hours of review plus administrative overhead. The chair-person or a designee collates the comments of the committee members and writes a draft report that will be sent to each member for concurrence or further discussion. Once agree-ment is reached, the final draft is sent to the excipient sponsor for review and comment. If the expert committee cannot reach agreement on one or more points in the final draft, the sponsor is told about the disagreements and the reasons for them. The sponsor may discuss the final draft with the expert committee, request clarifications or explanations and when satisfied, the final report is signed by the chairperson and sent to the sponsor who is the sole owner of the committee report. The committee report will contain at a minimum:

1. A discussion of chemical and toxicological data and human safety concerns based upon intended use of the excipient

2. Opinions on conformance with data needs according to the FDA guidance on safety evaluation for excipients

3. Identification of any data gaps4. Points of reviewer disagreement if not resolved with the

reasons identified in the final draft.

The expert committee’s review of Solutol HS 15BASF novel excipient, Solutol HS 15, a non-ionic solubilizer, was developed to fulfill an unmet need for a safe and effec-tive excipient for parenteral and solid oral dose formulations containing poorly soluble APIs. Chemically, Solutol HS 15 is composed of polyglycol mono- and di-esters of 12-hydroxy-stearic acid and contains approximately 30% polyethylene gly-col. Solutol HS 15 is listed as Macrogol 15 hydroxystearate in the European Pharmacopoeia (PhEur). The excipient has been used in approved drugs in some countries, including Canada and Argentina. Even though the Solutol HS 15 drug-master file (DMF) was filed with FDA in January 1992 (DMF #9501), it has not yet been used in FDA-approved drugs because of its novel excipient nature and absence of FDA-review status.

In 2007, IPEC–Americas Safety Committee Chair Jay Gold-ring, recognizing the urgent industry need for an excipient that

Table II: Estimated costs of a proposed tiered-testing toxicology program.Toxicology study Estimated cost ($)

Tier 1

In vitro cytotoxicity 1000

In vitro membrane penetration 1000*

Genotoxicity

Bacterial reverse mutation 8000

In vitro chromosomal aberration 28,000

In vitro metabolism 50,000

In vitro immunotoxicity 25,000–50,000

QSAR 1000

Tier 2

90-day toxicity

(OECD 422, rat, with micronucleus)

300,000

90-day toxicity (dog) 350,000

Tier 3

Developmental

and reproductive toxicity

See Table I

Safety pharmacology See Table I

Carcinogenicity See Table I

*Cost is dependent on tissue system (e.g., dermal, gastrointestinal).

QSAR is quantitative structure activity relationship. OECD is Organization

for Economic Cooperation and Development.


Position Paper

meets the requirements in formulations containing poorly solu-ble APIs, selected Solutol HS 15 solubilizer as the subject for the first NEEC review. The expert committee’s report would then be reviewed by FDA for consistency with its own review process.

As defined in the IPEC–Americas procedure in the previous section of this article, BASF entered into an agreement with Aclairo PDG to develop an independent safety evaluation of Solutol HS 15. To accomplish this, BASF prepared a package of information containing safety and chemistry information. The package included the following items:

• Technical information containing a summary of chemistry, manufacturing, and controls (CMC) information

• BASF’s safety expert report on Solutol HS 15Reports of all acute, subchronic, reproductive, and geno-toxicity studies conducted by BASF for Solutol HS 15 under different routes of administration

• Safety evaluation assessment report for Solutol HS 15 con-ducted by the European Medicines Agency

• Safety expert report of a related BASF solubilizer excipi-ent Cremophor (Polyoxyl 35 Castor Oil: NF Polyoxyl 40 Hydrogenated Castor Oil NF)

• FDA IID information for use of Cremophor in 15 FDA-approved drugs

• List of other excipients with related chemistry derived from the FDA IID.

The package also included a cover letter requesting that Aclairo PDG evaluate the information submitted and provide an inde-pendent safety evaluation for Solutol HS 15.

The independent safety evaluation procedures were coor-dinated and led by Dr. Osterberg. Aclairo conducted an in-dependent safety assessment using two other distinguished toxicologists. The six-month evaluation implemented all the steps of the review process described above. At the conclusion of the process, the expert committee issued an independent safety evaluation of Solutol HS 15 to BASF.

Following this process, BASF submitted a package to the IPEC–Americas Safety Committee Chair. This package in-cluded a cover letter from BASF that requested review and consideration for submission to FDA under the IPEC Novel Excipient Safety Evaluation Procedure, a safety expert re-port from Aclairo PDG and all the documents submitted to Aclairo PDG outlined in the previous paragraphs in this section. The BASF submission was forwarded to FDA by the IPEC-Americas Safety Committee. FDA provided its review letter of Solutol HS 15 to the committee which then informed BASF of the agency’s findings.

After receiving feedback, BASF approached the United States Pharmacopeia (USP) for consideration of an official monograph for Solutol HS 15 on the following grounds: FDA review of this excipient, monograph status in PhEur, and use in approved drugs in some countries outside the US. USP informed BASF that, as required by their procedure for de-velopment of official monographs, they consulted the com-pendial group at FDA. USP then requested that BASF submit materials for monograph development. Efforts by BASF and

•

USP led to the publication of Polyoxyl 15 Hydroxystearate (Solutol HS) NF monograph in the January/February 2009 issue of the USP Pharmacopeial Forum.

Excipient safety evaluation: a new paradigmExcipients received a great deal of notoriety in the early 1930s. At that time, a chemist at the Massengill Company used diethylene glycol (DEG) as a sweetening agent for elixir of sulfanilamide as the “teaspoon of sugar to help the medicine go down” because the elixir was somewhat sour for use in children. A principle in toxicology introduced by Paracelsius about 500 years ago was “Omnia venenum sunt, nec sine veneno quicquam existit; dosis sola fcit ut venenum non sit,” which, literally translated, states that “all substances are poisons; there is none which is not a poison.” This concept continues to be a basic tenet in the field of toxicol-ogy. The Massengill Company at the time had not completely investigated the potential toxicity of DEG. Hence, many children fell ill to the kidney toxicity associated with this compound, and many of those children unfortunately died (8).

Based on this tragic incident, the 1938 amendment to the Food, Drug, and Cosmetic Act was promulgated, essentially requiring that the safety of a drug be demonstrated before mar-keting. In spite of this regulation in the US and the incident that occurred in the 1930s, additional incidents of DEG contamina-tion occurred internationally in the 1980s and 1990s. An im-portant consideration with regard to these incidents, however, is that the safety of the drug substance was not in question, but rather the safety of the excipient had not been demonstrated before use in the drug-product formulation.

Indeed, the regulatory environment for the approval of ex-cipients has not kept pace with the innovations observed in the pharmaceutical industry. Except as associated with the sub-mission of an NDA for a new pharmaceutical that contains an innovative excipient, there is no regulatory process for the independent approval of the excipient.

During the past two decades, regulatory allowance of an excipient occurred only through the use of the material in a drug-product formulation. Hence, with approval of the drug product came acceptance of the excipient (excipients are not approved but their use is allowed). That excipient could be used subsequently in other drug products up to the concentration and duration used in the previously approved drug formula-tion. Moreover, the excipient could be used in a new drug prod-uct for a different route of administration only if toxicology data generated via that route was accepted by FDA. P. Baldrick proposed that a guidance was urgently needed for excipients, and further suggested that this would be a useful topic for ICH consideration (9). This suggestion was not a new concept as several years before, Steinberg et al. proposed a testing scheme for the evaluation of new excipients and that testing scheme was ostensibly similar to that used in the evaluation of a new drug substance (5). In that paper, the authors described a nonclinical program for excipients based on the oral route of administra-tion because most drugs are approved for oral use.

Baldrick’s paper was followed by several publications, each


Position Paper

further indicating the need for a regulatory process for excipi-ents as well as a proposal for how to manage new excipients. In 2003, G. Pifferi and P. Restani suggested that new excipients be evaluated much in the same way as food additives (i.e., by the International Toxicological Committees such as the Joint Expert Committee on Food Additives, a committee of the World Health Organization) (10). The authors demonstrated that there are a large number of substances that can be used as excipients with a very diverse chemical profile, sources, tech-nological functions, and so forth. The Pifferi/Restani paper of 2003 followed a 1999 paper describing the need for standards of characterization and quality review, just one more aspect needed for a regulatory framework for excipients (11).

Also in 2003, at the American College of Toxicology an-nual meeting, a symposium on issues associated with food and excipient safety was presented (12). M. Steinberg and I. Silverstein reviewed several concepts for addressing the regulatory status of new excipients but clearly noted that there was no regulatory process in the US compared with what had been established in Europe and Japan (13). Osterberg and N.A. See subsequently described the testing paradigm of what had been recently published draft guidance from FDA on excipient testing. In that guidance, which was subsequently approved (14), the various toxicity studies needed for a new excipient are outlined.

Overall, the guidance is similar to what Steinberg et al. had

proposed several years earlier in 1996 (5), although the provi-sion for safety pharmacology studies was included in the FDA guidance. Regardless, a provision for a stand-alone regulatory process remained elusive. As described above, IPEC–Americas established an expert working group to review the safety of new excipients based on testing, and proposed to FDA that the studies represent good science and excipients should be allowed in drug products without going through a regulatory process in conjunction with a drug approval. Because of the absence of a regulatory process, the innovation of new excipients has been restricted. Moreover, because of the costs associated with a standard toxicity program for a new excipient, innovation and development have been limited (see Table I).

The IPEC program described is a typical toxicology pro-gram with costs based on 2009 pricing of studies within the contract research organization (CRO) industry. Moreover, the costs reflect a basic study design and do not include toxi-cokinetic assessment which could add about 5–10% of the total cost. In addition, to initiate the 90-day studies, shorter-term repeat-dose studies would be needed to assist in setting dose levels. The added costs for these studies could approach $200,000. Finally, the costs associated with this program do not include discovery, development, and manufacturing costs for the new excipient.

The undertaking of a toxicology program represents a risk to a business, but in the current regulatory environment, such a

program is needed. There remains an option to the excipient development process that does not require such an outlay of resources early in the development phase. Lessons learned from the drug discovery and development process may be helpful in toxicological screening of excipients for use with active pharmaceutical substances.

Toxicology program considerations. In the developmental toxicology program, in vitro assays are used to screen for potential toxicity before undertaking more expensive toxic-ity tests. In this process, a compound that causes an unde-sirable toxicity can be eliminated from consideration. This “discovery” program leads to less cost and allows for a more rapid screening of multiple compounds to select those that represent potential utility as an excipient. In addition, the discovery program can be developed into different tiers of testing (i.e., as the compound is developed, additional test-ing is undertaken to further determine the potential safety of the compound).

In the first tier, a compound is subjected to different in

vitro assays to determine the potential genotoxicity, cytotox-icity, and metabolism and the ability of the compound to be absorbed across biological membranes. At the outset, how-ever, it is recommended that a quantitative structure-activity relationship (QSAR) model be developed. A QSAR model enables the prediction of various toxicities based on struc-tural similarity to existing chemicals. Hence, compounds can be easily limited from consideration if structural alerts for certain endpoints are revealed (e.g., carcinogenicity). There are several QSAR models that have been developed

PharmTech .comPharmTech .com80 Pharmaceutical Technology NOVEMBER 2009

over the years, each with its own advantages and disadvantages. The model overall is useful for predicting potential toxicity for potentially allowing the use of short-term bridging studies that could be used to determine the toxicity of the new excipient compared with an excipient that has a more robust database.

Following QSAR, it is recommended that the compound be subjected to in vitro genotoxicity and cytotoxicity assays. These studies are comparably inexpensive to the longer-term in vivo toxicity studies. A cytotoxicity assay is valuable to determine the potential for the compound to cause cell disruption, and such a study is particularly useful if the compound would be administered intravenously. In addition to these in vitro studies, an in vitro metabolism study can be done as a screening assay to determine the extent of metabolism and whether potential reactive metabolites would be formed. Finally, membrane penetration studies would be conducted. Ideally, the excipi-ent would not be absorbed across biological membranes, but may enhance the penetration of API. Immunotoxicity studies would be done only if there is an important structural alert or the compound is from a class of excipients that may be known to induce an immunotoxic effect.

If the data developed in this first phase of the program re-veals limited or no concern for toxicity, then the compound is tested in repeat-dose toxicity studies with the idea that these additional tests will be compliant with FDA guidance for ex-cipient testing. In the second phase, data could be developed that would allow the sponsor to “bridge” to existing, structur-ally related compounds. In this case, for example, a repeat-dose toxicity study would be conducted with a new pegylated sub-stance based on the extensive toxicity data that exists for PEG-400. In this manner, the sponsor would not necessarily need to conduct studies if the data demonstrate a similar toxicity profile. In addition, in the repeat-dose study, groups of animals (rats) could be included to examine for potential reproductive and developmental toxicity following the Organization for Eco-nomic Cooperation and Development’s Guideline 422. Finally, as part of the subchronic study, a micronucleus assay can be incorporated rather than conducting a separate study.

One issue that arises as part of this second phase is con-ducting the studies in a rodent and non-rodent species. In-deed, it would be recommended that a separate study in, for example, the dog, be conducted. If long-term toxicity studies in the non-rodent species have not been conducted with the structural analog, then the sponsor will need to conduct at least a 90-day study.

Based on the results of the second phase of the program, the sponsor would then conduct studies in a third and final phase of the program. In this final stage of excipient development, many of the studies outlined in FDA’s excipient testing guidance would be conducted (e.g., safety pharmacology). More thorough me-tabolism studies also would be conducted in this phase. These studies can be complex depending on the compound. For poly-meric materials, these studies may not be possible although a consideration for undertaking metabolism studies with the monomer or oligomers of the polymer would provide useful

data on absorption and distribution. Based on the outcome of testing in phase two, definitive developmental and reproductive toxicity studies may be warranted. For developmental studies, a second species (e.g., rabbit) would be necessary.

Undertaking a toxicology program in accordance with FDA’s excipient guidance leads to significant costs (see Table I) compared with the costs associated with alternative paradigm (see Table II). Because of the absence of a regulatory process, the timing to gain FDA acceptance can be very prolonged, par-ticularly if the sponsor of a drug product uses a new excipient in the formulation and in nonclinical testing of the drug product. Although the process described here is no panacea for approval, this tiered process will permit the excipient sponsor to plan a program in conjunction with the drug product sponsor and thereby avoid toxicological surprises.

ConclusionThe program outlined herein considers typical excipients. With the advent of biotechnology derived pharmaceuticals, new excipients for biotechnology drugs becomes a program development issue. How these new excipients would be ex-amined in toxicology programs is yet to be determined. Moreover, with increasing emphasis on nanotechnology, these materials potentially represent new processes for drug delivery. Safety assessment of nanotechnology products is in its infancy, and how these materials will be evaluated remains to be determined as well. Finally, the outline of this tiered approach has not been a consideration by FDA, although a tiered-testing rationale is part of several regulatory guidance documents (e.g., metabolite testing, ICH Q3b impurity quali-fication). Hence, how the regulatory agency and, more impor-tantly, API sponsors, will accept such an approach remains to be seen. Regardless, excipient sponsors should consider such an approach because it will limit cost and could advance a new excipient in a timelier manner.

References 1. B. Hughes, Nat. Rev. Drug Discov. 8, 93–96 (2009). 2. P. Van Arnum, Pharm. Technol. 33 (4), 44–51 (2009). 3. M.J. Hall et al., Supplement to Pharm. Technol., s26–s29 (April

2009). 4. FDA, Guidance for Industry: Nonclinical Studies for the Safety Evalu-

ation of Pharmaceutical Excipients (Rockville, MD, 2005). 5. M. Steinberg et al., Reg. Toxicol. Pharmacol. 24, 149–154 (1996). 6. FDA, Draft Guidance for Industry: Nonclinical Studies for the Devel-

opment of Pharmaceutical Excipients (Rockville, MD, 2002). 7. ICH, M3 Nonclinical Safety Studies for the Conduct of Human Clinical

Trials for Pharmaceuticals, 1997. 8. P. M. Wax,. Ann. Intern. Med. 122, 456–461 (1995). 9. P. Baldrick, Reg. Toxicol. Pharmacol. 32, 210–218 (2000). 10. G. Pifferi and P. Restani, Il Farmaco 58, 541–550 (2003). 11. G. Pifferi, P. Santoro, and M. Pedrani, Il Farmaco 54, 1–14 (1999). 12. E. Knight, Int. J. Toxicol. 22, p. 371 (2003). 13. M. Steinberg and I. Silverstein, Int. J. Toxicol. 22, 373–375 (2003). 14. R.E. Osterberg and N.A. See, Int. J. Toxicol. 22, 377–380 (2003). PT


Position Paper


The United States Pharmacopeia (USP) held its Annual Scientific Meeting in Toronto in September.

At the meeting, USP released a series of whitepapers (all seven are available at www.usp.org) that discuss the role the pharmacopeia’s public standards play in an “era of healthcare crisis and reform” (1, 2).

USP’s Council of the Convention (CoC) assembled the whitepapers. Established in 2005 to facilitate and educate United States Pharmacopeial Convention (USPC) representatives, CoC is responsible for examining the purpose, role, and composition of USPC membership, including voting procedures. These responsibilities are critical to defining a revision cycle. A revision cycle is defined as the five-year period between conventions in which the Expert Committees set standards (i.e., develop and revise monographs and general chapters) of the USPC. Convention representatives are re-sponsible for selecting USP committee chairs and voting on the resolutions that will define USP’s strategic direc-tion. The 2010 convention will take place Apr. 21–24, 2010, in Washington, DC, and the 2010–2015 revision cycle will commence on July 1, 2010.

A bit of historyEnvisioned as a liaison between USP’s Council of Experts, scientific staff, and convention members, CoC also holds responsibility for reviewing with key stakeholders the progress on resolutions adopted at annual meetings. These an-nual interactions are expected to result in a more educated membership that is prepared to deal with the complex issues facing USP when all parties meet at the convention every five years. USPC meets every five years to set the goals, objec-tives, and direction for USP during the upcoming revision cycle.

USP was founded in 1820, long before the pharmaceutical industry came into existence. At that time, medicines were prepared by pharmacists, making them the pharmaceutical manufacturers of the day. Because of this and other his-torical developments, USPC membership is based heavily in the pharmacy com-munity. The pharmaceutical industry is represented in USPC by trade organiza-tions such as the Generic Pharmaceutical Association, the Parenteral Drug Associ-ation, and the Pharmaceutical Research and Manufacturers of America. Each member organization sends a represen-tative to the convention, where he or she is expected to vote on changes to the USP Constitution and bylaws, select (by vote) the members of the Board of Trustees as well as the Council of Experts Chairs, conduct business meetings, debate, and vote on resolutions.

The upcoming conventionFast forward to September 2009 when CoC released seven whitepapers at the

USP Annual Scientific meeting. The seven papers address areas of inter-est for USP (e.g., food ingredients and dietary supplements), but three are of special interest to the pharmaceutical industry, as summarized below.

Whitepaper: “USP’s Role in Setting En-

forceable Quality Standards for Medicines.” The content of this CoC whitepaper discusses USP’s ongoing mission to establish standards for all pharma-ceutical products approved for sale in the US. According to this paper, USP’s monograph universe consists of 5720 articles. Of these 5720 products, 1960 (34%) do not have monographs and 583 (10%) have monographs that do not meet current standards and need to be updated. The paper justifies the out-of-date monographs by stating that, “USP has no way to compel information and receipt of candidate materials to sup-port a public monograph.” The paper further indicates that the US Food and Drug Administration’s Freedom of Information Act prevents USP from obtaining the necessary information to establish monographs from com-panies’ new drug and abbreviated new drug applications. The paper explains some of the efforts undertaken to es-tablish missing monographs, including establishing performance-based mono-graphs (3) and developing monographs from existing sources outside the US. In addition, CoC explores USP’s poten-tial role in supply-chain management to prevent economically motivated adulteration through the convention’s standards-development process.

A New Direction for USP?

Susan J. Schniepp

With a five-year revision cycle around the corner,

USP will hit or miss the collaboration mark.

INSIDER SOLUTIONS

PharmTech.com/solutions

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Susan J. Schniepp

is vice-president of

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02140, tel. 617.499.4709,

sschniepp@

javelinpharma.com. continued on page 88


A popular definition of insanity defines it as repeating the same task over and over again while expecting a

different result. Using that definition, it would appear that a lot of people in the contract-services industry think that the major global biopharmaceutical and phar-maceutial companies are insane. That’s because they expect the major companies to continue to seek new drugs the way they have in the past—that is, by throwing a lot of money at a lot of new drug-development candidates in hopes that a few of them will make it to commercial approval.

Are the major drug companies really that crazy?

The dismal track record of the bio-pharmaceutical and pharmaceutical in-dustry for new drug development is well known. Since 1996, the number of drugs in development has doubled, and company spending on research and development (R&D) has tripled, but the number of new molecular entities (NMEs) approved by the US Food and Drug Administration has dropped by half. The cost of develop-ing a new drug has soared to more than $1 billion, and the phrase “R&D productiv-ity” has become an oxymoron.

Until recently, the failure of R&D at the major biopharmaceutical and pharmaceutical companies has largely

been a failure of strategy. Their pur-suit of the next blockbuster led them to undervalue a candidate with a mere $500-million market opportunity. They maintained their historical focus on tech-nologies that were reaching their limits of efficacy and safety, like nonsteroidal anti-inflammatory drugs, while ignoring the

promise of monoclonal antibodies and other large molecules. They pursued economies of scale in R&D operations but wound up building unwieldy and unpro-ductive bureaucracies.

Reducing pipeline dependenceIn recent years, however, global pharma-ceutical companies have made dramatic moves to reduce their dependence on the new product pipeline. Through mergers, acquisitions, and licensing deals, they have diversified their business portfolios into new business opportunities not depen-dent on new products. These portfolios now include emerging markets and generic drugs, and they address technology gaps, especially with regard to biologics.

At the same time, the large biopharma-ceutical and pharmaceutical companies have hacked away at their traditional R&D model, closing R&D facilities, terminating large numbers of development candidates, and exiting entire therapeutic areas. They are experimenting with new organizational structures such as Eli Lilly’s (Indianapolis)

Chorus initiative, that are aimed at find-ing ways to spend less on drug discovery and early development, where a high per-centage of candidates fail. Identifying un-promising candidates sooner, and killing them quicker, is now a major objective of the drug-development process.

Recent developments in the commercial environment will drive biopharmaceutical and pharmaceutical companies to reduce their spending on new products even fur-ther. Regulatory bodies are making com-mercial approval of new products ever more difficult out of concern for patient safety and to encourage drug companies to develop products that are better than what is already on the market.

In the meantime, pressure on drug prices is intensifying, making it increasingly dif-ficult to make a financial return on new drugs. The insurance companies and gov-ernments that pay most of the tab for new drugs are refusing to reimburse payments for some new drugs, demanding use of ge-neric products, stiffening price controls, and in some countries, paying for certain drugs only if the patient shows progress.

Venture capital pullbackAlthough the major drug companies are looking to reduce their drug-development spending, another major source of R&D spending is also likely to decline. Venture capital has fed the growth of the early de-velopment pipeline for the past 10 years, pumping more than $1 billion per quarter into US biopharmaceutical and pharma-ceutical start-ups.

The global financial crisis has changed the outlook for venture capital dramati-cally, however. It has made the major in-

Facing reality

Jim Miller

Contract organizations waiting for the pipeline

to come roaring back are kidding themselves.

The new product

gravy train is

coming to an end.

OUTSOURCING OUTLOOK

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vestors in venture capital funds, pension funds, and university endowments much more risk averse—and contributions to those funds are declining. The economic downturn has also highlighted the fact that returns on venture capital during the past 10 years have not been significantly better than returns on less risky invest-ments, including stocks and bonds. This is a direct reflection of the fact that far too much venture capital has chased too few worthwhile opportunities.

Coming to termsThe contract-services industry needs to come to terms with the fact that the new-product gravy train is coming to an end. The number of candidates in develop-ment is shrinking, and the amount spent on them is falling. R&D spending by small bio/pharma companies dropped 20% in the first half of 2009, and the large and mid-

size companies slowed their spending. We may get a bounce up in the second half of the year as some delayed programs are ac-celerated, but the trend seems pretty clear.

A decline in R&D spending will hurt smaller contract research and manufac-turing organizations (CROs and CMOs) the most, because it will be concentrated in the discovery, preclinical, and Phase I segments of the pipeline. Those are the segments that will feel the greatest effects of the venture capital pullback, and the venture-backed biopharmaceutical and pharmaceutical companies are the most dependent on contractors.

The large public CROs and CMOs will also feel the heat, however. Their stock prices were driven up to record levels dur-ing mid-decade, as high double-digit rev-enue and profit growth rates became the norm. Those growth rates have slowed dramatically, and aren’t likely to reach

their pre-2008 levels. Phase II and Phase III research programs have been well-supported thus far, but efforts to kill likely failures more quickly will ultimately shrink the late-stage pipeline.

CROs and CMOs benefit from the in-creased willingness of the major biophar-maceutical and pharmaceutical companies to outsource more of their development activities. However, much of that benefit will accrue to large CROs and CMOs, and to service providers with operations in the emerging markets.

Owners and investors of contract-service providers must come to terms with this new reality. The venture capitalists and executives of the major companies are not insane, and they have already turned away from the practices that fueled the great pipeline explosion of this decade. CROs and CMOs will need to find other ways to fuel their growth. PT

Whitepaper: “Importance of Standards in As-

suring Good Quality Food Ingredients and Foods.” During the 2005–2010 revision cycle (August 2006), USP purchased the Food Chemicals Codex (FCC) from the Insti-tute of Medicine (IOM). In February 2008, under the auspices of USP, the sixth edition was published, followed by supplements in February 2009 and August 2009. USP also established a web-based publication, the FCC Forum, for users to review and com-ment on proposed changes to FCC mono-graphs. This whitepaper indicates that the industry has been slow to respond to the standards in FCC and discusses potential avenues for enhancing the use and prestige of the FCC on a global basis.

The pharmaceutical industry uses the FCC because it contains monograph infor-mation for some common ingredients that are used in drug-product formulation but that are not subjects of USP monographs. The industry needs to monitor the interna-tional activities of the FCC to ensure they are consistent and appropriate.

Whitepaper: “USP’s Role in Assuring Global Ac-

cess to Quality Medicines.” During the 2005-2010 revision cycle, USP made concerted efforts to expand its global presence. This

whitepaper describes USP’s current inter-national efforts and identifies possible ways to advance this initiative. One unique con-cept presented in this white paper is a pro-posal to establish an independent Global Health Care Secretariat as a means to secure and control global registrations of products and medicines. As stated in the paper, this initiative would be “based in a vision of a collaborative global health care secretariat with multiple components, in-volving representatives from all countries and yielding decisions suitable for national adoption. The components would focus on a) discovery, b) research and development, c) sound regulatory decision-making and, when appropriate, rapid registration deci-sions, d) optimal pricing–payment strate-gies, e) evidence-based healthcare delivery based on outcomes/pharmacoeconomic studies, f) quality of care, and g) safe medi-cation use.”

Summing it upWhat does all of this mean? In April 2010, USPC will convene and vote on resolutions that will effect the next five years of USP activities. These whitepa-pers may set the stage for those votes. It is important for industry to read these papers in their entirety and be prepared

to engage in debate on the pros and cons during the open-floor discussion of the convention. This is the best way to as-sure that USP will appropriately repre-sent all parties of the pharmaceutical-products process, and it may be your best opportunity to influence the direction of USP as it strategizes the next five years.

Many of the ideas brought forth in these whitepapers appear to be altruistic. It is hard to argue with the concepts of secur-ing safe food, providing safe medication, and establishing appropriate standards for the global community. However, other organizations such as the International Conference on Harmonization and the Pharmaceutical Inspection Cooperation Scheme are trying to address many these same issues. It would seem appropriate for USP to engage them in dialogue so that efforts are not duplicated and to prevent a divergent set of standards from evolving.

References 1. USP whitepaper, USP’s Role in Patient

Safety, Sept. 23, 2009. 2. USP whitepaper, Opportunities for Drug

Information and Use Standards, Sept. 23, 2009.

3. Performance-based Monographs, Pharmaco-peial Forum 35 (3), 2009, 765–770. PT

Outsourcing Outlook

Insider Solutionscontinued from page 84


PHARMA CAPSULES

Milestones

Alcan Courts Canadian ClientsThe Alcan Packaging Pharma

Center group attended Inter-

phex Canada in Toronto for

the first time this year. The

company’s objective was to

meet with Canadian custom-

ers and provide them with a

better understanding of how

the Pharma Center’s special-

ized capabilities are designed

to meet marketplace needs.

At the show, Alcan’s represen-

tatives discussed their depth

of experience with high-

barrier cold-formable and

thermoformable blister

materials and child-resistant

lidding materials.

Catalent’s German Facility Completes FDA AuditCatalent Pharma Solutions’s

(Somerset, NJ) integrated

dose-form development,

manufacturing, and packag-

ing facility in Schorndorf,

Germany, successfully com-

pleted a US Food and Drug

Administration inspection.

The inspection was prompted

by preapproval inspection

requirements for two sepa-

rate products and resulted

in three minor observa-

tions on FDA Form 483. The

Schorndorf facility produces

products approved by other

regulators including those in

Germany, Brazil, and Taiwan.

Catalent’s Schorndorf busi-

ness was founded in 1973

and provides formulation

and development services

and clinical and commercial

manufacturing for oral tablets

and capsules, powders, and

other dose forms. The busi-

ness also provides clinical

and commercial packaging,

clinical supply-chain manage-

ment services, and integrated

product development and

commercial supply-chain so-

lutions for products in these

dosage forms.

PTI Completes Four Class 100,000 CleanroomsPharma Tech Industries

(PTI, Royston, GA), a leading

provider of contract manu-

facturing and packaging

services for pharmaceutical,

medical-device and personal-

care products, completed

four Class 100,000 clean-

rooms. Three of the rooms

are housed in the company’s

Royston facility, and one

cleanroom is in its Union, Mis-

souri, facility.

The specially engineered

rooms have highly-sensitive

control features to regulate

and monitor temperature and

humidity closely. The three

Royston cleanrooms are used

for unit-dose and pouch fill-

ing as well as compounding

and blending of powder-

based products. The com-

pounding–blending room

also has an area dedicated to

preweighing and sampling.

The Union cleanroom is for

bottle filling of powder-based

products.

Operators work in one of

Pharma Tech Industries’s

new cleanrooms.

Hans Engels, business unit president

and CEO of DSM Pharmaceuticals

PharmTech:What is the biggest industry

challenge you’re now facing?

Engels:With the complexity we

have in the supply chain for

pharmaceutical products, it is

absolutely necessary that the

different elements of the sup-

ply chain interact much closer

together than they have done

in the past. Previously, a large

pharmaceutical company controlled everything from the

top down. By having enough excess capacity in all elements

of the supply chain, they were able to fulfill the paradigm of

always having product available in the marketplace.

Now this is going away. Now you have high-performing

elements in your network that might be your own facility or

might be somebody else’s facility. You need to make sure that

the information exchange between these elements in the

network is flawless so that if there is any problem in one ele-

ment of the network, everybody else becomes aware of it and

can take appropriate action. The paradigm is still that product

has to be available at all times in the marketplace. If you don’t

have product, that’s the most costly failure you can have.

PharmTech:A lot of people talk about just-in-time manufacturing, but

do you think many pharmaceutical companies are actually

trying to do it?

Engels:If you want to apply it in the pharmaceutical industry, a lot of

minds have to change. I think the pharmaceutical industry is

far away from on-demand manufacturing for multiple rea-

sons. One of the reasons is the culture of the industry, other

reasons are compliance constraints. But I think this should not

prevent us from getting as close as possible to that paradigm.

PharmTech:Has DSM tried new ways of exchanging information with its

clients?

Engels:Yes. For instance, the whole supply chain must know about

the progress of deviations in the quality system. We created

a dashboard that tracks deviation handling throughout man-

ufacturing, quality assurance, and the laboratories. Because

we have not found a way to directly and securely tie clients

into our systems, we created data rooms that are automati-

cally updated so the customer can see data we have agreed

upon up front that they want to see.

Q&A with


Culturing set SGM’s DriAmp

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Releasat medium

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high-temperature,

direct-air exposure

or submersion in

nonwater-based solutions. The DriAmp BI is a

1-mL, snap-top glass ampul containing inoc-

ulated silica. The Releasat medium provides

a reduced incubation time of 72 h. A color

change indicates positive test results. SGM

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MANUFACTURING EQUIPMENT & SUPPLIES



Fluid-bed dryer bags Kavon provides custom replacement fluid-

bed dryer bags for US and European equip-

ment 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.

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Quality-

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final-product

quality on assembly lines that fill contain-

ers 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

Product

catalogCole-Parmer

published its 2009

Mixers Catalog,

which includes the

company’s latest

overhead mixers.

The 32-page cata-

log describes the

company’s selec-

tion of mixers and overhead stirrers, includ-

ing laboratory- and industrial-process scale

mixers, static mixers, sanitary mixers, powder

mixers, and process mixers. Mixer accessories

are also available. Cole-Parmer, Vernon Hills, IL

• www.coleparmer.com • tel. 800.323.4340

Sanitary

double-

planetary mixer Ross offers a sanitary

model of its line of

double planetary

mixers. The DPM-S

model is available in

working capacities as

large as 750 gal. The

unit is appropriate for materials with viscos-

ity as high as 8 million cps. Two HV mixing

blades revolve within the mix vessel. Charles

Ross and Son Company, Hauppauge, NY • www.

mixers.com • tel. 631.234.0500

INDUSTRY PIPELINE

Vertical

laminar-flow

stationThe Vertical Lam-

inar Flow station

incorporates fan

or filter modules

with filters to

provide a

contaminant-

free work environment. Fabricated of

powder-coated or 304 stainless steel, the

cleanroom-compatible system includes

transparent side panels that restrict the

laminar flow to ensure an effective wash of

filtered air over the work surface. Terra

Universal, Fullerton, CA • www.terrauniversal.

com • tel. 714.578.6000

Semiautomated filling system The FPC50 semiautomated filling and plug-

ging system provides accuracy, flexibility,

and fast changeover in small-batch filling of

clinical trial materials. The device is compact

and saves space in the facility. The system

also offers an easy transfer into a full-

production scale-up operation. Watson-

Marlow Flexicon, Wilmington, MA • www.

flexiconamerica.com • tel. 888.771.3201

Single-body design valve Swagelok’s DR series radial diaphragm valves

offer various compact multivalve and mul-

tiport configurations that provide a clean,

compact way to manage sterile flow streams.

Available in 316-L stainless steel and five sizes

from 0.5 in. to 2 in., the valves are appropriate

for various applications. Swagelok, Solon, OH •

www.swagelok.com • tel. 440.349.5934

Disposable

filtration

technologiesThe Sartopore 2

Gamma MidiCaps

are designed to offer

mechanical stability

and a high maximum

allowable differential

pressure at room

temperature. Their

double-vent valves with O-rings facilitate ini-

tial setup. The heterogeneous double-layer

membrane filters are offered in 0.45- and

0.2-μm or 0.2- and 0.1-μm combinations.

Sartorius Stedim Biotech, Bohemia, NY • www.

sartorius-stedim.com • tel. 800.368.7178


INDUSTRY PIPELINE



Fluid-path assemblies One-Touch single-use fluid-path assemblies

are designed for secure fluid transfer in critical

biopharmaceutical processing applications.

The products can be customized to end-user

requirements and include combinations of

connectivity, tubing, and other components.

Fluid paths can be integrated with filter cap-

sules in various surface areas, end-connection

configurations, and media. Meissner Filtration

Products, Camarillo, CA • www.meissner.com •

tel. 805.388.9911

Mopping

system Perfex offers a

TruCLEAN mop-

ping system

designed for

small-area clean-

ing and disinfect-

ing. The system

allows the use of

the bucket-in-

bucket concept

with a sieve on the waste-containment

bucket. Operators also can use a sieve alone

on the 36-L bucket. The system is completely

autoclavable. Perfex, Poland, NY • www.

perfexonline.com • tel. 315.826.3600

Laboratory blenders

MaxiBlend and MiniBlend

laboratory blenders 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

Silicone tubingSani-Tech ULTRA low-

extractable silicone

tubing was devel-

oped specifically for

the biopharmaceuti-

cal industry. The

high-performance

tubing has an extract-

able level lower than

that of many common fluid-transfer materi-

als. The product is laser-etched for trace-

ability, fully autoclavable and sterilizable.

Typical applications include media process-

ing, sterile fill, and transfers. Saint-Gobain

Performance Plastics, Beaverton, MI • www.

biopharm.saint-gobain.com • tel.

888.387.0067

Tablet pressSpecialty Measurement offers the MiniTab

press, which is designed to manufacture

tablets ranging from 0.5 to 4 mm in diam-

eter. The introduction model can produce

<300,000 tablets/h; larger models will be

capable of making >2 million tablets/h. The

compact size of the machine, less than 250

500 × 500 mm, makes it ideal for glove-box

applications. SMI, Lebanon, NJ • www.smitmc.

com • tel. 908.534.1546

Low relative-humidity enclosureUPM Pharmaceuticals has incorporated a

validated, low relative-humidity enclosure

into its Xcelodose 600 encapsulator. This

custom-designed chamber can be used at

relative humidities in the single digits. UPM

successfully completed several research and

manufacturing projects with the enclosure

and added it to its manufacturing capabili-

ties. UPM Pharmaceuticals, Baltimore, MD •

www.upm-inc.com • tel. 410.843.3738

OUTSOURCING & CONSULTING SERVICES

Outsourcing servicesStiefel produces liquids and

semisolids, including gels,

creams, ointments, topical

solutions, and liquid orals

in prescription and over-

the-counter formulations.

The company manufac-

tures batch sizes from 170

to 3300 kg. Its packaging

capabilities include metal,

plastic, and laminate tubes.

Stiefel also packages tottles and glass and

plastic bottles. Stiefel Outsourcing Services, Oak

Hill, NY • www.stiefel.com • tel. 518.261.8766

Contract

manu-

facturing Abbott offers

high-quality and

cost-effective con-

tract manufactur-

ing services in the

areas of biologics,

potent drugs, fer-

mentation, finish-

ing, and packaging. The company also offers

various compendium-grade active pharma-

ceutical ingredients. Abbott Contract Manu-

facturing Services, North Chicago, IL • www.

abbottcontractmfg.com • tel. 800.240.1043

Contract servicesAptuit provides consulting expertise, facilities

that comply with good manufacturing prac-

tices, technologies designed to expedite the

development process, project-management

capabilities, and regulatory-compliance

services. Aptuit also offers a package for stra-

tegic and regulatory consulting, informatics,

preclinical and clinical technologies, phar-

maceutical sciences, clinical packaging and

logistics, and active pharmaceutical ingredi-

ent development and manufacture. Aptuit,

Greenwich, CT • www.aptuit.com •

tel. 816.767.3900



Contract servicesFounded in 1994, QPharma has built its

reputation on delivering value to the life-

science and related industries through a

wide range of regulatory and compliance

solutions. QPharma’s suite of professional

services spans the product-development life

cycle, from quality and validation solutions to

fulfillment services. QPharma, Morristown, NJ •

www.qpharmacorp.com • tel. 973.656.0011


Product-development services Azopharma Product Development Group

provides clients with comprehensive services

from discovery through commercialization.

The company maximizes communication and

minimizes downtime by bundling services

from key sections of the drug-development

process. Azopharma offers stand-alone

services and comprehensive programs to fit

clients’ needs. Azopharma Product Development

Group, Hollywood, FL • www.azopdogroup.

com • tel. 954.433.7480

Cytotoxic contract

manufacturingAn eight-page brochure

describes Baxter’s cy-

totoxic manufacturing

facility in Halle, Germany.

It includes information

about cytotoxic contract

manufacturing using barrier-isolator technol-

ogy and services such as lyophilization,

liquid-vial filling, dry-powder filling, and

sterile crystallization. The facility manu-

factures for distribution markets, includ-

ing the United States, Europe, and Japan.

Baxter BioPharma Solutions, Round Lake, IL •

www.baxterbiopharmasolutions.com • tel.

800.422.9837

Sterile

manufacturing

capabilitiesPfizer CentreSource

offers various sterile

manufacturing capa-

bilities. The company

manufactures sterile

suspension solutions,

lyophilized products,

and cytotoxic products. Development and

commercial-scale production are available.

Other services include stability testing, scale-

up, technology transfer, process optimiza-

tion, and validation. Pfizer CentreSource (PCS),

Kalamazoo, MI • www.pfizercentresource.

com • tel. 269.833.5844

INDUSTRY PIPELINE


Contract researchPPD is a leading global contract research

organization providing discovery, develop-

ment, and postapproval services. PPD ap-

plies innovative technologies, therapeutic

expertise, and a commitment to quality to

help its clients and partners maximize returns

on their research investments and acceler-

ate the delivery of therapeutics to patients.

PPD, Wilmington, NC • www.ppdi.com • tel.

910.251.0081

Contract servicesMetrics offers potent and cytotoxic solid-

oral drug development and clinical-supplies

manufacturing for Phase I–III projects as

large as 10 kg. The company’s dedicated facil-

ity provides total engineered containment of

pharmaceutical processes through custom-

ized hard-wall isolation technologies that

eliminate the need for powered air-purifying

respirators. Metrics, Greenville, NC • www.

metricsinc.com • tel. 252.752.3800

Contract services Mikart has provided contract development,

manufacturing, and packaging services to

the pharmaceutical industry since 1975. The

company’s capabilities include formulation

development; analytical services; solid- and

liquid-dose manufacturing; packaging in

bottles, blisters, and multilaminate pouches;

project management; and regulatory ser-

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

tel. 888.4MIKART

Formulation-

development programsXcelience provides defined formulation-

development programs that help enable a

fast, cost-effective path to proof of concept.

The services can reduce the time to first-

in-human studies by 45% compared with

traditional formulation development. These

programs are intended to provide compa-

nies with a lasting advantage through the

combination of expertise, innovation, and

quality systems. Xcelience, Tampa, FL • www.

xcelience.com • tel. 813.286.0404


Contract servicesPatheon’s services range from preclinical

development through commercial manufac-

turing of a full array of dosage forms. Patheon

uses innovative technologies, including single-

use disposables, liquid-filled hard capsules,

and various modified-release technologies.

Its range of pharmaceutical development

services includes preformulation, formula-

tion, analytical development, clinical manu-

facturing, scale-up, and commercialization.

Patheon, Durham, NC • www.patheon.com • tel.

905.821.4001


INDUSTRY PIPELINE

Virology

services Compliance

Insight offers

virology consult-

ing services for

biologic phar-

maceuticals and devices. Clients may now

choose from consultative services such as

viral clearance and cleaning validation, raw-

materials testing, product-lot release testing,

and product risk assessments for viral con-

tamination. Compliance Insight, Fairfield, OH •

www.compliance-insight.com • tel.

513.860.3512

Contract

manufac-

turing Therapex

offers turn-

key services

for oral

liquid and

topical healthcare products in small or large

volumes. Services include product develop-

ment, technology transfer, and commercial

manufacturing and packaging in a plant

approved by the US Food and Drug Adminis-

tration. The company provides the skills and

technological capabilities that clients require.

Therapex, Montreal, Canada • www.therapex.

com • tel. 800.465.5820


High-tech facility

Binswanger offers its 441,362-ft2 high-tech

complex on 21 acres in Arlington, Texas. Fifty

acres are available for the site’s expansion.

The facility includes 73,000 ft2 of cleanroom

space, which is mostly ballroom style. Clean-

rooms are fully operational and all systems

are functioning. Binswanger, Philadelphia, PA

• www.binswanger.com • tel. 215.448.6289

INDUSTRY PIPELINE

Fluid chroma-

tographyRegis Technologies

offers RegisSEP

supercritical-fluid

chromatography

(SFC) services for

chiral 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 “Reg-

isSEP SFC Services” brochure is available for

download on its website. Regis Technologies,

Morton Grove, IL • www.registech.com • tel.

800.323.8144

Application

notebookWaters offers a liquid

chromatography (LC)–

mass spectrometry

application notebook

that explores the ver-

satility, performance,

and ease-of-use of the

ACQUITY ultraperfor-

mance LC with the Xevo family of advanced

tandem quadrupole and benchtop quadru-

pole time-of-flight mass spectrometers. The

notebook also describes specialized infor-

matics solutions for biopharmaceutical and

pharmaceutical applications. Waters, Milford,

MA • www.waters.com • tel. 508.478.2000

Weighing

terminal The IND560

weighing termi-

nal from Mettler

Toledo allows

users to choose

between conventional strain gauge or high-

precision, electromagnetic-force restoration

weighing technologies. The unit is compati-

ble with direct program logic controllers such

as Profibus and DeviceNet, as well as Ether-

net communication interfaces and internal

and external digital I/O control. An IP65-rated

panel and IP69k heavy-washdown mounting

are available options. Atlantic Scale Co.,

Nutley, NJ • www.atlanticscale.com •

tel. 973.661.7090

Mass

spectrometerThe ProMaxion

process mass

spectrometer

from AMETEK

provides con-

tinuous real-time

monitoring and control of solvent-drying

processes. The instrument controls all as-

pects of the drying cycle from product entry

to removal. It signals the end of the drying

cycle, determines the optimum time for

vacuum drying after filtration, and tracks

process variables such as air entry into the

drying chamber. AMETEK Process Instruments,

Pittsburgh, PA • www.ametekpi.com • tel.

412.828.9040

LABORATORY EQUIPMENT & SUPPLIES

LABORATORY EQUIPMENT & SUPPLIES

Membrane

chromatography Mustang Q XT chro-

matography capsules

help process develop-

ers reduce purifica-

tion time, increase

throughput, and cut

buffer consumption. The open-pore struc-

ture of Mustang membranes makes the cap-

sules suitable for high flow-rate contaminant-

removal applications and for the capture or

removal of large molecules. Pall, East Hills, NY

• www.pall.com • tel. 516.484.5400

Total

organic

carbon analyzerThe Sievers 500 RL

on-line total organic

carbon (TOC) ana-

lyzer delivers the ac-

curacy, automation,

and confidence needed for switching from

laboratory to on-line TOC. The unit uses no

reagents and provides continuous quality

assurance for real-time water release and

cleaning validation. The four-port Super iOS

standards-introduction device automates

system protocols. GE Analytical Instruments,

Boulder CO • www.geinstruments.com • tel.

303.444.2009


Brand-protection technologyNanoGuardian’s NanoEncryption technol-

ogy is an on-dose, multilayered, brand-

protection technology that enables manu-

facturers to trace and authenticate each dose

from plant to patient. The technology has

intrinsic layered security features at the overt,

covert, and forensic levels and can be applied

directly to tablets, capsules, and vial caps.

NanoGuardian, Skokie, IL •

www.nanoguardian.net • tel. 847.679.6266

PACKAGING EQUIPMENT & SUPPLIES

Packaging solution The NextBottle package from Catalent and

One World Design and Manufacturing 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

Transfer

packaging for pre-

fillable syringesBD TSCF packaging en-

sures the secure transfer

of sterile prefillable

syringe components into the pharmaceuti-

cal filling environment. The packaging is

compatible with IDC Biosafe doors for aseptic

filling machines within isolator or barrier

systems. This packaging is part of the BD

SCF global offer, which features expertise in

sterile processing of preservative-free drugs;

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

ready-to-fill; and drug master file and techni-

cal dossier. BD Medical–Pharmaceutical Systems,

Franklin Lakes, NJ • www.bdpharma.com •

tel. 800.225.3310

Cleaning

wipesVeltek Associates

offers sodium-

hypochlorite and

hydrogen-

peroxide wipes.

Both wipes are

Class 10 laun-

dered, filtered at

0.2 µm, formu-

lated with water

for injection, have laser-cut edges, and are

guaranteed sterile with lot-specific docu-

mentation. Veltek Associates, Malvern, PA •

www.sterile.com • tel. 610.644.8335

CLEANROOM EQUIPMENT & SUPPLIES

WebsiteNatoli has redesigned its website to provide

clients with more information. The new web-

site features quote-request forms for tooling

and products. Advanced search capabilities

allow users to easily search products or parts

by name, manufacturer, part or item number,

or product description. Natoli Engineering

Company, St. Charles, MO • www.natoli.com •

tel. 636.926.8900

INFORMATION TECHNOLOGY

INDUSTRY PIPELINE

Microcrystalline celluloseCeolus UF-711 is a highly compactible micro-

crystalline cellulose with excellent powder

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

CHEMICALS, RAW MATERIALS,

INTERMEDIATES, & EXCIPIENTS

Gelatine

propertiesEastman’s gelatin

formulations

provide products

for the chang-

ing needs of the

pharmaceutical

industry. The

company offers compounds that withstand

the degrading effects of light, moisture,

and oxygen. Other gelatins mask tastes and

odors and isolate irritant or unstable drugs

for time-delivery products. Eastman Gelatine,

Peabody, MA • www.eastmangelatine.com •

tel. 978.767.6299

Mineral guideJost has developed a mineral guide for

formulators and researchers. The reference

describes the solubility, metal content, and

taste associated with mineral salts. These

details are key points to consider when

formulating a product. The mineral guide is

available in the Customer Support section of

Jost’s website. Jost Chemical Co., St. Louis, MO •

www.jostchemical.com • tel. 314.428.4300

CHEMICALS, RAW MATERIALS, INTERMEDIATES, & EXCIPIENTS

Orally-

disintegrat-

ing tablet

technologyAdvaTab orally

disintegrating

tablet (ODT)

technology is distinct from conventional

ODT methods because it can be combined

with proprietary Microcaps taste-masking or

Diffucaps controlled-release technology to

create robust tablets, packaged in bottles or

blisters, with high dose capacity, customized

release profiles, and good taste and mouth-

feel. Eurand, Vandalia, OH • www.eurand.com

• tel. 937.898.9669

INDUSTRY PIPELINE

Pharmaceutical Technology NOVEMBER 2009 99

PharmTech .com

PRODUCTS AND SERVICES SHOWCASE

EQUIPMENT & SUPPLIES OUTSOURCING RESOURCES

Contact: Dr. Matharu

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email: [email protected]

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• Formulation Development

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OUTSOURCING RESOURCES

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Services

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Pharmaceutical

Contract ManufacturingGels, Creams, Ointments

Topical Solution

Liquid Orals

Please Contact: Lance Haskin

800-633-7647 x8766

518-261-8766 [email protected]


100 Pharmaceutical Technology NOVEMBER 2009


SL Pharma Labs, Inc.

• Well-established & Experienced GMP-Compliant Contract Service Organization

• CMC Development for Innovative & Generic Drug Products Including Biotechnology Products

• Clinical Manufacture (Phase-1 & 2): Parenterals, Ophthalmics, Nasals & Topicals

• Microbiological Methods Development/Validation and Testing Antibiotics and Antiseptics

• Sterility, Microbial Limits, Bacterial Endotoxins & Preservative Testing

• Antimicrobials R&D & Microbiological Assays Development/Validation

WWW.SLPHARMALABS.COM

SL Pharma Labs, Inc.

(302) 636-0202 • [email protected]

1300 First State Blvd • Suite C

Wilmington, DE 19804 United States

MICROBIOLOGICAL

DEVELOPMENT

PRODUCTS AND SERVICES SHOWCASE


Punches & Dies

Turrets

Tablet Presses

Replacement Parts

Accessories

Tool Management Software

Technical Training Courses

636.926.8900 • natoli.com • [email protected]

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TOOLS & DIES

REACTORS

The Rayonet Photochemical Mini-Reactor For ICH Testing

Model RMR-600

STANDARD EQUIPMENT:

The “Mini” reactor is supplied with 8 350NM and 8 cool white for ICH Testing. Normal operating temperature is 37o C. Low cost lamps provide longrunning life, (approximatly 3000 hours). The reactor’s power consumption is about one amperes @ 110/120 volts, 50/60 Hz., A.C. Simple to operate.

SPECIFICATIONS:

The RMR-600 is 10” in diameter and 10 1/2” high. The chamber is 9” deep x 7” diameter. The reactor comes supplied with 16, 4 watt lamps, with an arc length of 3” each (32 lamp watts total). The top opening is 5” diameter, weight 10 lbs. Finished in durable baked enamel, with a one year guarantee.

The Rayonet’ Model RMR-600 is a versatile, efficient, easy-to-use photo-chemical reactor. Ideal for applications where instrument simplicity and reliabil-ity are of prime importance, and cost ef-fectiveness is a determining factor. This reactor is complete in a “Ready to Use” package with no assembly required.

A photochemical system for the limited budget. High-performance, small size and low price makes it ideal for both undergraduate and graduate studies.

$1,195.00

Southern New England Ultraviolet550 E. Main St., Ste 29, Branford, CT 06405

(203) 483-5810 www.rayonet.org

Rayonet RMR-600


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102 Pharmaceutical Technology NOVEMBER 2009

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Process Development Scientist (New England area)Contact:

Dan Becker

Millipore Corporation

290 Concord Rd., Billerica, MA 01821

Telephone: 978-715-1281 • Fax 978-715-1398

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Process Development Scientist (Greater DC area)Contact:

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Millipore Corporation

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Telephone: 978-715-1281 • Fax 978-715-1398

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ABBOTT ........................................................7

Ametek ..................................................... 51

Aptuit ........................................................ 55

Asahi Kasei America, Inc. ...........................73

Azopharma .......................................Covertip

Baxter BioPharma Solutions ...................... 19

Becton Dickinson & Co. ............................. 107

Binswanger/Real Estate ............................ 10

Canreg .......................................................63

Catalent Pharma Solutions ...................... 108

CBI .............................................................91

Chemic Laboratories, Inc. ........................... 75

Coating Place Inc .......................................71

Cole-Parmer .............................................. 14

Compliance Insight Inc. .............................43

CRS Controlled Release Society ..................95

Croda Inc .....................................................9

DPT Laboratories, Ltd. ...............................87

Dionex .......................................................27

EMD Chemicals Inc. ....................................77

Eastman Gelatine ......................................80

Emerson Process Management .................. 35

Enzon Pharmaceuticals ..............................57

ExcipentFest ..............................................89

GlobePharma Inc .......................................22

HollisterStier Contract Mfg. ....................... 13

ITT Pure-Flo ...............................................25

Industrial Dynamics Company, Ltd. ............ 41

Jost Chemical Co. ....................................... 61

JT Baker .....................................................79

Magnetrol International............................59

Mallinckrodt Baker ...................................79

Meissner Filtration Products, Inc. .................2

Mikart ....................................................... 33

NanoGuardian ...........................................65

Natoli Engineering Company,Inc. ...............49

PDA ...........................................................97

P-MEC India ...............................................93

Pall BioPharm............................................ 53

Patheon .................................................... 37

Perfex Corporation ....................................23

PfizerCentreSource .................................... 67

PPD, INC. .................................................... 31

PYRAMID Laboratories, Inc .........................83

Q Pharma ..................................................39

Regis Technologies, Inc. .............................48

rommelag USA, Inc. ...................................45

SMI ............................................................ 21

Saint-Gobain Performance Plastics ............ 15

Sartorius Stedim Biotech ........................... 47

Sparta Systems, Inc ......................................3

Stiefel Outsourcing Services....................... 11

Swagelok ..................................................69

Terra Universal ................................. 6, 43, 50

Therapex .....................................................6

UPM Pharmaceuticals ..................................4

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

Vetter Pharma International GmbH ........... 17

Waters Corporation ...........................Outsert

Watson-Marlow Pumps Group ...................29

Ad IndexCOMPANY PAGE COMPANY PAGE COMPANY PAGE

cally been responsible for ensuring that vendors and suppliers are up to date and compliant with current good manufac-turing practice (CGMP). The ASTM standard does not give this responsibil-ity to QA but FDA, in other documenta-tion, does give QA the responsibility for overall vendor certification.

FDAWhat is more intriguing is that, based on industry committee meetings in-volving regulatory bodies, FDA and even the European Union agree with the concepts of commissioning and the deemphasis of IQ and OQ. FDA not only participated in the drafting of the documents, but also tacitly approved them. As a result, most of industry in-stituted the new methodologies.

Even though FDA has not abandoned the concept of qualification, the agency states in the draft guidance that verifica-tion is to be achieved through qualification. In the ASTM standard, the word qualifica-tion is replaced by verification. It seems that verification, however, is one step removed from qualification; these words are not

necessarily interchangeable.

Final thoughtsOver the years, the practice of validation has been truncated, revised, and rein-vented. The old standbys of IQ, OQ, and PQ have been criticized by some as not being in step with current technology and practice. Many in industry argued that most people understood GXP, in-cluding GEP. Although the industry may have matured in this sense, human nature may not have. Quality problems and re-calls still occur.

FDA has not entirely abandoned the concept of qualification as pointed out in its draft guidance on process validation. But relying solely on verification processes and eliminating the role of QA and QUs is not enough to ensure quality. The cur-rent situation is further complicated by the variety of unharmonized approaches and standards throughout the global in-dustry. Even within existing regulations, there is inconsistency of meaning and implementation.

Some potential solutions include: Involving QA from the onset to par-ticipate in the review and acceptance

•

of vendor documentation and the commissioning and verification of related documentation. Commissioning and verification testing for every applicable system. Testing should be completed with a QA reviewer and approved in a closeout reportAbove all, requalification and revali-dation should take place as needed and when necessary.

References 1. FDA, Draft Guidance for Industry—Process

Validation: General Principles and Practices (Rockville, MD, Nov. 2008).

2. ASTM, Standard E2500-07 Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment (West Conshohocke, PA, 2007). PT

Read more on this topic by Louis Angelucci,

includng additional proposed solutions, online at

PharmTech.com.

•

•

Viewpoint

Your opinion matters.To contribute to this column,

send your proposal to

[email protected].

continued from page 106


This article compares the pertinent aspects of the US Food and Drug Ad-ministration’s 2009 draft guidance for

industry on process validation (1) and the 2007 ASTM E2500-7 standard guide on the specification, design, and verification of pharmaceutical and biopharmaceutical manufacturing systems and equipment (2). There are several inconsistencies be-tween the two documents in terms of terminology and expectations for equip-ment and system qualification. In addition, the timing of both documents gives the impression that previously understood qualification documentation practices are being abandoned for newer terminology and proposed practices.

During the past few years, there seems to have been a directed effort to eliminate the concept of and need for installation qualification (IQ) and operational quali-fication (OQ). Industry developed these techniques to address FDA’s validation requirement. The purpose of IQ and OQ was to verify that equipment and systems were able to perform as intended.

Today, many companies still follow the premise of IQ and OQ, but the in-troduction of other terms has down-sized the importance of these activities. In particular, the term commissioning has been introduced into industry’s ver-nacular to define traditional IQ and OQ tests, among other tests. Today, IQ and OQ have been reduced to lists indicat-ing that commissioning tests have been

properly completed and leveraged.

The present situationWith the introduction of the ASTM standard and FDA draft guidance, in-dustry needs to adjust its understand-ing of the word qualification for systems and equipment once again. For example, both documents deemphasize IQ and OQ. The ASTM standard does not men-tion the word qualification and the draft guidance does not specifically mention the terms IQ or OQ in its discussions on equipment and system qualification. (The draft guidance does call for perfor-mance and process qualification [PQ] as part of overall process validation.)

It can be argued that the two docu-ments address two different but related subjects within the scope of validation. The ASTM standard, for example, is geared toward the acceptance of equip-ment and systems before performance qualification, and the FDA draft guid-ance emphasizes PQ.

Role of quality assurance Traditionally, quality assurance (QA) was carried out by an independent reviewer and approver. The QA department had no direct role in the design or manufac-turing process of the drug product and

had an independent reporting structure from engineering and manufacturing. With the onset of commissioning, the role of QA in the overall qualification scheme came into question. Nowhere in industry guidelines was it stated that QA should review and approve commission-ing tests or related documentation. QA review was strictly for critical systems and equipment.

The FDA draft guidance on process validation gives more responsibility to the quality unit (QU) than does the ASTM standard. The QU is supposed to approve the qualification plan as well as PQ protocols and reports. The FDA draft guidance document notes

that the QU should approve individual equipment and system qualifications, as well as the qualification plan and sum-marizing report.

The ASTM standard does not for-mally mention the QU other than sug-gesting that the QU approve the veri-fication plan and verification review documents, and decide on vendor docu-ments as they apply to criticality. The QU does not participate in the review or approval of the verification documents but only the final review documents.

In addition, the QA group has typi-

Are We Abandoning IQ and OQ?

Louis A. Angelucci

New standards from FDA and ASTM

may overlook critical qualification needs.

VIEWPOINT

PharmTech.com/view

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Louis A. Angelucci is the director of

corporate validation at MedImmune,

One MedImmune Way, Gaithersburg,

MD 20878, tel. 301.398.2949,

[email protected].

There seems to have been a directed

effort to eliminate the concept of and

need for installation qualification and

operational qualification.

continued on page 105


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