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BioPharmThe Science & Business of Biopharmaceuticals

INTERNATIONALINTERNATIONAL

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Volume 27 Number 5

BREAKTHROUGHS

IN VACCINE

DEVELOPMENT

PEER-REVIEWED

REGULATORY

REQUIREMENTS FOR VIRAL-

CHALLENGE STUDIES:

INFLUENZA CASE STUDY

EXPRESSION SYSTEMS

IMPROVING PROTEIN

EXPRESSION WITH

NOVEL SYSTEMS

DISPOSABLES

STANDARDIZING

PRACTICES FOR

DISPOSABLES

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INTERNATIONAL

BioPharmThe Science & Business of Biopharmaceuticals

EDITORIALEditorial Director Rita Peters [email protected]

Managing Editor Susan Haigney [email protected]

Scientific Editor Adeline Siew, PhD [email protected]

Community Editor Melanie Sena [email protected]

Art Director Dan Ward [email protected]

Contributing Editors Jill Wechsler, Jim Miller, Eric Langer, Anurag Rathore, Jerold Martin, Simon Chalk, and Cynthia A. Challener, PhD Correspondents Hellen Berger (Latin & South America, [email protected]), Jane Wan (Asia, [email protected]), Sean Milmo (Europe, [email protected]) ADVERTISING

Publisher Mike Tracey [email protected]

National Sales Manager Steve Hermer [email protected]

East Coast Sales Manager Scott Vail [email protected]

European Sales Manager Chris Lawson [email protected]

Senior Sales Executive Christine Joinson [email protected]

Market Development, Classifieds, and Recruitment Tod McCloskey [email protected]

Direct List Rentals Tamara Phillips [email protected]

Reprints 877-652-5295 ext. 121/ [email protected] Outside US, UK, direct dial: 281-419-5725. Ext. 121 PRODUCTION Production Manager Jesse Singer [email protected] AUDIENCE DEVELOPmENT Audience Development Kelly Kemper [email protected]

Joe Loggia, Chief Executive Officer; Tom Florio, Chief Executive Officer Fashion Group, Executive Vice-President; Tom Ehardt, Executive Vice-President, Chief Administrative Officer & Chief Financial Officer; Georgiann DeCenzo, Executive Vice-President; Chris DeMoulin, Executive Vice-President; Ron Wall, Executive Vice-President; Rebecca Evangelou, Executive Vice-President, Business Systems; Julie Molleston, Executive Vice-President, Human Resources; Tracy Harris, Sr Vice-President; Michael Bernstein, Vice-President, Legal; Francis Heid, Vice-President, Media Operations; Adele Hartwick, Vice-President, Treasurer & Controller

©2014 Advanstar Communications Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording, or information storage and retrieval without permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or the internal/educational or personal use of specific clients is granted by Advanstar Communications Inc. for libraries and other users registered with the Copyright Clearance Center, 222 Rosewood Dr. Danvers, MA 01923, 978-750-8400 fax 978-646-8700 or visit http://www.copyright.com online. For uses beyond those listed above, please direct your written request to Permission Dept. fax 440-756-5255 or email: [email protected].

Advanstar Communications Inc. provides certain customer contact data (such as customers’ names, addresses, phone numbers, and e-mail addresses) to third parties who wish to promote relevant products, services, and other opportunities that may be of interest to you. If you do not want Advanstar Communications Inc. to make your contact information available to third parties for marketing purposes, simply call toll-free 866-529-2922 between the hours of 7:30 a.m. and 5 p.m. CST and a customer service representative will assist you in removing your name from Advanstar’s lists. Outside the U.S., please phone 218-740-6477.

BioPharm International does not verify any claims or other information appearing in any of the advertisements contained in the publication, and cannot take responsibility for any losses or other damages incurred by readers in reliance of such content.

BioPharm International welcomes unsolicited articles, manuscripts, photographs, illustrations, and other materials but cannot be held responsible for their safekeeping or return.

To subscribe, call toll-free 888-527-7008. Outside the U.S. call 218-740-6477.

EDITORIAL ADVISORY BOARDBioPharm International’s Editorial Advisory Board comprises distinguished specialists involved in the biologic manufacture of therapeutic drugs, diagnostics, and vaccines. Members serve as a sounding board for the editors and advise them on biotechnology trends, identify potential authors, and review manuscripts submitted for publication.

K. A. Ajit-Simh President, Shiba Associates

Rory Budihandojo Director, Quality and EHS Audit

Boehringer-Ingelheim

Edward G. Calamai Managing Partner

Pharmaceutical Manufacturing

and Compliance Associates, LLC

Suggy S. Chrai President and CEO

The Chrai Associates

Leonard J. Goren Global Leader, Human Identity

Division, GE Healthcare

Uwe Gottschalk Vice-President,

Purification Technologies

Sartorius Stedim Biotech GmbH

Fiona M. Greer Global Director,

BioPharma Services Development

SGS Life Science Services

Rajesh K. Gupta Vaccinnologist and Microbiologist

Jean F. Huxsoll Senior Director, Quality

Product Supply Biotech

Bayer Healthcare Pharmaceuticals

Denny Kraichely Associate Director

Johnson & Johnson

Stephan O. Krause Principal Scientist, Analytical

Biochemistry, MedImmune, Inc.

Steven S. Kuwahara Principal Consultant

GXP BioTechnology LLC

Eric S. Langer President and Managing Partner

BioPlan Associates, Inc.

Howard L. Levine President

BioProcess Technology Consultants

Herb Lutz Principal Consulting Engineer

EMD Millipore Corporation

Jerold Martin Sr. VP, Global Scientific Affairs,

Biopharmaceuticals

Pall Life Sciences

Hans-Peter Meyer VP, Special Projects Biotechnology

Lonza, Ltd.

K. John Morrow President, Newport Biotech

David Radspinner Global Head of Sales—Bioproduction

Thermo Fisher Scientific

Tom Ransohoff Vice-President and Senior Consultant

BioProcess Technology Consultants

Anurag Rathore Biotech CMC Consultant

Faculty Member, Indian Institute of

Technology

Susan J. Schniepp Vice-President

Quality and Regulatory Affairs

Allergy Laboratories, Inc

Tim Schofield Managing Director

Arlenda, USA

Paula Shadle Principal Consultant,

Shadle Consulting

Alexander F. Sito President,

BioValidation

Michiel E. Ultee Chief Scientific Officer

Laureate BioPharmaceutical Services, Inc.

Thomas J. Vanden Boom Vice-President, Global Biologics R&D

Hospira, Inc.

Krish Venkat CSO

AnVen Research

Steven Walfish Principal Statistician

BD

Gary Walsh Professor

Department of Chemical and

Environmental Sciences and Materials

and Surface Science Institute

University of Limerick, Ireland

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4 BioPharm International www.biopharminternational.com May 2014

Contents

BioPharmINTERNATIONAL

BioPharm International integrates the science and business of

biopharmaceutical research, development, and manufacturing. We provide practical,

peer-reviewed technical solutions to enable biopharmaceutical professionals

to perform their jobs more effectively.

COLUMNS AND DEPARTMENTS

BioPharm International ISSN 1542-166X (print); ISSN 1939-1862 (digital) is published monthly by Advanstar Communications, Inc., 131 W. First Street, Duluth, MN 55802-2065. Subscription rates: $76 for one year in the United States and Possessions; $103 for one year in Canada and Mexico; all other countries $146 for one year. Single copies (prepaid only): $8 in the United States; $10 all other countries. Back issues, if available: $21 in the United States, $26 all other countries. Add $6.75 per order for shipping and handling. Periodicals postage paid at Duluth, MN 55806, and additional mailing offices. Postmaster Please send address changes to BioPharm International, PO Box 6128, Duluth, MN 55806-6128, USA. PUBLICATIONS MAIL AGREEMENT NO. 40612608, Return Undeliverable Canadian Addresses to: IMEX Global Solutions, P. O. Box 25542, London, ON N6C 6B2, CANADA. Canadian GST number: R-124213133RT001. Printed in U.S.A.

BioPharm International is selectively abstracted or indexed in: • Biological Sciences Database (Cambridge Scientif c Abstracts) • Biotechnology and Bioengineering Database (Cambridge Scientif c Abstracts) • Biotechnology Citation Index (ISI/Thomson Scientif c) • Chemical Abstracts (CAS) • Science Citation Index Expanded (ISI/Thomson Scientif c) • Web of Science (ISI/Thomson Scientif c)

ON THE WEBwww.biopharminternational.com

EmErging OutsOurcing

trEnds in BiOpharma

May 2014

BioPharmINTERNATIONAL

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The Science & Business of Biopharmaceuticals

eBook Supplement

Cover: blackred/E+/Getty Images

Social Media

Follow us on Twitter@BioPharmIntl

Join our BioPharmInternational Group

BioPharm BulletinSubscribe to the one industry newsletter focused on the development and manufacturing of biotech drugs and vaccines. Catch up on regulatory actions, new technologies, industry deals & more.

biopharminternational.com/subscribe

Outsourcing eBook Be sure to check out BioPharm

International’s Outsourcing Strategies eBook for articles on patent translations, technology transfer, outsourcing trends, R&D, and more.

6 From the Editor Changes are needed to maintain US biopharma innovation leadership.Rita Peters

8 US Regulatory Beat New formulations and expanded vaccine production are encouraged.Jill Wechsler

12 Insider Solutions Industry players offer suggestions for quality metrics.Susan J. Schniepp

14 Perspectives on Outsourcing The CMO industry’s value proposition is limiting its market penetration.Jim Miller

16 The Disposables Advisor Progress is being made in the development of harmonized best practices for single-use systems. Jerold Martin

40 Analytical Best Practices Characterization of stability performance provides a clear, statistically defendable method for determining accelerated stability. Thomas A. Little

44 New Technology Showcase

44 Ad Index

46 The Word

VACCINE DEVELOPMENT

Novel Vaccine Technologies Meet the Need for Pandemic and Therapeutic SolutionsCynthia A. Challener

New approaches to vaccine production

are targeting rapid supply for pandemic

situations and therapeutic treatments. 20

EXPRESSION SYSTEMS

Improving Protein Expression with Novel SystemsCynthia A. Challener

New human and plant-based expressions

systems can enable faster product

development and improve quality at

potentially lower costs. 26

PEER-REVIEWED

Regulatory Requirements for Viral-Challenge Studies: Influenza Case StudyBruno Speder

This article provides an overview of viral-

challenge studies in drug development. 30

EMERGING MARKETS

India’s Developing Market Offers OpportunitiesJill E. Sackman and Michael Kuchenreuther

Biopharma companies should not

overlook India’s growing market. 36

Volume 27 Number 5 May 2014

FEATURES


©2014 Waters Corporation. Waters and The Science of What’s Possible are registered trademarks of Waters Corporation.

Pharmaceutical | Health Sciences | Food & Environmental | Chemical Materials

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From the Editor

Changes are

needed to maintain

US biopharma

innovation

leadership.

Biopharma Takes a Nervous Glance Over Its Shoulder

The US biopharmaceutical industry’s status as the global leader in inno-

vative biopharmaceutical R&D is not guaranteed. Both R&D and

manufacturing could shrink or shift to other countries if the business

operating environment for the biopharmaceutical industry in the nation

does not improve. This prediction is the focus of a new report, The U.S.

Biopharmaceutical Industry: Perspectives on Future Growth and The Factors That

Will Drive It, published by Battelle and the Pharmaceutical Research and

Manufacturers Association or PhRMA. The conclusions were based on industry

statistics and input from senior-level executives at companies that represent 75%

of US biopharmaceutical sales.

Leading threats to US dominance are the increasing capability of emerging

economies to meet rising manufacturing demand for new medicines to treat

their own growing middle class populations and a global race to attract research

and development investment. Therefore, the nation “must assess its policies

relative to other countries to ensure that the nation’s ability to compete is not

impeded,” the report says.

The report identified 10 attributes necessary to “advancing a more favorable

business operating environment” in the United States. These factors include a

competitive corporate tax rate; private funding of R&D in early stage and emerg-

ing companies; robust government investment in basic R&D; a strong R&D and

science, technology, engineering, and mathematics workforce; favorable trade

policy environment for US biopharmaceutical products; a robust manufacturing

workforce; and competitive state-level incentives for innovation. Three other

factors were noted as most crucial to bolstering US competitiveness.

Coverage and payment policies that value innovative medicines.

According to the study findings, executives feel that US payers increasingly

are not adequately valuing new treatments and are too focused on reducing

prescription drug costs. This short-term approach creates uncertainty about

reimbursement and can make drug development companies more risk-adverse.

Strong, science-based regulatory system. FDA has long been viewed

as the gold standard for a science-based regulatory system. However, the report

says, the number and complexity of regulatory requirements has increased,

and executives are concerned that the US regulatory process may soon be less

favorable than that of other countries.

Robust intellectual property (IP) rights and enforcement in the

US and abroad. The executives expressed concern about patent challenges

occurring earlier and more frequently, and with efforts by policymakers to

reduce the favorability of IP rights in the US.

If the current “negative trends increasing business uncertainty” continue, the

report says, the US industry can expect 19% growth in domestic biopharmaceu-

tical R&D activities and a 21% increase in domestic biopharmaceutical manu-

facturing activities over the next decade. However, efficiencies in productivity

could result in a decrease of 4.5% in employment, translating to more than

140,000 total jobs lost across the US economy over the next decade.

However, if “reasonable” improvements are made to the US business operat-

ing environment, a 36% increase in US biopharmaceutical R&D activities, a 31%

increase in US biopharmaceutical manufacturing output, and a 5.4% increase

in employment, or a gain of 180,000 total jobs across the economy, could occur

over the next decade. However, the executives projected that this scenario has a

less than 20% chance of taking place within the current business environment.

The report spells out sobering projections and daunting challenges for the US

biopharmaceutical industry. However, if the industry wants to be the leader in

innovation, it needs to find business, as well as technological solutions. ◆

Rita Peters is the editorial director of

BioPharm International.


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Regulatory Beat

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Vaccine development is on a roll, boosted

by biomedical research uncovering new

molecular targets for preventives and

treatments, as well as innovative techniques

for enhancing vaccine potency and production.

There is high demand for new vaccines to pre-

vent deadly tropical diseases, illustrated by the

recent Ebola virus outbreak, and for capacity to

respond quickly to global pandemics and bioter-

rorist attacks at home and abroad. More manu-

facturers seek to devise new versions of vaccines

for pneumococcal disease, meningitis, and more

potent influenza preventives, encouraged by

positive coverage and reimbursement decisions.

At the same time, early optimism about devel-

oping vaccines to prevent and treat HIV/AIDS

has diminished, along with hopes for prompt

discovery of a vaccine against drug-resistant

tuberculosis. There has been progress in research

on therapeutic vaccines for cancer, but so far

these are highly targeted and expensive. The

ability of manufacturers to produce high-qual-

ity, safe and effective vaccines to meet public

health needs remains crucial to building public

confidence in vaccination schedules that have

expanded with the approval of more

effective products.

Boosting capacityMeanwhile, frequent vaccine shortages

point to the need for more extensive

and reliable manufacturing operations.

David Swerdlow, associate director

for science of the National Center for

Immunization and Respiratory Disease

at the Centers for Disease Control and

Surveillance (CDC), emphasized the

need to increase United States vaccine

manufacturing capability at Terrapin’s

World Vaccine Congress in Washington,

D.C. in March. Swerdlow noted grow-

ing concerns about the MERS outbreak in Saudi

Arabia and the Near East, and the potential for this

and other deadly diseases to travel to Europe and

elsewhere.

Jesse Goodman, former chief scientist at FDA

and now forming the Center on Medical Product

Access, Safety and Stewardship (COMPASS) at the

Georgetown University Medical Center, com-

mented on the importance of vaccine supply

chain security in assuring global access to treat-

ment. He acknowledged considerable progress

in establishing a more reliable influenza vaccine

supply, noting advances in dual-use capacity and

in developing cell-based products. Goodman also

cited numerous challenges. Current flu vaccines

have limited effectiveness, and health authorities

have difficulty each year predicting which sea-

sonal flu strains pose the most risk. Vaccine pro-

duction capacity is limited, he added, and supply

shortfalls occur all too frequently.

The Biomedical Advanced Research and

Development Authority (BARDA) in the

Department of Health and Human Services (HHS)

is responding with funds to support flexible man-

ufacturing capacity that uses disposable technol-

ogy to enhance US capability for fast scale-up of

vaccines and treatments during a pandemic or

health emergency. Such facilities also can pro-

vide support for biotech firms developing new

Demand for New Vaccines Spurs InnovationNew formulations and expanded vaccine production are encouraged.

Jill Wechsler is BioPharm

International’s Washington editor,

chevy chase, MD, 301.656.4634,

[email protected].

Read Jill’s blogs at

pharmtech.com/wechsler.

BaRDa has awarded more

than $400 million to establish

three centers for innovation

in advanced Development

and Manufacturing.


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Regulatory BeatRegulatory Beat

vaccines and medical countermea-

sures. BARDA has awarded more

than $400 million to establish three

Centers for Innovation in Advanced

Development and Manufacturing

(CIADMs): Emergent Manufacturing

is forming a biologics develop-

ment and manufacturing suite in

Baltimore; Novartis Vaccines and

Diagnostics is expanding its cell-

based vaccine production facility in

North Carolina with a pilot plant

to produce clinical lots of medical

countermeasures; and Texas A&M

University is establishing several

development and manufacturing

facilities. Each organization also is

partnering with other biopharma

companies and research entities to

develop new pandemic influenza

vaccine candidates.

BARDA also is forming a Fill

Finish Manufacturing Network

with $40 million awarded to Cook

Pharmica (Bloomington, Ind.), DMS

Pharmaceuticals (Greenville, NC),

JHP Pharmaceuticals (Parsippany,

NJ), and Nanotherapeutics (Alachua,

FL). The network will be capable of

packaging 117 million doses of flu

vaccine in 12 weeks and will sup-

port the CIADMs in building capac-

ity for four-month production of 150

million doses of pandemic flu vac-

cine. The CIADMs will produce test

countermeasures for clinical trials

and provide commercial capacity to

help remedy shortages in vaccines

and biologics. A recent report on

the program by the Government

Accountability Office (1) notes that

the value of this investment will

begin to emerge as BARDA issues

task orders this year to test the qual-

ity of CIADM core services and their

success in spurring development of

new therapies and vaccines.

MoRe aDJuvantsAnother prominent strategy for

expanding the nation’s vaccine sup-

ply is to develop adjuvanted prod-

ucts that require less antigen for

comparable or expanded immune

response. FDA is working with

manufacturers to facilitate licen-

sure of such products, noted Marion

Gruber, director of the Office of

Vaccine Research and Review in

FDA’s Center for Biologics Evaluation

and Research (CBER), at the Vaccine

Congress. Such formulations may

boost immune response in elderly

and other special populations;

achieve immunity with fewer doses;

and reduce booster shots needed to

extend immune response. While a

number of adjuvanted vaccines have

been approved in Europe, Gruber

reported that FDA “finally” has done

the same with the licensing of two

adjuvanted products in the US.

Gruber explained that FDA has

no special pathway for approving

adjuvanted vaccines, as adjuvants

are not active ingredients, but con-

sidered “constituent materials” to a

vaccine formulation. The adjuvanted

vaccine must be pure and of high

quality, and it must demonstrate

that the added ingredient does not

reduce vaccine safety and potency.

Manufacturers have to establish

consistent production processes and

provide a rationale for using an adju-

vant, usually based on studies that

compare a vaccine with and without

the adjuvant to see what advantage is

created. While FDA does not require

an adjuvanted vaccine to demon-

strate added benefit, such data may

be requested if safety concerns

emerge or if the manufacturer plans

to make comparative claims for the

reformulated product.

FDA is willing to infer effective-

ness of an adjuvanted vaccine from

the immune response induced in

populations in clinical trials and

then confirm clinical benefit in

post-marketing studies, as is usual

for seasonal influenza vaccines.

The agency wants to see 12 months

follow-up to be sure to detect fur-

ther adverse effects, but empha-

sizes that there’s no one-size-fits-all

approach to developing and testing

these products.

supply chain iMpRoveMentsManufacturing innovation also

can address many of the chal-

lenges in distributing vaccines to

patients in third-world regions.

While efforts continue to develop

thermostable vaccines and medi-

cal products, Raja Rao, senior pro-

gram officer at the Bill & Melinda

Gates Foundation, noted at the

Vaccine Congress that interest is

growing in additional strategies.

He discussed the need to miti-

gate the dangers of vaccine freez-

ing under current distribution

systems, which can greatly reduce

potency, as well as identification

of products that don’t need refrig-

eration if delivered to clinics in 30

or 60 days. Gates is looking more

at improving supply-chain equip-

ment and at devising more effi-

cient vaccine delivery networks

as less costly approaches than a

“moon shot” investment in ther-

mostability, Rao observed.

Many of these initiatives are

outlined in the March 2014 HHS

National Vaccine Plan, which cites

efforts by BARDA and other gov-

ernment agencies to ensure stable

supply and public access in the US

to recommended vaccines (2). One

innovation is the SMART vaccines

program that uses software and

other tools to help set priorities for

developing and testing new vaccine

targets. The report also describes

federal programs for developing

new vaccine production technolo-

gies, including use of a silk-based

stabilizer to enhance vaccine stabil-

ity in hot climates, and new vaccine

delivery methods that conserve anti-

gen and may be important during

emergencies.

RefeRences 1. GAO-14-329 (March 2014), www.gao.

gov. 2. HHS, The State of the National Vaccine

Plan–2013, Department of Health and

Human Services, www.hhs.gov/nvpo/

vacc_plan/annual-report-2013/nvp-2013.

html, accessed Apr. 8, 2014. ◆


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Insider Solutions

12

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There are two topics in today’s pharmaceuti-

cal landscape commanding the attention of

both the industry and the regulators: drug

shortages and quality metrics. It is increasingly

difficult to discuss one of these topics without

discussing the other. Establishing, maintaining,

and interpreting quality metrics to measure the

suitability of pharmaceutical products and the

capability of the manufacturer to provide these

products consistently and without delay has

become a high priority for the industry and FDA.

Preventing drug shortagesThe first piece of this puzzle emerged in

2012 when Congress passed the Food Drug

Administration Safety and Innovation Act

(FDASIA) enhancing FDA’s capability to proac-

tively react to, prevent, and alleviate drug short-

ages. This direction is codified in the language

contained in Title VII—Drug Supply Chain and

Title X—Drug Shortages. Specifically, Title VII

Section 705 of the Act states FDA “shall inspect

establishments described in paragraph [1] that

are engaged in the manufacture, preparation,

propagation, compounding, or processing of

a drug or drugs (referred to in this subsection

as ‘drug establishments’) in accordance with

a risk-based schedule established by

the Secretary” (1). Additionally, this

section also describes the risk factors

to be considered in establishing the

inspection schedule. The last risk fac-

tor listed in this section is “Any other

criteria deemed necessary and appro-

priate by the Secretary for purposes

of allocating inspection resources.”

Section 706 of the same act allows

FDA to request certain information

from companies in advance of or in

lieu of inspections by stating “Any

records or other information that the

Secretary may inspect under this section from a

person that owns or operates an establishment

that is engaged in the manufacture, preparation,

propagation, compounding, or processing of a

drug shall, upon the request of the Secretary,

be provided to the Secretary by such person, in

advance of or in lieu of an inspection…”

The next piece of this puzzle is found in Title

X section 506C–1 (Annual Reporting on Drug

Shortages). Title X section 506C–1 requires FDA

to annually provide Congress “a report on drug

shortages…”

The third piece of the puzzle fell into place

in a Feb. 12, 2013 Federal Register Notice. FDA

asked the industry to “assist the Food and Drug

Administration in drafting a strategic plan on

drug shortages as required by the Food and Drug

Administration Safety and Innovation Act…” This

notice asked a series of thought-provoking ques-

tions including “What metrics do manufacturers

currently use to monitor production quality?” and

“How frequently would such metrics need to be

updated to be meaningful?” (2).

The last piece of the puzzle revolves around

the industry reaction to this information. Many

trade organizations responded to the questions in

the Federal Register. Some prepared white papers

while others held meetings to discuss the issue

with their members. The general consensus, and

the easy part from this activity, was that indus-

try needed to actively engage with the agency

in defining suitable quality metrics to provide

information to the agency supporting their efforts

to eliminate drug shortages and determine the

appropriate quality metrics to be used in establish-

ing a risk-based approach to inspections.

Pda ProPoses metricsCompanies currently use a variety of metrics to

measure performance including, but not lim-

ited to, corrective action and preventive action

Linking Drug Shortages and Quality MetricsIndustry players offer suggestions for quality metrics as FDA continues to try and solve the problem of drug shortages.

Susan J. Schniepp

is vice-president of quality

and regulatory affairs at

allergy Laboratories.


May 2014 www.biopharminternational.com BioPharm International 13

insider solutions

(CAPA), out of specification (OOS),

batch rejection rate, complaints, field

alerts, recalls, batch yield, training

effectiveness, and environmental

monitoring excursions. The goal is

to review and define which of these

metrics can be used to measure per-

formance based on product qual-

ity and suitability as opposed to

performance based on compliance

standards. The hard part is trying to

define them so they are not subject

to interpretation: they are simple but

comprehensive and applicable to tra-

ditional, biotech, virtual, contract

manufacturers, drug substance man-

ufacturers, etc. The industry needs

to ensure the metrics chosen pro-

vide meaningful data while avoid-

ing unintended consequences. The

metrics need to be simple so they

do not divert or dilute a company’s

resources from daily activities associ-

ated with producing and delivering

high quality medicines.

So, what might these metrics be?

The Parenteral Drug Association

(PDA) held their Annual Meeting

in San Antonio in April 2014 (3).

During this meeting, there was an

open member session where PDA

proposed seven potential metrics

for consideration. For each metric

proposed, there was a definition to

consider, a calculation, a recommen-

dation on how to report the metric

to FDA, and a discussion of poten-

tial unintended consequences that

might result from the implementa-

tion of the metric. The metrics pro-

posed by PDA were:

• Complaints by product

• Batch reject rate by product

• Batch reject rate by site

• OOS rate by product

• OOS rate by site

• Recalls by product

• Recalls by site.

The PDA recommendations

included some guidelines and prin-

ciples clarifying the reporting of

these metrics. Product metrics were

defined as items with the same for-

mula regardless of their final packag-

ing configuration. Under this model,

drug substance manufacturers would

consider each drug substance batch

as a product batch. Site metrics

would be a compilation of the prod-

uct metrics for the site and would

combine drug-product and drug-sub-

stance metrics for sites that manu-

facturer both. The recommendation

for reporting was to collect the data

monthly and report annually, per-

haps using annual product reviews

or annual report dates to determine

the cycle.

QuaLity cuLtureThe metrics proposed by PDA seem

reasonable but there is a miss-

ing piece to this puzzle. The most

important metric used to deter-

mine a company’s well-being is a

measure of their quality culture.

The culture of a company dic-

tates the veracity of their metrics.

Achieving a quality culture requires

management and employees to

establish an environment where

responsibility, accountability, and

reliability are paramount, and to

understand the role each person

performs in delivering a high-qual-

ity product to the customer and

sustaining that performance on a

continual basis. Management must

educate employees and provide the

tools and environment where they

can perform their functions in an

atmosphere that encourages excel-

lence and continuous improvement.

The trouble with using quality

culture as a metric is determining

how to measure it. An unhealthy

quality culture is easy to identify.

People in a poor culture do not

understand their job and its impor-

tance to the business. They often

appear stressed, and they hide

their mistakes or blame others for

their errors. There is no evidence

of teamwork. People work in silos

and rarely, if ever, seek input or

advice from others. The metrics

that could potentially be used to

measure a poor culture include a

large employee turnover, an over-

abundance of deviations attributed

to human error, and lack of pride

in the performance of their jobs.

In contrast, a robust, healthy qual-

ity culture can be evidenced by

alignment of goals between qual-

ity and operations, self-sustained

work teams that focus on con-

tinual improvement, and employ-

ees who incorporate quality into

their jobs on a daily basis. They

are not afraid to speak up and

offer suggestions for improvement

to their colleagues. People under-

stand the importance of their jobs

and respect each other and their

management. This culture wel-

comes inspections and views these

inspections as another tool to use

in their continual improvement

initiatives.

The establishment of simple qual-

ity metrics that not only measure

the quality of the product but also

reflect the quality culture of an

organization is required to assist

FDA in establishing a risk-based

audit program.

references 1. FDASIA, www.gpo.gov/fdsys/pkg/PLAW-

112publ144/pdf/PLAW-112publ144.pdf

2. FDA, Federal Register, Vol. 78, No. 29 (Feb.

12, 2013) 9928-9929, www.gpo.gov/fdsys/

pkg/FR-2013-02-12/html/2013-03198.htm

3. PDA Annual Meeting, Apr. 7-11, 2014,

Session titled Quality Metrics Update

and Proposed Definitions. ◆

the most

important metric

used to determine

a company’s well-

being is a measure of

their quality culture.



Perspectives on Outsourcing

Do

n F

arr

all/G

ett

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ge

s

The contract manufacturing industry

isn’t gaining market share. Could it

be that the CMO business model is

out of synch with the current realities of the

bio/pharmaceutical industry?

PharmSource recently completed an anal-

ysis of the dose CMO industry’s share of

new FDA approvals (1). Our research found

that of the 90 new drug applications (NDAs)

approved in 2013, 32 (36%) used CMOs for

dose manufacture. This was below the 2004-

2014 10-year average of 43%.

Outsourcing for both new molecular enti-

ties (NMEs) and non-NMEs was below the

long-term average. Among NMEs, 41% were

outsourced, compared to 47% for the 10-year

average. For non-NMEs, just 32% were out-

sourced, well below the 10-year average of 40%.

The share of NDA approvals that are out-

sourced can vary widely from year to year.

The share of NMEs that have been contract

manufactured has ranged from just 37% in

2011 to 59% in 2008. Contract dose manu-

facturing of non-NMEs has ranged from 31%

in 2011 and 2013 to as high as

60% in 2012.

Nevertheless, the data clearly

suggest that contract dose manu-

facturing has largely plateaued in

terms of its share of new product

approvals at the 45% level over a

sustained period. Why can’t the

CMO industry break through to

manufacture a greater share of

drugs?

Rooted in an old RealityContract manufacturing arrange-

ments for products approved

in 2013 were negotiated in the

2008-2010 period. That was the

middle of the global f inancial

crisis, when heightened concerns about risks

of all types may have driven companies to

keep manufacturing in-house where they

could more directly control things. The

2008-2010 period, however, was also the

beginning of a new reality for the bio/phar-

maceutical industry, and it is likely that stag-

nation of contract manufacturing may be

rooted in the inability of CMOs to respond

to that new reality.

The old bio/pharmaceut ica l indust ry

model was characterized by high volume

products and generous annual price increases

that fueled high profit margins and relegated

cost-of-goods and inventory management to

minor considerations. The new bio/pharma-

ceutical business model that has emerged in

the past five years must incorporate smaller

volume products that are expensive to manu-

facture but that face increasing resistance

from the governments and insurance com-

panies that are expected to pay for them.

Further, the industry has become more

global, with bio/pharmaceutical companies

looking beyond their traditional markets to

boost sales in emerging markets.

HigH costs of legacy facilitiesMost CMOs are not positioned to deal effec-

tively with the changing industry realities.

Nearly all CMO manufacturing sites are older

facilities built by global bio/pharmaceutical

companies to fit the old industry business

model. They are expensive to operate thanks

Most cMos are not positioned

to deal effectively with the

changing industry realities.

Stuck in Neutral The CMO industry’s value proposition is limiting its market penetration.

Jim Miller is president of Pharmsource

information services, inc., and

publisher of Bio/Pharmaceutical

Outsourcing Report,

tel. 703.383.4903,

twitter@JimPharmsource,

[email protected],

www.pharmsource.com.



Perspectives on outsourcing

to their large footprints, bulky HVAC systems, and

need for indirect labor to move products and com-

modities from one processing suite to a holding

area to the next processing suite. They require

high unit volumes to spread the fixed costs to

acceptable levels.

Further, most CMOs are not very flexible when

it comes to scheduling production. They insist on

locking down production schedules at least three

months in advance, and don’t have the flexibility

to adjust schedules for a particular client product

in the face of market demand changes. Increasingly,

bio/pharmaceutical companies are trying to pro-

duce to demand rather than to inventory and need

more flexible manufacturing operations.

The traditional CMO proposition offers bio/pharma

companies the opportunity to avoid the capital costs

of building their own facility, and the fixed operating

costs of running a GMP-compliant operation. This

rationale still has currency for smaller companies,

but it doesn’t really hold much sway with global bio/

pharmaceutical companies—and many mid-size com-

panies—that are generating record levels of cash flow.

They are looking for manufacturing operations that

can serve a global supply chain in a flexible and cost-

effective manner.

a new ModelThe fact is that if one were to launch a CMO busi-

ness today, its manufacturing assets would look

nothing like the facilities that CMOs currently

operate. Rather, a CMO built to fit the current bio/

pharmaceutical business model would have the fol-

lowing characteristics:

• Facilities would be purpose-built with much

smaller footprints and more flexible configura-

tions.

• The equipment would be geared to smaller

batch sizes; would incorporate continuous/

multi-step processes like the new equipment

that can blend, granulate, and tablet in a single

unit; would use disposable or dedicated contact

parts; and would be highly automated.

• Sophisticated control and planning systems

would enable short production scheduling and

supply-chain management practices that would

support just-in-time production.

• These smaller, appropriately equipped facilities

would be distributed in a global network that

reflected the places where bio/pharmaceutical

companies are trying to sell product (i.e., in

emerging markets as well as North America and

Western Europe). This would deliver significant

cost savings to bio/pharmaceutical companies

in the form of reduced logistics costs, tariffs,

and other import-related expenses.

It is unlikely that we will see any CMOs mov-

ing toward this model in the foreseeable future.

There will be significant upfront investment costs

in establishing a network of such sites, and most

CMOs currently generate barely enough cash flow

to cover the capital investment needs of their cur-

rent facilities.

However, establishing such a contract manufac-

turing network with a partner, say, one or more

bio/pharmaceutical companies or a national gov-

ernment trying to establish a local bio/pharmaceu-

tical infrastructure, could work. We know that bio/

pharmaceutical companies are looking for manu-

facturing partners in a lot of third-tier markets like

Algeria and Vietnam; we get inquiries about pos-

sible CMOs in such countries regularly.

RefeRence 1. PharmSource, CMO Market Penetration as Evidenced by

Outsourced NDA Approvals, 2014 Edition (PharmSource,

2014). ◆

• Lot traceability

• Type III DMF

• EP

• Passivation

www.eaglestainless.com

Contact sales at

215-957-9333



The Disposables Advisor

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Jerold Martinis Sr. VP Global Scientific

Affairs at Pall Life Sciences,

Port Washington, NY

and Chairman of the Board,

Technology Committee

Bio-Process Systems Alliance,

1.516.801.9086,

[email protected].

Exciting progress is being made in the

development of consensus in best practice

recommendations and standardization

guides for single-use disposable technologies,

facilitating implementation, quality, and safety.

These industry efforts include the Parenteral

Drug Association’s (PDA) forthcoming new

technical report; the BioProcess Systems

Alliance’s (BPSA) new single-use guides; and in

collaboration with the BioPhorum Operators

Group (BPOG) and the American Society for

Mechanical Engineering–BioProcess Equipment

Committee (ASME-BPE), BPSA’s constructive

discussions towards standardizing supplier

extractables test data for single-use components.

NeW PDA SiNGLe-uSe TeChNiCAL RePoRT PDA’s Technical Report on Single-Use System

Manufacturing Strategy is currently pending

for final approval by PDA’s Scientific Advisory

Board (1). This extensive guide, to be pub-

lished by PDA in 2014, provides extensive rec-

ommendations on how to consider and adopt

single-use technologies. These recom-

mendations are written by a broad

panel of industry experts from end-

user and single-use equipment sup-

plier companies, as well as regulators

and consultants. The goal of this doc-

ument is not to be prescriptive, but

rather to provide an understanding of

key principles and concepts for selec-

tion, qualification, validation, and use

of single-use technologies. It should

serve to better enable people at vari-

ous levels in an organization to ask

the right questions and make better

decisions for their individual situa-

tions. Organizations will be able to

draw an effective road map to single-

use implementation that suits them

best, regardless of whether they are small or

large, dedicated or multi-product, or contract

manufacturers.

The draft PDA single-use technical report has

dedicated chapters for key topic areas including

manufacturing strategies for multi-use versus

single-use systems, an overview of the variety

of single-use technologies, and a tutorial on

business drivers influencing selection of multi-

use and single-use systems. Also included are

dedicated sections on qualification of assem-

bled single-use products and implementation of

single-use systems in a manufacturing process.

The authors recognized that each area has a

situation-dependent role in the decision process

and may be weighed differently depending on

the circumstances of the reader’s organization.

The manufacturing strategies section cov-

ers variables including process compatibility,

facility requirements, and operational consid-

erations. The business drivers section covers

capital design, fixed and variable operating

costs, and other factors. The qualification sec-

tion includes recommendations on supplier

qualification; verification of materials, com-

ponents and completed assemblies, including

extractables and leachables issues; risk evalu-

ation (i.e., balancing pro and cons for multi-

use and single-use systems); microbial control

and sterilization; system process validation;

filter integrity and leak testing; installation

Jerold Martin

Standardizing Practices for DisposablesProgress is being made in the development of harmonized best practices for single-use systems.

These efforts will serve

to reduce a barrier to

implementation of

single-use technology.




qualification and acceptance tests;

and supplier audits. The imple-

mentation section introduces

themes of stakeholder manage-

ment, technical feasibility and risk

management, scoping and tech-

nology survey, making the busi-

ness case, and a project execution

plan including user requirements.

Once these are established, rec-

ommendations are provided for

approaches to testing and valida-

tion, process control strategies,

integration considerations (e.g.,

facility, equipment, and opera-

tional deployment), operator train-

ing and safety, supplier agreements,

technical diligence, materials man-

agement, logistics practices, and

waste management.

BPSA SiNGLe-uSe PARTiCuLATeS GuiDeBPSA has also been active in pre-

paring new best-practice guides. A

key topic of discussion at the 2013

BPSA International Single-Use

Summit (ISUS) was the concern for

particles in SUS flow paths, espe-

cially those without inline filtra-

tion, as employed for non-filter

sterilizable vaccines manufactured

under aseptic sterile conditions,

or simply downstream of steril-

izing filters in single-use systems

designed for filling of bulk or final

dosage protein biopharmaceuticals

and vaccines.

To address these concerns and

provide users and system suppli-

ers with best practices to mini-

mize risks of particles from the

systems potent ia l ly reaching

final dosages, BPSA has devel-

oped Recommendations for Control,

Testing and Evaluation of Particulates

in Single-Use Process Equipment (2).

This document, developed jointly

by technical and engineering rep-

resentatives of user and supplier

member companies, contains

major sections on risks of particles,

characterization and sources of

particles in single-use technologies,

chain of responsibility, measure-

ment methods, and visual inspec-

tion (surveillance) programs. Also

included are major sections on rec-

ommended methods for suppliers

to control introduction of particles,

best practices for handling single-

use components to minimize risk

of particulate generation, evalua-

tion of single-use containers and

filling systems for particulates dur-

ing end-user manufacturing, and

recommendations for developing a

particulate deviation response and

mitigation plan.

The BPSA document will be of

interest to vaccine manufacturers

and final filling operators employ-

ing single-use disposable filling

technologies. It will be published

in July 2014 in coordination with

the BPSA International Single-Use

Summit annual meeting. It will

also be made available via the BPSA

website, www.bpsalliance.org.

BPSA SiNGLe-uSe ComPoNeNT QuALiTY TeST RefeReNCe mATRiCeSBPSA’s first best practices guide

for single-use equipment, the

B i oP ro c e s s Sy s t e m s A l l i a n c e

Component Quality Test Matrices,

published in 2007, provided a sup-

plier consensus of standards, regu-

latory guidance documents, and

industry guides applied in the

manufacture of single-use com-

ponents for qualification, valida-

tion, and quality control to ensure

product quality and performance

claims, consistent with require-

ments of the biopharmaceutical

industry (3). The document was

divided into four sections for bio-

containers, tubing, connectors,

and filters.

In the ensuing years, the indus-

try has been well served with this

easy-to-use reference guide to sup-

plier component quality testing. In

the ensuing years, however, many

newcomers to the field have been

unaware of it, some new references

have come to be implemented, and

new components have come into

broader use, that were not con-

sidered in the original document,

namely single-use (or campaign)

chromatography modules and sin-

gle-use sensors for bioreactors and

other systems.

T he ne w l y up d at e d a nd

e x p a n d e d B P S A S i n g l e - U s e

Manufacturing Component Quality

Test Matrices will be published in

July 2014 in coordination with

the BPSA International Single-Use

Summit annual meeting (4). It will

be made available via the BPSA

website, www.bpsalliance.org.

BPSA SiNGLe-uSe eQuiPmeNT QuALiTY AGReemeNT TemPLATeBPSA has recognized a need

among end-users and suppliers

for a common template for qual-

ity agreements. End-users have

been challenged to herd a vari-

ety of single-use component and

system suppliers to agree to com-

mon requirements, or to manag-

ing different agreements among

multiple suppliers. Likewise, sup-

pliers engage in quality agreement

discussions with end-users, many

of whom have disparate sets of

requests and requirements. This

challenges suppliers to manage

differing requirements and agree-

ments among multiple customers,

and often, instead, acts as a barrier

to the establishment of effective

quality agreements.

T h e f o r t h c o m i n g B P S A

Consensus Qualit y Ag reement

Template for Single-Use Bio/pharma-

ceutical Manufacturing Products is

intended to provide a common

structure for quality agreements

between suppliers and end-users

of single-use products (5). The

template is not intended to substi-

tute for close dialog and negotia-

tion between the two parties, but

rather, it will hopefully serve to

facilitate that discussion by provid-

ing a common structure to follow.

The template’s content will better




enable end-users to communicate

specific expectations and for sup-

pliers to communicate the attri-

butes of their quality system and

operating procedures, more read-

ily providing the content for the

final quality agreement between

the two parties.

As a template, the document

does not proscribe all activities

and specify provisions. These

s t i l l have to be negot iated

between the parties to establish

an effective agreement. There are

areas where the template is left

intentionally blank for the sup-

plier and end-user co-authors to

propose, negotiate, and either

discard, change, or complete to

establish a final agreement. The

template should support the pro-

cess, however, and facilitate the

establishment of quality agree-

ments to build the partnership

and transparency needed for suc-

cessful implementation of single-

use technologies. As with the BPSA

Particulates Recommendations and

Component Quality Test Reference

Mat r i c e s , t he BP SA Q ua l it y

Agreement Template will also be

published in July 2014 in coordi-

nation with the BPSA ISUS annual

meeting and it also will be made

available from the BPSA website,

www.bpsalliance.org.

PRoGReSS ToWARDS exTRACTABLeS STANDARDizATioNEarly in 2013, the extractables

committee of the BioPhorum

Operators Group (BPOG), a con-

sortium of end-user companies,

released a proposal for standard-

ized extractables testing and anal-

ysis it would like to see provided

by single-use component sup-

pliers (6). While suppliers recog-

nized the benefit to end-users of

standardized component extract-

ables data packages, especially in

terms of extraction sample size,

solvents, and conditions, extrac-

t ion temperatures and t imes,

analytical methods and data pre-

sentation, there was also objec-

tion by suppliers to some of the

test requirements and rationales,

and the overall extent of testing

proposed, which would demand

extensive resources and time com-

mitments. Supplier responses were

consolidated by BPSA, and after

meeting with BPOG representa-

tives at the July 2013 BPSA ISUS

meeting, negotiation between

the two groups began in Autumn

2013 to harmonize a consensus

proposal that could be submitted

to a standards body such as ASTM.

Negotiations have proceeded over

the winter, and much has been

agreed to, especially in regard to

many of the extraction conditions

and analytic methods. At time of

this writing, it is hoped that a doc-

ument that recognizes both the

interests of end users (and regula-

tors) and the resources of suppliers

can be brought to consensus by

the July 2014 BPSA ISUS meeting.

Other organizations are also

looking at developing extract-

ables test ing standards. The

United States Pha r macopeia

(USP) has proposed a new section

to its standards Chapter <661>

on Plastic Containers currently

under revision. A sub-chapter

<661.3>, Plastic Systems Used for

Manufacturing Pharmaceutical

Products (differentiated from Sub-

chapter 661.2 on Plastic Packaging

Systems for Pharmaceutical Use),

is currently on hold pending draft

revisions of subchapters 661.1 and

661.2, along with evaluation of

an ultimate BPOG/BPSA consen-

sus proposal (7). Independently,

A SM E -BPE has approved an

expansion of their Bioprocess

Equipment Standard Part PM,

Polymeric and Other Nonmetallic

Mater ials, sect ion PM 3.2 on

Ext rac tables and Leachables,

which will be published at the

end of this year (8). The ASME-

BPE Standard Extractables and

Leachables section 3.2 covers

key concepts and includes a non-

mandatory appendix suggest-

ing possible extraction solvents.

These general recommendations

are useful in principle, but do

not achieve the degree of sup-

plier extractables data standard-

ization proposed by the BPOG

Extractables Committee. There

will be more to come in this area,

but real progress toward the stan-

dardization of supplier extract-

ables data packages desired by

end-users is being made. These

efforts will ultimately serve to

reduce a perceived barrier to fur-

ther implementation of single-use

technology.

RefeReNCeS 1. PDA, Technical Report on Single-use

System Manufacturing Strategy

(DRAFT), publication pending Spring/

Summer 2014, www.pda.org/

Publications_1/PDA-Publications/

Technical-Reports.aspx, accessed Apr.

4, 2014.

2. BPSA, Recommendations for Control,

Testing and Evaluation of Particulates in

Single-Use Process Equipment (DRAFT),

publication pending Summer 2014,

www.bpsalliance.org, , accessed Apr.

4, 2014.

3. BPSA, Bioprocess System Alliance

Component Quality Test Matrices,

BioProcess International, April-May

2007, www.bpsalliance.org/assets/

files/BPSAMATRICES_BPI-Reprint-

Final.pdf, accessed Apr. 4, 2014.

4. BPSA, Single-use Manufacturing

Component Quality Test Matrices

(DRAFT), publication pending Summer

2014, www.bpsallance.org, accessed

Apr. 4, 2014.

5. BPSA, Consensus Quality Agreement

Template for Single-Use Bio/

pharmaceutical Manufacturing

Products (DRAFT), publication pending

Summer 2014, www.bpsallance.org,

accessed Apr. 4, 2014.

6. Wong, K., “Extractable Protocol

Standardisation Efforts for Disposable

Systems from BPOG Working Group,”

Biopharma Asia, Jan. 27th, 2014.

7. USP, Chapter <661> “Plastic

Packaging Systems And Their

Materials of Construction” (DRAFT),

Pharmacopeial Forum, 39(5), Sept.–

Oct. 2013

8. ASME, Bioprocess Equipment Standard

Part PM, Polymeric and Other Nonmetallic

Materials, section PM 3.2 on

Extractables and Leachables (DRAFT),

publication pending Fall 2014. ◆


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Following the 2009 outbreak of

the H1N1 pandemic flu and the

numerous delays in producing

vaccines against the virus, the

US Department of Health and Human

Services (HHS) recognized the need to

invest in new vaccine technologies that

can ensure national preparedness for a

pandemic influenza or other diseases.

Many other countries are focused on

developing similar capabilities. There is

also a significant requirement for ther-

apeutic vaccines to treat existing and

prevent further chronic viral infections.

As a result, there is an urgent need to

develop alternative vaccine production

methods that can either generate large

quantities of vaccines in a much shorter

time and/or produce more broadly effec-

tive vaccines than is possible using tradi-

tional egg-based technology. Examples

include cell-culture, synthetic DNA, chi-

meric antigen, and recombinant protein

nanoparticle vaccine technologies.

Egg-vaccinE tEchnology limitationsTraditional vaccine manufacture begins

with a “seed” virus identified and pro-

vided by the Centers for Disease Control

and Prevention. This virus is introduced

into fertilized chicken eggs. It then

reproduces and builds up in the white

novel vaccine technologies meet the need for Pandemic

and therapeutic solutionsCynthia A. Challener

New approaches

to vaccine production

are targeting rapid supply

for pandemic situations

and broadly effective

therapeutic treatments.

Cynthia A. Challener is a contributing

editor to BioPharm International.

vaccine Development



(allantoic fluid) of the egg, which is

collected and purified. It takes two

eggs to generate enough vaccine for

one dose, and thus large numbers of

eggs must be produced in advance,

which is always a challenge. The

limited availability of eggs prevents

the rapid production of vaccines,

which is a major concern in a pan-

demic situation. In fact, it takes

many months to organize egg sup-

plies, incubate the virus, and obtain

produced vaccine that can be deliv-

ered, according to Novartis.

Another difficulty with this

approach is the fact the seed virus

is not always accurately replicated,

and as a result, the virus in the

vaccine may not be the same as

the infective strain, which thus

prov ides reduced immunit y.

Extensive DNA and protein analy-

sis is required to help avoid this

problem, and further testing is

conducted to ensure that no patho-

gens from the eggs are transferred

to the vaccine. All of this testing

extends the production time and

increases the manufacturing cost.

cEll-culturE tEchnology Cell-culture technology enables the

use of raw materials that are read-

ily available and not threatened by

pandemic events, as well as closed-

system bioreactors that reduce the

required biosafety level for the man-

ufacturing space. In addition, it is

possible to provide rapid response

to potential pandemic influenza

threats while fulfilling the need for

seasonal influenza vaccines, accord-

ing to Novartis. The company

received the 2013 Facility of the Year

Award issued by the International

Soc ie t y for Pha r maceut ica l

Engineering (ISPE) for its flu cell-cul-

ture technology, which it has imple-

mented at a new facility in Holly

Springs, North Carolina.

In cell-based flu culture, immor-

talized canine kidney cells are typi-

cally employed; these cells can be

stored in advance until needed and

then rapidly amplified, enabling

the production of large quantities

of vaccine in a much shorter period

of time than is possible using fertil-

ized eggs. Cell-culture technology

also enables more robust virus pro-

duction, and therefore, the virus in

the vaccine is more consistent and

more closely resembles the seed

strain, which leads to increased effi-

cacy. In addition, the size of the bio-

reactors required to produce large

numbers of doses is much smaller

than the space required to produce a

similar number of doses using eggs.

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Furthermore, the use of bioreactors

ensures a closed, sterile, controlled

environment, and thus the risk of

potential impurities is reduced. As

a result, Novartis’ Flucelvax vaccine

does not contain any preservatives,

such as thimerosal, or any antibiot-

ics. Finally, unlike vaccines produced

in fertilized eggs, cell-culture-derived

vaccines can be administered to

patients who are allergic to eggs.

Development of Novartis’ tech-

nology and construction of the

plant were funded in part by the

HHS Office of the Assistant Secretary

for Preparedness and Response and

the Biomedical Advanced Research

and Development Authority. The

Holly Springs facility has the capa-

bility to produce seasonal flu cell-

culture vaccine, pre-pandemic

vaccine, and 150 million doses

of pandemic vaccine within six

months of an influenza pandemic

declaration, according to Novartis.

A fill-finish set up for the produc-

tion of both flu and non-flu prod-

ucts has also been installed in the

facility. The company received FDA

approval for Flucelvax, the first cell-

culture vaccine in the US designed

to protect against seasonal influenza

in individuals 18 years of age and

older, in November 2012 and made

its first shipments in August 2013.

synthEtic Dna vaccinEs One of the biggest drawbacks of tra-

ditional vaccines is that for diseases

that change rapidly and evolve into

many different strains, the genetic

makeup of the antigen introduced

to the body by the vaccine may be

different than what it encounters in

an actual pathogen in the future,

according to J. Joseph Kim, president

and CEO of Inovio Pharmaceuticals.

“Since the immune system isn’t look-

ing for the mutated version of the

antigen, it may not be able to prevent

or fight an infection,” he explains.

To address this problem, Inovio

has developed synthetic DNA vac-

cines based on the genetic codes

of viruses. “We can consciously

manipulate and engineer protein

sequences that are flexible and can

recognize multiple viruses in a par-

ticular subfamily, which provides

more comprehensive protection

and is a more universal approach

to the development of influenza

and other vaccines,” Kim states.

The synthetic DNA is encoded

with instructions that enable cells

in the body to produce only the tar-

geted antigen relating to the patho-

gen or cancer of interest and cannot

replicate or cause the disease. “This

approach results in the body creating

an immunogen capable of induc-

ing strong, multi-faceted immune

responses similar to actual patho-

gens,” Kim observes. As a result, the

vaccines generate very strong T-cell

immune responses, and particularly

T-cells that are able to kill the tar-

geted infected or diseased cells.

In animal models and early clin-

ical studies, Inovio has shown that

its H1N1 vaccine provides protec-

tion against all strains of the H1N1

virus identified over the last 90

years (since the 1918 Spanish Flu).

“We believe the synthetic DNA

vaccines are a paradigm-changing

technology,” says Kim.

There are other advantages to the

technology. The synthetic DNA vac-

cines are produced in pure water

and do not contain any live virus,

parts of a virus, adjuvants, or preser-

vatives and are thermostable (i.e., no

cold-chain requirements). The DNA

plasmids are manufactured using

conventional fermentation technol-

ogy (i.e., no eggs) that is scalable, is

engineered for maximum expres-

sion in the host cells, and can be

rapidly produced in large quantities

in a pandemic situation. Delivery is

achieved through injection followed

by in vivo electroporation, which

involves application of a brief low-

voltage electric field (three pulses

of 0.05 s) that causes the cell mem-

brane to open and allow entry of

the DNA plasmid.

In addition to its H1N1 vaccine,

Inovio has a therapeutic vaccine

for cervical cancer in Phase II tri-

als. It currently has a partnership

with vaccine manufacturing com-

pany VGXI for clinical trial quanti-

ties, and will be selecting a contract

manufacturer for the production of

Phase III and commercial quanti-

ties later in 2014. Inovio is also par-

ticipating in a National Institutes

of Health malaria vaccine initia-

tive focused on the development of

novel technologies and is develop-

ing new candidate DNA vaccines

for various cancers and other dis-

eases, particularly prostate cancer

and hepatitis B, which are being

pursued in conjunction with Roche.

mimicking natural antigEn PrEsEntation PathwaysThe Chimigen vaccine technology

developed by Akshaya Bio is based

on chimeric antigens that bind to

specific receptors on antigen-pre-

senting cells, particularly dendritic

cells (Fcγ and Lectin receptors), and

mimic natural human antigen pre-

sentation pathways to generate anti-

gen-specific, balanced, cellular (for

clearing virus-infected and cancer

cells) and humoral (antibody-medi-

ated) immune responses, accord-

ing to president and CSO Rajan

George. As a result, the vaccines

generate broad immune responses,

“re-educate the immune system,”

and “break tolerance” to chronic,

infections and cancer. “Because a

Chimigen vaccine has the char-

acteristics of both an antigen and

antibody in a single entity (i.e., it

is a fusion protein), the technology

is versatile and highly adaptable to

disease-specific multiple molecu-

lar antigens and can be used to

develop both prophylactic vaccines

and immunotherapeutic agents,”

he notes. The level of each type of

response depends on the type of

antigens used in the vaccine.

George adds that the incorpora-

tion of a xenotypic antibody frag-

vaccine Development




vaccine Development

ment makes the entire molecule

“foreign” and thus more immuno-

genic. Production of the vaccines in

insect cells is also beneficial, because

they impart non-mammalian gly-

cosylation, thus increasing the

immunogenicity and enabling the

vaccines to be effective at low doses,

according to George. Furthermore,

adjuvant-related adverse reactions

are not an issue with this technol-

ogy, and cellular responses are pro-

moted because no adjuvants are

used in the vaccine formulations.

The major technical challenge

that Akshaya Bio is currently tack-

ling relates to the production of the

vaccine. “In heterologous protein

production, the quantity of protein

produced depends on the type of

antigen (intracellular/extracellular)

and the size of the protein molecule,”

George explains. To date the com-

pany has been able to produce ~5-7

mg/L for vaccines with a size of ~75

kilodaltons (KDa) to ~3-5 mg/L for

vaccines with a size large than ~250

KDa. Due to the high immunogenic-

ity of Chimigen vaccines, however,

George notes that the lower produc-

tion levels are still economical.

The company’s lead candidate is

a therapeutic vaccine for the treat-

ment of chronic hepatitis B virus

(HBV) infections, for which there

is currently no effective treatment.

The Chimigen HBV vaccine is in

late pre-clinical development, hav-

ing achieved ex vivo proof of concept

and is ready for out-licensing to a

pharmaceutical/biotech partner for

clinical development, according to

George. The vaccine also has prophy-

lactic application in non-respond-

ers to currently available vaccines.

Akshaya also has a Chimigen vac-

cine for hepatitis C virus (HCV), for

which there are some newer treat-

ments that are effective, but a vac-

cine is desirable for preventing new

infections. The Chimigen HCV vac-

cine is ready for clinical development

and Akshaya is looking for partner-

ship opportunities.

Additional earlier-stage pipeline

products include products for vari-

ous cancers, influenza, malaria,

and HIV. The HIV vaccine, which

is being tested in animals to eval-

uate immune responses, is being

developed with support f rom

a Government of Canada/Bill &

Melinda Gates Foundation part-

nership and the National Resource

C ou nc i l C a nad a I ndu s t r i a l

Research Assistance Program. The

Chimigen malaria vaccine was

initially developed using a Grand

Challenge Exploration award from

the Gates Foundation.

“The short-term goal is to estab-

lish proof of concept in humans

for at least one of the Chimigen

vaccines. In the long-term, we

look forward to Akshaya’s products

helping to alleviate suffering due

to infectious diseases and cancer,”

George remarks.

FlExibility anD sPEEDNovavax’s recombinant protein

nanoparticle vaccine technol-

ogy combines the flexibility and

speed of genetic engineering with

the efficiency of single-use dispos-

able technology to produce highly

immunogenic nanoparticle vaccines,

according to the company, which

is developing vaccines against viral,

bacterial, and parasitic diseases.

With the Novavax technology,

the genetic code of a virus of inter-

est can be used to produce, within a

few weeks, a vaccine candidate that

is designed to generate protective

immunity for that specific virus.

Two different types of immuno-

genic particles are used: virus-like

particles (VLPs) and recombinant

protein micelles. Novavax’ seasonal

and pandemic influenza vaccines

consist of VLPs or recombinant

particles with matrix proteins that

provide a structure onto which

the surface proteins hemaggluti-

nin and neuraminidase are incor-

porated. “VLP constructs resemble

the virus they are designed to pro-

tect against; however, because they

do not contain any RNA, they are

not infectious, and thus are gener-

ally highly immunogenic,” states

Novavax’s vice-president of Vaccine

Development, Gale Smith.

The recombinant protein micelles

are generally composed of a single

target protein, engineered to assem-

ble into stable nanoparticles that

elicit an immunogenic response

like the virus itself. For example,

Novavax’s Respiratory Syncytial

Virus (RSV) vaccine candidate is

composed of recombinant micelles

engineered as modified full-length

fusion (F) proteins with the poten-

tial to induce protection against all

strains of RSV, according to Smith.

The vaccine nanoparticles are

produced in Sf9 fall army worm

(Spodoptera frugiperda) ovary cells,

which grow in perpetuity in spe-

cial culture media. The cells produce

recombinant proteins when infected

with an insect virus (Baculovirus or

BV) engineered to carry the foreign

gene or genes of interest. “The Sf9/

BV genetic engineering technology

is now well established in the bio-

pharmaceutical industry, and has for

example been used for the produc-

tion of a licensed human papilloma

virus vaccine and a recently licensed

influenza subunit vaccine,” Smith

observes. In addition, Sf9/BV effi-

ciently expresses large antigens and

particles with proper folding, which

promote superior immunogenicity

and better functional immunity.

Smith also notes that the adoption

of single-use manufacturing tech-

nology accelerates process validation

and analytical testing for Novavax’s

vaccines and may allow for ultimate

regulatory approval of the compa-

ny’s vaccines derived from a com-

mon platform.

Novavax has also produced new

vaccine candidates for the preven-

tion of SARS and the newly emerged

MERS-CoV virus, malaria, rabies,

and other diseases where new or

improved vaccines are needed. ◆


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filtration sensorsautomated systems



Henrik

Jo

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on/E

+/G

ett

y Im

ag

es

Expression Systems

Biopharmaceuticals are gen-

e r a l l y m a nu f a c t u r e d i n

established cel l l ines that

are dominated by mamma-

lian cells, particularly those based on

Chinese hamster ovary (CHO) cells, but

that also include E. coli (bacterial) and

S. cerevisiae (yeast) cells. While these

traditional cell lines are productive,

their development can be slow and

costly, and animal-derived systems pro-

vide non-human glycosylation patterns.

Despite these difficulties, these tradi-

tional expression systems are gener-

ally used because they are approved

by FDA, they are familiar, and there

are established downstream purifica-

tion processes for removing contami-

nants. Alternative expression systems,

on the other hand, are being designed

to avoid the performance issues associ-

ated with traditional cell lines. They

offer biopharmaceutical manufacturers

the chance to establish a stronger intel-

lectual property position and improve

their processes. New animal (including

human), yeast, and plant-based expres-

sion systems have been shown to be

effective for the production of biologics.

Human cEllS idEal for ExprESSing Human protEinSHuman ce l l s present the proper

background to express human pro-

teins. They can add the correct post-

translational modifications to these

proteins, according to Nicole Faust,

senior v ice -president of develop-

ment a nd se r v ices w it h CEV EC

Pharmaceuticals. “Having the correct

posttranslational modifications is of

particular importance when express-

improving protein Expression with novel Systems

Cynthia A. Challener

New human and plant-

based expressions systems can

enable faster product

development and improve

quality at potentially

lower costs.

Cynthia A. Challener is a contributing

editor to BioPharm International.



Expression Systems

i ng comple x g lycoprote i n s ;

human cells only add modifica-

tions normally found in humans,

while with rodent cells, foreign

structures can be added to the

proteins that are potent ia l ly

immunogenic in humans, such

as N-glycolylneuraminic acid,”

she explains.

The use of human cells is also

advantageous because any poten-

t ia l host-cel l proteins (HCPs)

present in the final preparation

of the therapeutic protein will

be of human origin and there-

fore present a far lower immuno-

genic risk than host-cell proteins

derived from nonhuman cells.

Such an immune response to

contaminating HCPs has been

observed with rhFIX produced

by CHO cells, according to Faust.

“Some human host-cell expres-

sion systems can also be used

to propagate a variety of differ-

ent human-pathogenic viruses,

which extends the versatility of

the expression host from recom-

binant proteins per se to relevant

vaccines and viruses,” she adds.

plant-baSEd ExprESSion offErS SpEEd and SimplicityWith plant-based expressions

systems, such as the transient

express ion system in whole

green plants (Nicot iana ben-

thamiana) from iBio, there is no

requirement to identify, amplify,

and adapt high-expressing cell

clones to large-scale culture, sav-

ing a year to 18 months in prod-

uct development time, according

to Terence E. Ryan, iBio’s senior

vice-president and chief scien-

tific officer. With iBio’s system,

production of protein can take

place within 21 days of knowing

a gene sequence, and this speed

has attracted a lot of attention

in the area of vaccine antigen

production for pandemic dis-

eases, particularly for influenza,

according to Ryan.

The process is also simple, with

plant biomass grown over five

weeks prior to vector infiltration.

The plants are grown in hydro-

ponic medium in a soil-free sub-

strate under controlled conditions.

Once the plants reach an appropri-

ate size, the vectors are introduced

by vacuum, delivering the vectors

to all of the leaf cells at the same

time. Once gene expression reaches

its peak, the plants are ground and

homogenized, allowing the desired

protein to be purified by standard

chromatography. “No bioreactors

or staff skilled in aseptic cell cul-

ture are required, and thus this

technology is highly attractive in

areas of the world where capital

and a highly skilled biopharma-

ceutical work force are in short

supply,” Ryan says. In addition,

he notes that because the process

is virtually the same regardless of

the product (only the purification

chromatography varies signifi-

cantly), a single factory design can

support multiple products, allow-

ing for “campaign-style” produc-

tion in one site.

The speed and flexibility offers

tremendous advantages, particu-

larly at the early stages of devel-

opment, by al lowing product

optimization and product risk

mitigation in much less time and

at much lower cost, according to

Gene Garrard Olinger, a principal

science advisor with MRIGlobal.

He adds that in comparison with

CHO, plant systems, specifically

the rapid antibody manufactur-

ing platform (RAMP) developed

by Icon Genetics and Kentucky

BioProcessing, of fer the abi l-

ity to control specific glycosyl-

ation patterns on the protein (1).

“For antibodies, this specificity

in glycosylation yields products

with superior antibody-depen-

dent, cell-mediated cytotoxicity

(ADCC) profiles,” he observes.

Ultimately, Olinger believes that

with scale, the method should

offer a significant cost advantage

compared to cell-culture-based

production.

mEaningful SciEntific advantagESPlant-based expression systems are

also valuable because plants are

capable of producing just about

every type of biopharmaceutical

product, including vaccine anti-

gens, enzymes, replacement pro-

teins, monoclonal antibodies,

and others, according to Ryan. In

addition, because no animal prod-

ucts are used in iBio’s technology,

there is no risk of contamination

by animal viruses or other adven-

titious agents.

Meanwhile, the human amnio-

cy te CAP cel ls developed by

CEVEC, which are not derived

f rom cancer cel ls or abor ted

embryos, are designed to eff i-

ciently produce complex proteins

and glycoproteins at commercial

scale, and therefore high prod-

uct titers can be obtained even

for difficult-to-express proteins,

according to Faust. “We have

found that in some cases, CAP

cells have yielded 5- to 10-fold

more protein than CHO cells. In

addition, less or no proteolytic

degradation of sensitive proteins

was observed with the CAP sys-

tem,” Faust observes. She adds

that the cells are robust and easy

to handle, and unlike traditional

expression systems, the product

quality is unaffected by small

variations in the upstream process,

Human cells

present the proper

background to express

human proteins.



Expression Systems

making production runs highly

reproducible. CEVEC has also

developed a highly efficient tran-

sient protein expression platform

(CAP-T cells) that is based on CAP

cells and produces proteins with

nearly identical post-translational

modifications. “As a result, the

transition from transient protein

production in CAP-T cells at early

project stages to stable production

in CAP cells at later stages is very

easy,” Faust says.

furtHEr advancES and dEmonStration of utilityGoing forward, Faust believes that

an increasing number of genet-

ically engineered cell lines that

have a bias towards certain post-

translational modifications will be

developed. She also expects fur-

ther improvements in expression

levels of CEVEC’s human expres-

sion systems through optimiza-

tion of vectors, the use of cells

with altered metabolisms, and fur-

ther improvements in chemically

defined media.

With respect to plant-based

e x p r e s s io n s y s t e m s , L a r r y

Z e it l i n , pre s ident of Mapp

Biopharmaceutical, expects rapid

increases in yield to be realized.

Zeit l in is hopeful that exist-

ing facilities such as the one at

Kentucky BioProcessing, which can

produce 10 kg of GMP protein per

year, will be expanded to produce

100s of kg/year. “We also hope

that the reduced capital costs to

build plant manufacturing facili-

ties will enable local production

in developing nations to address

their unique public health needs,”

he says. Olinger adds that there is

advancing work in tobacco with

vaccines that use production of

protein subunits to fully-formed,

virus-like particles (VLPs), and he

anticipates that with FDA approval

of elelyso, which is derived from

a carrot-based expression system,

more plant-derived pharmaceuti-

cals will be commercialized over

the short and long term.

Efforts at iBio are directed at

demonstrating the utility of its

expression systems in new bio-

therapeutic classes, which often

requires the coexpression of heter-

ologous proteins within the same

cell to provide helper functions

or enzymatic cleavages not nor-

mally accomplished by plant cells.

“Many interesting biotherapeutics

are naturally expressed as ‘pre-

pro’ proteins whose active form is

produced as a result of post-trans-

lational cleavage or other activa-

tion,” he explains. iBio’s long-term

focus is on the recapitulation of

the complete human glycosylation

machinery so that plant proteins

are identical at the glycoform level

to human products, according to

Ryan.

collaborating to advancE novEl ExprESSion tEcHnologiESOne area that iBio is particularly

proud of is the use of its technol-

ogy to develop a next-generation

yellow fever vaccine in partner-

ship with the Fraunhofer Center

for Molecular Biotechnology, the

Oswaldo Cruz Institute (Fio-Cruz),

and Bio-Maguinhos, with the latter

two entities from Brazil, accord-

ing to Ryan. “Bio-Maguinhos is

the largest manufacturer of yellow

fever vaccines in the world, and

the perceived safety advantages

of a recombinant subunit vaccine

over the current (but 70-year old)

live attenuated virus vaccine has

spurred the development of the

new vaccine,” he notes. In fact, the

design for a manufacturing facility

in northeastern Brazil capable of

processing 1000 kg of plant mate-

rial per week is in the second of

three planning stages under spon-

sorship by the Brazilian govern-

ment. “Through this project, we

have received major endorsement

of our technology and been able to

demonstrate how quickly it can be

recognized, adapted, and brought

into manufacture,” Ryan concludes.

iBio is also collaborating with

Caliber Biotherapeutics (College

Station, TX) to establish a turn-

key plant-based biopharmaceutical

development capability, from the

earliest stage of product selection

and optimization through large-

scale production.

For CEVEC, the growing mar-

ket for complex, glycosylated mol-

ecules is reflected in the increasing

number of worldwide licensees

using its CAP technology, accord-

ing to Faust. In addition to several

top pharmaceutical customers, the

company recently signed a licens-

ing deal with Yuhan Pharma, one

of the larger Korean drug manu-

facturers. A clinical Phase I study

with CAP cell-derived human

alkaline phosphatase was success-

fully completed in Q4 of 2013 in

the Netherlands, and several cus-

tomer molecules are nearing clin-

ical trials. CEVEC also achieved

two major milestones by showing

excellent viral yields for influenza

and RSV in addition to licensing

its CAP cell line for the exclusive

production of a cytomegalovirus

vaccine based on dense bodies.

rEfErEncE 1. Zeitlin et al. PNAS 108 (51),

18030–18035 (2011). ◆

plant-based

expression systems are

capable of producing

just about every type

of biopharmaceutical

product.


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In v i r u s c ha l le nge s t ud ie s ,

healthy volunteers are admin-

istered a pathogenic or virulent

strain of virus. Such strains can

be attenuated viruses that produce a

much milder set of symptoms com-

pared to the naturally occurring or

fully active virus. If the volunteers

are administered an investigational

drug (e.g., antiviral, vaccine, immu-

nomodulatory drug) besides inocula-

tion with the virus, the studies are

called viral-challenge studies.

In a historical context, the con-

cept of challenge studies is not new.

The experiments conducted by Louis

Pasteur in the 19th century, where

chickens were challenged with a

weakened bacteria causing chicken

cholera and immunized from fur-

ther chicken cholera infection, can

be seen as a type of challenge study.

In the early 20th century, scientists

used a self-challenge approach when

developing vaccines and drugs

Vira l inoculat ion studies have

been per for med in the United

K ingdom since 1946 when the

Medical Research Counci l estab -

lished the Common Cold Unit (CCU)

(also known as the Common Cold

Research Unit [CCRU]) at Salisbury,

Wiltshire (1, 2). The aim was to

undertake laboratory and epidemio-

logical research on common colds

in view of reducing human and eco-

nomic costs. Common colds account

for a third of all acute respiratory

infections and the economic costs

are substantial in terms of days off

work. The volunteers were infected

with preparations of corona- and rhi-

ABSTRACTViral-challenge studies are used as proof-of-concept trials after initial activity assessments and Phase I human pharmacokinetic and tolerability studies. In virus inoculation studies, healthy volunteers are inoculated with established challenge strains of a virus and administered an investigational drug (e.g., antiviral, vaccine, or immunomodulatory drug) either before or after inoculation with the challenge strain. Challenge strains are attenuated viruses that produce a much milder set of symptoms compared to the naturally occurring virus. Challenge studies can provide useful exposure-response and safety information as well as the opportunity to demonstrate pharmacological activity in humans under controlled conditions. Data from challenge studies contribute to dose selection for Phase IIb and Phase III studies, and provide the opportunity to explore the effects of different times of drug initiation relative to virus exposure. Challenge studies can, therefore, be used to assess a first efficacy. This article provides an overview of the use of viral-challenge studies in drug development and the regulatory requirements for this type of study.

regulatory requirements for Viral-challenge studies:

influenza case studyBruno Speder

Bruno Speder is head of

clinical regulatory affairs,

clinical research,

sgs life science services,

[email protected].

PEER-REVIEWEDarticle submitted: Jan. 14, 2014.

article accepted: feb. 27, 2014.

Ph

oto

Cre

dit: S

CIE

PR

O/G

ett

y I

ma

ge

sPeer-reviewed: Viral-challenge studies



noviruses and were housed in small groups

of two or three, with each group strictly

isolated from the others during the course

of the stay. In 1989, the CCU closed down

after failing to find a cure.

In current clinical research practice, the

use of viral-challenge studies as proof-of-

concept (POC) studies is gaining wider

acceptance. Healthy volunteers are inocu-

lated with a challenge strain of a virus,

usually influenza, and administered a vac-

cine or antiviral before or after the inocu-

lation. Although viral inoculation studies

can be performed with a wide range of

viruses, this article will focus on respira-

tory viruses and influenza in particular.

Viral-challenge studiesThe vaccine or antiviral first goes through

a complete non-cl inical development

program to assess its safety and efficacy.

Afterwards, it goes through a full Phase I,

first-in-man, pharmacokinetic (PK) and tol-

erability study.

The inf luenza virus is isolated by a

combined nasal/throat swab from an ill

patient. An aliquot of this clinical sample

is then used to inoculate specific pathogen-

free eggs (SPF), which are grown through

sequential passages. Another option is to

grow the virus through a cellbank. The

virus is then manufactured under GMP

standards and ensured that it is free of

adventitial agents and other pathogens. A

non-clinical program with the virus is then

initiated (see Figure 1).

To establish the correct viral dose for the

viral-challenge POC study, in which the

vaccine or antiviral drug will be admin-

istered, a dose-finding study in humans

must f irst be conducted. The virus is

administered to the study subjects using

intranasal drops. The viral dose to be

selected for the viral-challenge POC stud-

ies is the dose at which 80% of the inocu-

lated volunteers show clinical symptoms.

After the phase I study with the vaccine or

antiviral and the viral-inoculation dose-

finding study, sufficient information is

available to start the POC studies.

Two possible study designs are used for

the POC studies—treatment and prophy-

laxis. In treatment studies, the volunteers

are screened and randomized. They are

first inoculated with the challenge strain

and after a given incubation period, the

investigational vaccine/antiviral or pla-

cebo treatment will be initiated (either to

both symptomatic/asymptomatic or to

symptomatic volunteers alone). Patients are

quarantined during the study if indicated,

depending on the type of inoculum (3–5).

In prophylactic studies, the volunteers

are screened and randomized. They first

receive the investigational vaccine/anti-

viral, or placebo treatment, followed by

inoculation with the challenge strain.

Patients are quarantined during the study

if indicated, depending on the type of

inoculum. Depending on the indication,

study considerations, and objectives, one

of the two designs, or a combination of

both, may apply.

Pharmacodynamic (PD) endpoints in

challenge studies usually include mea-

surements, such as clinical respiratory AL

L F

IGU

RE

S A

RE

CO

UR

TE

SY

OF

TH

E A

UT

HO

RPeer-reviewed: Viral-challenge studies

Figure 1: Development fow of virus and vaccine or antiviral up to viral-challenge

proof-of-concept study.

Isolation andGMP

manufacturingvirus

GMPmanufacturing

of vaccine/antiviral

Non-clinicaltestingvaccine/antiviral

Vaccine/antiviralfrst-in-human

study

Non-clinical testing virus

Dose-fnding viral-inoculation study

Proof-of-conceptstudy

vaccine/antiviral +virus

Further developmentvaccine/antiviral



symptoms, nasal discharge weight, and

quantitative measurements of viral shed-

ding, and/or cytokines in nasal washes.

Challenge studies can provide useful

exposure-response and safety informa-

tion and the opportunity to demonstrate

pharmacological activity in humans under

controlled conditions. Data from chal-

lenge studies contribute to dose selection

for Phase IIb and Phase III studies, and

provide the opportunity to explore the

effects of different times of drug initiation

relative to virus exposure. Challenge stud-

ies can be used to assess a first efficacy.

required quality information on the VirusThe influenza virus to be used first needs

to be isolated from a patient showing clini-

cal signs of infection with the virus. The

virus is usually isolated by nasal/throat

swab. Given that virulence decreases with

age, the virus is usually isolated from

young patients. The reduced risk of co-

infection and a better-defined medical his-

tory also make young patients the preferred

host to isolate the virus from. In addition

to evaluating acute respiratory illnesses of

the patient and his family members, infor-

mation on current and past medical history,

travel history, and social history should

be systematically recorded. The sample

should be tested by reverse transcription-

polymerase chain reaction (RT-PCR) for the

presence of the desired virus.

To avoid co-infection of the sample, the

sample needs to be screened for the pres-

ence of other viruses. In the case of iso-

lation of an influenza virus, the sample

should also be tested by PCR for human

rhinovirus, respiratory syncytial virus

(RSV), parainfluenza virus types 1, 2, and

3, human metapneumovirus, and adeno-

virus, and the results should be negative.

Plasma samples from the patient should

also be negative for human T-cell leu-

kemia virus 1 and 2, human immuno-

deficiency virus type 1 or 2 (HIV-1 or

HIV-2), HIV ribonucleic acid (RNA), hepa-

titis B surface antigen (HBsAg), hepatitis B

deoxyribonucleic acid (DNA), anti-hepati-

tis C virus (HCV) antibody, HCV RNA and

Hepatitis A virus. The patient, from whom

the influenza virus has been isolated, will

be followed to assess that he remains in

good health.

An aliquot of this clinical sample will

then be used to inoculate SPF eggs that are

then grown through sequential passages

or using mammalian cells. The number

of passages will depend on the required

infectious virus titre for preclinical (i.e.,

ferret model) and human testing. The

virus should be manufactured according

to GMP requirements.

non-clinical testingNon-clinical testing of a virus requires

both in-vit ro and in-vivo pharmacology

studies. In-vitro pharmacology in cellular-

based assays includes in-vitro infectivity,

antigen characterization, and susceptibil-

ity to antiviral agents.

The in-vivo non-clinical testing is usu-

ally performed in ferrets. Ferret models

(Mustela putorius furo) have been estab-

lished for numerous viruses that cause

respiratory infections, including human

and avian influenza viruses, coronavirus,

nipah virus, and morbillivirus among oth-

ers. Ferrets are an appropriate mamma-

lian model for these studies because they

show numerous clinical features associ-

ated with human disease, such as fever,

lethargy, and sneezing. In addition, sick

ferrets have the ability to infect healthy

ferrets. Ferrets and humans share similar

lung physiology, and human and avian

influenza viruses exhibit similar patterns

of binding to sialic acids (i.e., the receptor

for influenza viruses), which are distrib-

uted throughout the respiratory tract in

both species. Furthermore, their small size

eases the logistic burden (6–9).

During the in-vivo pharmacology stud-

ies, infect iv ity and safety are tested.

Temperature and body weight changes,

clinical observations (e.g., sneezing), and

infectious viral load are monitored. Safety

pharmacology studies are not needed

and no formal toxicology is needed if the

profile of the virus corresponds with the

characteristics described in the literature.

No reproduction toxicology studies are

needed if appropriate contraceptive mea-

sures (i.e., double barrier method: chemi-

cal and physical contraception) are used in

the clinical studies.

Peer-reviewed: Viral-challenge studies



The non-clinical testing of the vaccine

or antiviral to be used in the viral-inocula-

tion study should be performed according

to standard non-clinical testing require-

ments descr ibed in the Internat ional

Conference on Harmonization (ICH) of

Technical Requirements for Registration of

Pharmaceuticals for Human Use (10–12).

regulatory requirements for studiesThe regulatory requirements for viral-chal-

lenge studies in humans can be divided in

two parts, the requirements for the studies

and the requirements for the infrastruc-

ture (Phase I units) where these studies

are performed. In general, given that the

concept is rather new, very little guidance

exists around this type of viral-challenge/

inoculation studies. There is no guidance

on this subject provided by the European

Medicines Agency (EMA) or any national

European authority. An FDA guideline on

the development of influenza drugs briefly

mentions this type of study (13).

In the viral dose-finding study, healthy

volunteers are inoculated with a virus to

establish the dose for the POC study. The

dose-finding study is usually an open-label

study in which several cohorts of volun-

teers receive an ascending dose of the virus

until the optimal dose is found. The opti-

mal dose is the dose that has the appropri-

ate safety and illness/infectivity profile to

be used as an influenza virus challenge

strain in future challenge studies. For each

strain, only one dose-finding study needs

to be done. The strain (in the optimal dose)

can then be used in multiple challenge

studies.

Whether or not this study can be con-

sidered a clinical study in the strict sense

remains a question for discussion. Because

the objectives of the stand-alone experi-

ment are not in line with the definition of

a clinical study as described in Directive

2001/20/EC article 2 (a) (14), the classifica-

tion as a clinical study can be challenged,

and the study is not considered a clinical

study as per Directive 2001/20/EC.

Viral-challenge studies, in this case,

would be regarded as an “experiment,”

which will only require approval from

the ethics committee and not from health

authorities. Such studies, however, should

be approached with care because although

the European directive does not consider

viral-challenge studies to be a clinical

study, national legislations may not agree

and may consider them as clinical studies.

Furthermore, there is the risk that the

dose-finding study may have to be repeated

if performed without health-authority

approval, especially if the chemistry, man-

ufacturing, and controls (CMC) data of the

virus are considered insufficient by the

health authority at the time of submission

of the POC study. It is, therefore, highly

recommended that dose-finding studies are

considered as clinical studies.

The POC study (in which the virus and a

vaccine or antiviral is administered) will in

any case be considered as a clinical study

according to Directive 2001/20/EC. The

virus, however, does not need to be consid-

ered an investigational medicinal product

(IMP) because it does not match the defini-

tion of an IMP given in Directive 2001/20/

EC, Article 2 (d) (14) and the Guidance

on Investigational Medicinal Products

(IMPs) and Non Investigational Medicinal

Products (NIMPs)(15).

If an inoculating virus is used to evalu-

ate the efficacy of an investigational prod-

uct, the inoculating virus is classified as

a “condition” and not as an “intervention”

(i.e., the disease or the health issue worth

studying in a clinical study according to

FDA classification at ClinicalTrials.gov) (16).

According to Eudralex Volume 10, guidance

on IMPs and NIMPs, revision 1, March

2011 (15), the inoculating virus could be

classified as NIMP in the European Union.

In this case, the inoculating virus is a

“challenge agent.” A challenge agent by

definition is usually given to study subjects

to produce a physiological response that

is necessary before the pharmacological

action of the IMP can be assessed. A chal-

lenge agent may be a substance without

marketing authorization, but could have a

long tradition of clinical use.

Informat ion regard ing the qua l it y

of the inoculating virus should be pro-

vided in the non-investigational medici-

nal product dossier (NIMPD). There is no

standard format available for presenting

the information regarding an inoculating

virus; however, guidelines on the require-




ments for quality documentation concern-

ing biological investigational medicinal

products in clinical studies, EMA/CHMP/

BWP/534898/2008 (17), could be used as a

reference.

The quality information regarding an

inoculating virus can be presented in

the sections 2.1.S, 2.1.P, and 2.1.A of the

NIMPD (18), similar to the quality docu-

mentation requirement for IMPs (14). It is

not necessary to provide extensive infor-

mation, similar to a biological drug used

for marketing authorization. The NIMPD

should mainly focus on the quality attri-

butes related to safety aspects, considering

the state of development or clinical phase.

Appropriate GMP requirements should be

applied (19–21).

The quality part of the NIMPD should

include information related to the qual-

ity, manufacture, and control of the NIMP.

It is preferable to present data in tabular

form accompanied by a brief narrative

highlighting the main points. The infor-

mation that should be provided include

virus isolation, manufacturing process,

control of materials, including master cell

bank and working cell bank systems, con-

trol of inoculating virus (i.e., quantity,

identity, and purity), analysis, and stabil-

ity, among others. In section 2.1.A.2 of

the NIMPD (adventitious agents safety

evaluation) (22), information assessing

the risk with respect to potential adven-

titious agents and other human patho-

gens contaminations should be provided

(guideline on virus safety, EMEA/CHMP/

BWP/398498/05) (23).

Another important issue is the regu-

latory and operat ional aspect of run-

ning the viral-challenge study itself. It is

extremely important to avoid cross-con-

tamination between the patients infected

with the virus on one side and the study

staff on the other side. Furthermore, a

back-up plan to treat a patient with an

antiviral agent or other drugs should he

or she become too ill after the challenge

should be available. This issue is equally

true for the virus dose-finding study as

for the challenge study together with the

vaccine. The aim is to avoid the virus from

being spread to the “outside world” and

to avoid infected study staff to infect the

patients and jeopardize the study results

by infecting placebo patients.

Patients will need to be isolated in a

specif ica l ly designed quarantine unit

and will be treated according to the prin-

ciple of “reversed-barrier nursing.” This

method is comparable to barrier nursing

used in an intensive care unit (ICU) set-

ting, where the aim is to keep pathogens

away from the ICU patients by creating a

barrier between the outside world and the

inside of a patient room by using gloves,

masks, gowns, and disinfectants. With

reversed-barrier nursing the aim is to keep

the challenging agents confined in the

facility using the same principles.

conclusionRecently, v iral-challenge studies have

become widely accepted as POC studies

to demonstrate the efficacy of antiviral

and vaccine therapeutics for RSV, influ-

enza, and other common cold viruses.

The regulatory framework for this type of

studies has not been fully developed. The

exact regulatory requirements for viral-

challenge studies need to be discussed

with the health authorities of the country

where the study will be performed.

Due to their nature, v iral-challenge

studies can only be performed in spe-

c ia l ized cl inica l pharmacolog y units.

Conducting these studies in a controlled

qua ra nt ine env i ron ment a l lows for

a superior study design, which is more

cost-effective. This approach crit ically

accelerates the selection of a safe and

effective dose and dosing regimen for a

new antiviral drug or vaccine because it

allows for early detection of efficacy. It,

therefore, lowers the risk of a negative out-

come when performing a large field-based

Phase III study.

Viral-challenge studies are performed

under tightly controlled circumstances,

and such studies do not seem appropriate

to replace large field-based trials in “real-

life” circumstances. In this respect, the

use of viral-challenge studies in the frame-

work of vaccine or antiviral drug develop-

ment needs to be discussed further with

regulatory authorities.


Continued on page 39


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Ab

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/Gett

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es

Emerging Markets

Recognizing that emerging mar-

kets continue to play a signifi-

cant role in terms of future

growth, most major pharmaceu-

tical companies have accelerated efforts

to strengthen their presence within these

markets through R&D investment, licens-

ing deals, acquisitions, or other part-

nerships. However, with global markets

facing dynamic demographic and disease

trends, changing market demands, and

evolving regulatory requirements, it has

been hard for manufacturers to devise the

strategies needed for success in each of

these areas.

India, a member of the BRIC nations

(Brazil, Russia, India, and China), is

much more comparable to the United

States in terms of market size and must

be included in this list of promising

potential markets for global pharmaceu-

tical manufacturers. Recent changes in

India’s population and economy have

contributed to a shift in the country’s

epidemiological profile towards ‘life-

style’ diseases that are more prevalent

in Western markets. Such changes have

increased the demand for better health-

care and for medications that address

chronic diseases. Furthermore, India’s

own pharmaceutical industry, a recog-

nized world leader in the production

of generic drugs, offers manufacturing

expertise to organizations looking to

outsource or create networks of collabo-

ration and discovery. However, a more

granular assessment of India’s pharma-

ceutical market reveals growing concerns

over patent protection, price capping,

quality, and safety. Understanding this

India’s Developing Market Offers Opportunities

Jill E. Sackman andMichael Kuchenreuther

Biopharma companies should not

overlook India’s growing

market.

Jill E. Sackman, DVM, PhD, is a

senior consultant at Numerof &

Associates, Inc. (NAI), St. Louis, MO,

www.nai-consulting.com. Michael

Kuchenreuther, PhD, is a research

analyst at Numerof & Associates, Inc.



Emerging Markets

country’s complex market dynam-

ics will be crucial for manufactur-

ers exploring new opportunities for

growth in India.

INDIA HEALtH AND PHArMAcEutIcAL MArkEt OvErvIEwIndia is the second most populous

country in the world with about

1.27 billion people, and is pro-

jected to surpass China by 2028

(1). As the Indian population has

continued to grow in recent years,

so too has the country’s economy.

Over the past decade, India’s econ-

omy grew above the Organization

for Economic Co-operation and

Development (OECD) average,

which can be attributed to rising

average income levels, an expand-

ing middle class, and a drive

toward urbanization (2). These

socio-economic changes are con-

tributing to a significant shift in

India’s epidemiological profile.

With working-age adults account-

ing for the majority of the over-

all population and more people

becoming affluent and living lon-

ger, Indian health service users are

facing increasing challenges associ-

ated with the prevention and treat-

ment of chronic diseases such as

obesity, heart disease, stroke, can-

cer, and diabetes (3).

At the same time, India contin-

ues to be challenged by a range

of infectious disorders. Despite

economic advancements, signifi-

cant income inequality still exists

throughout the country. In fact,

per capita gross national income

in India was only $3391 in 2012

when adjusted by purchasing

power parity (compared to $50,000

in US) (4). In rural areas, where

two-thirds of the nation’s citizens

are located, hundreds of millions

of people are still living in severe

poverty, and vaccination coverage

for children remains poor.

Taken together, this high inci-

dence of infectious and chronic

disease and the large number of

disadvantaged communities have

created an even greater need for

patient access to quality health-

care delivery as well as new and

innovative therapeutic products.

Historically, India has had one of

the world’s lowest levels of health

spending as a proportion of gross

domestic product (GDP). In 2011,

India’s total health expenditure

was 3.9% of GDP (public expendi-

ture was only 1.2% of GDP) com-

pared to 10.1% of GDP, an average

across all G-5 countries (4). The

lack of government funding in

healthcare has led to significant

gaps in the quality and availability

of public facilities and has pushed

an increasing proportion of Indian

patients to use private healthcare

facilities that are associated with

high costs. Where other countries

have a well-established insurance

sector that seeks to reduce this eco-

nomic burden, health insurance in

India is still in its infancy.

Approximately 243 million peo-

ple are covered by different forms

of government-sponsored insur-

ance schemes while approximately

55 million rely on commercial

insurers (5). With the vast majority

of people in India uninsured, out-

of-pocket payments are among the

highest in the world. According

to the World Health Organization

(WHO), 70% of Indians are spend-

ing their entire out-of-pocket

income on medicines and health-

care services (6). On top of this,

most insurance plans only provide

coverage for inpatient healthcare

services and do not include cov-

erage for outpatient treatments,

including prescription medicines.

Thus, it is no surprise that approxi-

mately 90% of India’s pharmaceu-

tical market is currently made up

of branded generic drugs (7).

Against this backdrop, India’s

Ministry of Health has been

focused on improving access to

healthcare facilities, increasing

population coverage by way of

healthcare insurance, and creating

initiatives for the prevention and

early stage management of chronic

diseases. In 2012, as part of the

country’s 12th Five-Year Plan, the

government proposed to double

its public expenditure on health-

care to 2-3% of GDP in an effort

to boost local access and afford-

ability to quality healthcare. In

light of these efforts, the Indian

healthcare industry as a whole is

expected to reach $158 billion by

2017 (8).

India’s pharmaceutical mar-

ket accounts for about 10% of the

global pharmaceutical industry in

terms of volume and represents a

major component of growth for the

country’s healthcare industry (9).

The Indian pharmaceutical mar-

ket was estimated at $18.4 billion

in 2012 and is expected to almost

double by 2016. Although India’s

market is currently dominated

by generic drugs, rising incomes,

enhanced medical infrastructure,

and insurance coverage could

provide a valuable opportunity

for manufacturers’ higher-priced

branded healthcare products mov-

ing forward.

kEy MArkEt cHALLENgES AND cONSIDErAtIONS

Regulatory

Similar to many other countries,

India’s medical regulatory struc-

ture is divided between national

and state authorities. The Drug

Cont rol le r Genera l of Ind ia

(DCGI) is the national authority

responsible for the regulation of

pharmaceuticals. The DCGI reg-

isters all imported drugs, new

drugs, and biologicals in selected

categories and has responsibility

for approving clinical trials and

quality standards in the country.

Recently, these standards have

come under question by FDA,

citing quality-control problems



Emerging Markets

ranging from data manipulation

to sanitation. While FDA and

regulatory bodies in other coun-

tries step up inspections of Indian

plants in response to these devel-

opments, global manufacturers

have had to reassess their con-

tracted relations with these plants

and give careful consideration to

developing new strategic partner-

ships in this country moving for-

ward (10).

Concerns over quality and data

integrity have also impacted man-

ufacturers’ perception of India’s

clinical trials system. India’s large

and diverse patient pool and low

drug trial costs have made the

country an attractive destination

for multinational pharmaceutical

clinical trials. However, India has

recently seen the number of clini-

cal trials fall dramatically among

allegations that protocols were not

being conducted properly and that

companies were taking advan-

tage of disadvantaged patients

(11). In response to these develop-

ments, manufacturers have been

forced to either shift their trials

to another country or encounter

significant delays in clinical trial

approval—both of which are hold-

ing their organizations back.

Market Access and Pricing

The high prevalence of self-pay

generic drugs throughout the

country has created little incen-

tive for the development of cer-

tain market access disciplines such

as health economics and outcome

research (HEOR) and reimburse-

ment. Government affairs and

pricing functions, on the other

hand, play an important role

and have been broadly cited as

the most crucial challenges global

manufacturers face in the Indian

marketplace.

India’s National Pharmaceutical

Pricing Authority (NPPA) con-

trols product pricing throughout

the country. In 2013, the NPPA

expanded the National List of

Essential Medicines (NLEM) to

include 652 drugs, a substantial

increase over the 74 drugs previ-

ously listed. These products will

now be subject to price controls

that are projected to reduce prices

by more than 20% for half the

drugs (12). As if this did not chal-

lenge manufacturers enough,

the Indian government recently

decided to revise the NLEM later

this year in response to com-

plaints that the list should include

all dosages, strengths, delivery

mechanisms, and combinations of

these previously identified drugs

(13). The NPPA is also allowed to

control prices of patented drugs

that lie outside this list, and last

month the government began

exploring the possibility of using

a reference pricing system for

these products (14). With intense

generic competition already driv-

ing down drug prices in India,

these additional controls pose a

significant threat to international

manufacturers’ ability to generate

revenue.

Intellectual Property

Aside from pricing, patent pro-

tect ion has a lso come under

the microscope as of late. In an

effort to ensure greater acces-

sibility to higher-cost, branded

drugs, India, as well as other

BRIC countries, has begun to

allow generic-drug manufactur-

ers to market these drugs at dra-

matically reduced costs without

consequence through compulsory

licenses. While only one compul-

sory license has been approved

by India’s government to date

(Bayer’s Nexavar), other manu-

facturers have recently had their

patents weakened, revoked, or

rejected. While appeals to some of

these rulings are still in process,

precedents have been set, leading

manufacturers to question their

future investment in India.

IMPLIcAtIONS fOr SuccESSfuL MArkEt ENtry Despite the aforementioned chal-

lenges, major pharmaceutical com-

panies recognize the long-term

prospects of this market and con-

tinue launching new patented

drugs and pursuing unique business

opportunities in India. To encour-

age future investment, the govern-

ment has made tax breaks available

to the pharmaceutical sector,

including a weighted tax deduction

of 150% for any R&D expenditure

incurred. In addition, the govern-

ment recently declared that all

drugs that offer some form of inno-

vation would be exempt from price

regulation for the first five years fol-

lowing approval. Here, innovation

refers to drugs or drug delivery sys-

tems that arise from native R&D

efforts or existing drugs that are

improved upon by an Indian com-

pany. This measure is aimed to spur

growth in the domestic pharmaceu-

tical market and to ensure that pric-

ing regulations do not turn global

manufacturers away from India.

Thus, companies that develop stra-

tegic partnerships with local busi-

nesses and outsource some of their

R&D and manufacturing activities

will be well-positioned to maximize

revenue by avoiding steep price

cuts. This opportunity for manufac-

turers will only apply, however, for

those products that offer true inno-

vation by providing economic and/

or clinical value.

Uncertainty over patent security

and obstacles to clinical trials are

discouraging Western companies

from conducting drug research in

India. With that said, the govern-

ment has already initiated clini-

cal research reform efforts through

new amendments and regulations

that could quickly restore the

growth of clinical trials through-

out the country. At the same time,

there is speculation that a transfer

of power in India’s upcoming elec-

tion could dampen fears of addi-



Emerging Markets

tional compulsory licenses (15).

Manufacturers should closely mon-

itor these internal developments

and react accordingly.

MOvINg fOrwArDA growing middle class that is pro-

jected to see a significant rise in

noncommunicable diseases pro-

vides an excellent opportunity for

global companies to launch their

premium products and expand

their market share. IndiaÕs under-

developed insurance industry and

high poverty rates, however, require

that manufacturers first develop

a careful pricing strategy. Pricing

products appropriately can go a

long way towards ensuring future

growth as well as avoiding disputes

over patent protection and licens-

ing agreements. In a country that

holds about one-fifth of the worldÕs

population, IndiaÕs market is too

big for pharmaceutical companies

to shy away from, despite all of the

hurdles placed in front of them.

rEfErENcES 1. BBC News Asia, “UN: India to be

world’s most populous country by

2028” (June 2013), www.bbc.com/

news/world-asia-22907307, accessed

Apr. 8, 2014.

2. OECD, “Crisis squeezes income and

puts pressure on inequality and poverty

(2013).

3. Patel V et al. Lancet 2011; 377:413-28.

4. The World Bank. Research and

Development Expenditure (% of GDP)

(2013).

5. Report of the Steering Committee on

Health for the 12th Five Year Plan,

Health Division, Planning Commission

(February 2012) p. 23.

6. Indians’ growing healthcare expenses

concern WHO. The Times of India (Nov.

2, 2011).

7. PricewaterhouseCoopers, India Pharma

Inc.: Capitalising on India’s Growth

Potential (2010).

8. India Brand Equity Foundation, Indian

Healthcare Industry Analysis (August

2013).

9. India Brand Equity Foundation,

Pharmaceuticals (August 2013).

10. Palmer E., “AstraZeneca says Nexium

pills with Ranbaxy ingredient are safe

to use,” FiercePharma (March 2014).

11. Garde D. Report: Indian clinical trials

fell 93% last year, FierceCRO (January

27, 2014).

12. Economic Times Bureau, “Government

to regulate rates of 652 medicines;

prices set to fall,” The Economic Times

(May 2013).

13. A. Jain A., “Analysts in India call for

urgent expansion of essential

medicines list,” BMJ (March 2014)

348.

14. Sidhartha, TNN. Patented drugs face

price caps, The Times of India, Jan. 27,

2014

15. Hirschler B and Siddiqui Z. Big Pharma

still betting on “messed up” Indian

drugs market, (Reuters, March 2014),

http://in.reuters.com/

article/2014/03/12/india-bigpharma-

patent-idINDEEA2B09220140312,

accessed Apr. 9, 2014. ◆

rEfErENcES 1. C. Andrews, Postgrad Med J, 55, 73-77 (1979).

2. D.A.J. Tyrrell, Postgrad Med J, 55, 117-121 (1979).

3. J.A. Maher and J. DeStefano, Lab Anim, 33, 50-53 (2004).

4. J. Devincenzo et al., Proc Natl Acad Sci USA, 107 (19) 8800-

8805 (2010).

5. S.L. Johnston, Am J Resp Crit Care Med, 168, 1145-1146 (2003).

6. J.C. Zambrano et al., J Allergy Clin Immunol, 111 (5) 1008-

1016 (2003).

7. J.A. Belser, J.M. Katz, and T.M. Tumpey, Dis Model Mech, 4

(5) 575-579 (2011).

8. A.W. Hampson, J Infect Dis, 194, 143-145 (2006).

9. D.L. Barnard, Antiviral Res, 82 (2) A110-A122 (2009).

10. ICH, M3(R2), Guidance on Nonclinical Safety Studies for the

Conduct of Human Clinical Trials and Marketing Authorization

for Pharmaceuticals, Step 5 version (2009).

11. ICH, S6(R1), Preclinical Safety Evaluation of Biotechnology-

Derived Pharmaceuticals, Step 5 version (2011).

12. EMA, Note for guidance on preclinical pharmacological and

toxicological testing of vaccines (London, 1997).

13. FDA, Guidance for Industry Influenza: Developing Drugs for

Treatment and/or Prophylaxis (Rockville, MD, April 2011).

14. EC directive 2001/20/EC, Approximation of the laws, regulations

and administrative provisions of the Member States relating to the

implementation of good clinical practice in the conduct of clinical

trials on medicinal products for human use (Brussels, April 2001).

15. EC, Guidance on Investigational Medicinal Products (IMPs)

and Non Investigational Medicinal Products (NIMP) (Brussels,

March 2011).

16. FDA website, “Conditions or Focus of Study Data Element,”

www.clinicaltrials.gov, access Apr. 7, 2014.

17. EC, Guidance on the requirements for quality documentation

concerning biological investigational medicinal products in

clinical trials (Brussels, May 2012).

18. EMA, Guideline on the requirements to the chemical and

pharmaceutical quality documentation concerning investigational

medicinal products in clinical trials (London, March 2006).

19. EC Directive 2003/94/EC, Laying down the principles

and guidelines of good manufacturing practice in respect

of medicinal products for human use and investigational

medicinal products for human use (Brussels, October 2003).

20. EudraLex Volume 4 Annex 2 Manufacture of Biological

active substances and Medicinal Products for Human Use

(Brussels, June 2012).

21. EudraLex Volume 4 Annex 13 Investigational Medicinal

Products (Brussels, February 2010).

22. EC, Guidance on the requirements for quality documentation

concerning biological investigational medicinal products in

clinical trials (Brussels, May 2012).

23. EC, Guidance Virus Safety Evaluation of Biotechnological

Investigational Medicinal Products (London, July 2008). ◆

Peer-Reviewed – Continued from page 34



Analytical Best Practices

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Accelerated Stability ModelingCharacterization of stability performance provides a clear, statistically defendable method for determining accelerated stability.

Understanding the factors that impact

stability and then generating product

stability knowledge are key consider-

ations detailed in the International Conference

of Harmonization (ICH) Q8 (1) develop-

ment standard as well as the Q1E standard.

Accelerated stability analysis is a strategy used

to quickly evaluate alternative formulations,

packaging and processes; however, it is not

always clear how to estimate expiry from the

accelerated data.

Understanding the product and process is

becoming more of an expectation based on FDA

guidance and technical presentations. Building

representative product and process models for

stability is now considered an essential part of

product and process development. Once a prod-

uct/process model has been established and veri-

fied it can be used to support and/or justify

potential formulation, process, site, and supplier

changes.

Linear and non-linear regression mod-

els are recommended in guidance from the

health authorities for stability determination.

Specifically, ICH Q1E 2.6 General Statistical

Approaches states (2):

“Regression analysis is considered an appropriate

approach to evaluating the stability data for a quantita-

tive attribute and establishing a retest period or shelf life.

The nature of the relationship between an attribute and

time will determine whether data should be transformed

for linear regression analysis. The relationship can be

represented by a linear or non-linear function on an

arithmetic or logarithmic scale. In some cases, a non-

linear regression can better reflect the true relationship.”

Building a product or process stability model

typically follows the following steps:

• State the purpose

• Perform a risk assessment to iden-

tify the key factors driving the

responses of interest (3)

• Develop a stability study design and associated

power analysis (4)

• Collect the data

• Fit the model (linear and or non-linear)

• Evaluate the model’s usefulness, accuracy, and

associated errors

• Evaluate the model’s predictive potential and

associated errors

• Determine rate of degradation and expiry at

nominal conditions and at accelerated condi-

tions

• Verify any early accelerated predictions with

long-term stability studies at nominal storage

conditions.

Traditionally there has often been an

attempt to use the Arrhenius transformation

for all accelerated conditions. This approach

is good when the assumptions associated with

the Arrhenius equation are valid; however,

often the Arrhenius transformation becomes

the erroneous equation as it does not fit the

data and the product or process assumptions

cannot be satisfied. The health authorities have

issued warning letters to companies that use

Arrhenius transforms when the data does not

support this method of stability estimation

(5). This paper will outline an approach to

model and predict linear and non-linear stabil-

ity data under accelerated and nominal storage

conditions. In general, the approach presented

in this paper is to model the measured data,

understand the scientific rational associated

with the degradation pathway (what makes

it degrade?), and then generalize the model

for multiple accelerated conditions and at the

nominal condition.

There are many factors other than environ-

mental that may impact product stability. These

factors should be considered as well when devel-

oping accelerated and long-term stability and

self-life claims:

Thomas A. Little, PhD is president,

Thomas A. Little Consulting,

12401 North Wildflower Drive, Highland,

UT 84003, [email protected].




• Temperature

• Humidity

• API concentration

• Water content

• Amount of an excipient

• Processing conditions and/or set

points

• Packaging materials/method.

Study deSignProper design of experiments for

data collection and factor effect iso-

lation is crucial for building linear

and non-linear stability models. All

factors should be orthogonal rela-

tive to each other and have zero

correlation (or near zero). For this

simple example, there are multiple

time points at multiple tempera-

tures. There are an equal number of

samples at each time and tempera-

ture condition. Replicates are sug-

gested at each condition to reduce

the analytical method variation

and to improve the precision of the

estimates. In this study, the num-

ber of replicates was three at each

time point. A power analysis (Figure

1) should be performed to assure

the stability study has good statisti-

cal power (>0.95). This study is a

3*3*9=81 runs, three temperatures

with three replicates and nine time

points. Simulation can also be used

to evaluate study plans and esti-

mate their impact on stability.

AnAlySiS MethodThe following is the step-by-step

procedure for accelerated stability

modeling and expiry determination:

Figure 1: Accelerated study power

analysis.

Figure 2: Accelerated impurity and temperature.

Figure 3: Whole model and effects test.

All F

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1.Measure the data at multiple

time periods and at multiple

temperatures. Generate a plot

of the data (Figure 2) to visualize

the relationship of the curves

over time. Save the slopes from

the curve and place them in

a table. Examination of the

slopes will indicate if the envi-

ronmental factor accelerates the

rate of change/degradation.

2. Use a multiple factor analysis

of covariance (ANCOVA) model

to fit the data. Examine the

effects test (Figure 3) to make

sure all terms in the model are

significant. The inverse predic-

tion (Figure 4) will provide the

expiry and the 95% lower con-

fidence interval. Also examine

the whole model to determine

the RSquare and the quality of

the ANCOVA model. Check the

residuals to make sure no hidden

factor has entered into the study.

3. Save the expiry and the 95%

predictions (Figure 5) at each

temperat u re into a t able .

Acceleration rate is the ratio of

each slope at temperature to the

nominal storage condition.

4. To build a generalized model

(Figure 6) of how temperature

accelerates the rate of degrada-

tion and expiry, fit a model of

temperature to the coefficients

(slopes), expiry, and 95% con-

fidence interval (CI) and accel-

eration rate. Models may be

linear or non-linear in their fit-

ting parameters. Make sure the

models selected makes good sci-

entific sense and can be general-

ized. Modern software programs

make this easy to do.

5. Save the equations for the fit for

the 95% CI, expiry, acceleration

rate, and the slope:

Predicted Slope=

(-0.0000009387967452312)

+ 0.0000001815600541022

* :Temperature +

0.0000000218633389171 *

:Temperature ^ 2, Quadratic Model

Predicted 95% CI=

(-27.8898211558579)

+ 23.9294245426114 *

Exp(0.0376760939674008 *

:Temperature), 3 Parameter

Exponential Model

Predicted Expiry=

33.5848316003024 +

7328.12608635937 * Exp(-

0.196329985274204 *


Exponential Model

Predicted Accelaration

Rate= 25.9675472550865 +

1008.32460629621 * Exp(-

0.116629176337002 *


Exponential Model

6. Check the model to make sure it

matches the actual data. Correct

any modeling errors.

7. Create a profiler (Figure 7) from

the equation. This can be done

using a modern statistical pack-

age such as SAS/JMP.

8. Predict expiry at any tempera-

ture using the profiler. A tem-

perature of 4 °C was not part

of the study design; however, it

now can be modeled using the

prediction profiler.

Figure 4: inverse prediction of expiry and the lower 95% confdence interval.

Figure 5: Factor and parameter table.




9. 95% CIs are often not helpful in

estimation of long-term stability

due to the limited sample size.

The sample size directly impacts

the 95% CI but not the slope as

much. Expiry based on the slope

is typically the primary focus.

In this example, it is estimated

at 4 °C the product will be stable

for 3375 days or 9.2 years.

10. Finally, long-term stability

evaluation at nominal storage

conditions will be used to con-

firm the early model prediction

and will provide an indepen-

dent secondary determination

of stability and changes in dis-

solution. Understanding rates

of degradation should factor

into shelf life and release speci-

fication limits (6).

SuMMAryReliable accelerated stability model-

ing and estimation has long been

a problem in a variety of process

and product modeling and predic-

tion situations. The novel proce-

dure discussed in this paper for

the characterization of stability

performance provides a clear, sta-

tistically defendable method for

determining accelerated stability.

Four primary tools are used in the

generation of the analysis: design

of experiments for the design of

the study, ANCOVA model fitting,

linear and non-linear model fit-

ting of the coefficients, and pro-

filers to integrate the equation

and improve visualization and

prediction. Long-term verification

of accelerated conditions should

always follow early determina-

tions of expiry, acceleration rates

and rates of degradation.

referenceS 1. ICH Q8 (R2) Pharmaceutical

Development (ICH, 2009).

2. ICH Q1E, Evaluation for Stability Data

(ICH, 2003).

3. ICH Q9 Quality Risk Management

(ICH, 2006).

4. ICH Q1A(R2) Stability Testing of New

Drug Substances and Products

(2003).

5. FDA, FDA Warning Letter to ACell

(April 26, 2013), www.fda.gov/ICECI/

EnforcementActions/

WarningLetters/2013/ucm352061.

htm

6. ICH Q6B Specifications: Test

Procedures and Acceptance Criteria

for Biotechnological/Biological

Products (ICH,1999). ◆

Figure 6: generalized temperature models.

Figure 7: generalized accelerated

stability profiler.



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THE WORD

NEW BIOLOGICS PIPELINE

• Aastrom Biosciences, a developer of patient-specific,

expanded multicellular therapies for the treatment of

severe, chronic cardiovascular diseases, reported that it

has entered into an agreement to acquire Sanofi’s Cell

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• Dana-Farber has been awarded a research grant of $1.2

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• Novartis reported that Bexsero has received a break-

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• PolyTherics, a technology solutions provider for biophar-

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RESEARCH NOTES

Virus-Fighting Genes Linked to Cancer

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This genetic deletion is found on chromosome 22

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had a greater quantity of mutations of this particular

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