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INTERNATIONAL

www.biopharminternational.com

INTERNATIONAL

Bio

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November 2014

Volume 27 Number 11

GENE AND

CELL THERAPY

MANUFACTURING

FORMULATION

DESIGN OF EXPERIMENTS

PROVIDES BENEFITS

GLOBAL MARKETS

GERMANY POST AMNOG

SETTING STANDARDS FOR

BIOTECH THERAPEUTICS IN INDIA

TROUBLESHOOTING

VIRAL CLEARANCE

CHALLENGES

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INTERNATIONAL


EDITORIALEditorial Director Rita Peters [email protected]

Managing Editor Susan Haigney [email protected]

Science Editor Randi Hernandez [email protected]

Science Editor Adeline Siew, PhD [email protected]

Community Editor Ashley Roberts [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]

West/Mid-West 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]

Direct List Rentals Tamara Phillips [email protected] 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 Rochelle Ballou [email protected]

Joe Loggia, Chief Executive Officer; Tom Ehardt, Executive Vice-President, Chief Administrative Officer & Chief Financial Officer; Georgiann DeCenzo, Executive Vice-President; Chris DeMoulin, Executive Vice-President; Rebecca Evangelou, Executive Vice-President, Business Systems; Julie Molleston, Executive Vice-President, Human Resources; Tracy Harris, Sr Vice-President; Dave Esola, Vice-President, General Manager Pharm/Science Group; 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 November 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

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solutions, trends in single-use bioreactors, and more! Download the eBook at BioPharmInternational.com/eBook+Series


INTERNATIONAL


INTERNATIONAL

November 2014

Volume 27 Number 11

Gene and

cell therapy

ManufacturinG

forMulation

DEsIgN Of ExpERImENTs

pROvIDEs BENEfITs

Global Markets

gERmANy pOsT AmNOg

sETTINg sTANDARDs fOR

BIOTEch ThERApEuTIcs IN INDIA

troubleshootinG

vIRAL cLEARANcE

chALLENgEs

6 From the Editor The US public catches Ebola hype, but lacks initiative for influenza prevention.Rita Peters

8 Regulatory Beat Manufacturers face regulatory overhaul, while brand-generic debates escalate over biosimilars and labeling changes.Jill Wechsler

12 Perspectives on Outsourcing European CDMOs want to get into the US market, but entry options are limited.Jim Miller

42 Troubleshooting Challenges remain for virus removal and validation. Cynthia A. Challener

45 Analytical Best Practices The ability to define a scientifically justified and statistically sound sampling procedure is a fundamental skill.Thomas A. Little

48 Ad Index

49 Product Spotlight

49 New Technology Showcase

50 The Word

GENE AND CELL THERAPY

Vector Manufacturing and Testing for Gene and Cell Therapy ApplicationsWolf Klump, Martin Wisher, Alison Armstrong, and Audrey ChangThe authors offer insight into cell

therapy manufacturing, vector

production, and the safety aspects

of testing for characterization. 14

Standardizing Practices for Cellular Therapy ManufacturingUplaksh Kumar and Naynesh R. KamaniCellular therapy developers learn

process development strategies

from pharma industry experiences. 24

FORMULATION DEVELOPMENT

DoE Provides Benefits, but Preparation Is NecessaryCynthia A. ChallenerDefining critical parameters and processing

large quantities of data can be a challenge. 28

GLOBAL PERSPECTIVES

Germany Post AMNOG: Insights for BioPharmaJill E. Sackman and Michael J. KuchenreutherThe authors take a look at some of the recent

developments in the German market. 30

Setting Standards for Biotech Therapeutics in IndiaRenu Jain, M. Kalaivani, Gunjan Narula, and G. N. SinghThe authors take a look at the

past and future impact of the

Indian Pharmacopoeia Commission. 35

Volume 27 Number 11 November 2014

FEATURES

Cover: REB Images/Getty Images

SecureSingle-uSe

SyStemS

November 2014

BioPharmINTERNATIONAL

The Science & Business of Biopharmaceuticals

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From the Editor

The US public

catches Ebola hype,

but lacks initiative

for influenza

prevention.

Hype vs. Health

Ebola virus disease (EVD), which first appeared in Africa 38 years ago, gen-

erally was perceived by people in developed nations as a scary, deadly, but

distant illness far removed from their lives.

EVD is a severe, often fatal disease that is transmitted human-to-human

through bodily fluids. According to World Health Organization (WHO) data,

nearly 2000 people in Africa were infected with EVD from 1976 through 2013

with an average fatality rate of 50%. The latest outbreak began in March 2014 in

Guinea and spread to Sierra Leone, Liberia, Senegal, and Nigeria. As of Oct. 14,

WHO reported 9216 confirmed, probable, or suspected cases of EVD worldwide

and 4555 deaths.

When the first patient with EVD walked into a US hospital, the facility was

not prepared; two nurses treating the patient were infected. Despite initial mis-

steps, federal and local officials contained the outbreak to that single hospital.

But it was too late to contain overreaction by the public, press, and politicians,

which spread much faster and wider than the disease itself and distracted pub-

lic attention from real health threats.

While the afflicted nurses battled the disease, politicians lined up to

criticize the reaction of the federal government. Demonstrators outside the

White House called for a halt to flights from West Africa. Schools closed. In

one extreme example of undue caution, a school in Maine placed a teacher

on a 21-day leave after she attended a conference in Dallas in mid-October,

even though she had no contact with any people, transportation, or facilities

involved in three EVD cases diagnosed in that area.

The 2014 outbreak clearly illustrates there is a need for effective vaccines

and therapies for EVD; a handful of vaccines and treatments are in early devel-

opment and testing stages. Questions remain, however, about the bio/pharma

industry’s ability or desire to develop and produce therapies or vaccines cost-

effectively.

Viruses here and now

While EVD generated alarm, two other health issues presented serious medical

challenges for US patients.

Between mid-August and mid-October, the Centers for Disease Control

(CDC) and state public health laboratories confirmed that 825 people, mostly

children, in 46 states and the District of Columbia had respiratory illnesses

caused by enterovirus D68 (EV-D68); seven patients died. Enteroviruses and

rhinoviruses cause millions of respiratory illnesses in children each year; how-

ever, the 2014 outbreak of EV-D68 was much greater than that reported in pre-

vious years. There are no vaccines to prevent EV-D68.

Influenza is an annual threat to the health of the general public and

patients with compromised medical conditions in particular. The October

to March flu season is just underway and CDC estimates that 5–20% of

Americans get the flu each year. While most people recover, CDC estimates

that between 3000 and 49,000 Americans die from the flu or its complications

every year.

The flu virus is contagious and, unlike EVD, can be spread through airborne

transmission (a cough or sneeze) and by someone infected with the virus who

is not showing symptoms. Unlike EVD and EV-D68, however, vaccines to

protect against the flu are readily available; CDC says the vaccine reduces the

chance of getting the flu by approximately 60%. Still, less than half of the US

population gets innoculated.

Count me among those lining up for an annual flu shot. The vaccine does not

come with a guarantee that I will avoid the flu, but a shot of prevention is worth

more than a pound of paranoia. ◆

Rita Peters is the editorial director of

BioPharm International.


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Regulatory Beat

Vis

ion

so

fAm

eri

ca

/Jo

e S

oh

m/G

ett

y Im

ag

es

The 30th anniversary of the Hatch-

Waxman Act in September generated

widespread recognition of how the leg-

islation created today’s vibrant generic-drug

industry. Generic drugs now account for more

than 85% of US prescription drug use, and the

development of biosimilars promises to extend

this trend to large molecules. Such transforma-

tion was unanticipated back in 1984 by the

authors of the legislation, Sen. Orrin Hatch

(R-Utah) and Rep. Henry Waxman (D-Calif),

who is retiring from Congress but continues to

urge vigilance to ensure that Americans retain

access to low-cost quality medicines.

A September conference commemorating

Hatch-Waxman sponsored by the Food & Drug

Law Institute (FDLI) described the world with

few generic drugs prior to 1984 and how the

legislation was born of a compromise between

brand-name firms seeking patent extensions

and consumers demanding a clearer pathway for

bringing low-cost drugs to market. Former FDA

officials recalled the challenges in establishing

new policies for testing and evaluating generic

medicines and how the program’s success has

generated thousands of abbreviated

new drug applications (ANDAs) and

supplements that are requiring major

operational changes at FDA. Hatch-

Waxman also has generated a host of

legal, regulatory, and economic issues

that complicate generic drug oversight

and distribution.

User fees alter landscapeThe Hatch-Waxman anniversary

also coincides with the beginning

of year three of the Generic Drug

User Fee Act (GDUFA), the fee scheme

approved by Congress in 2012 to

speed up ANDA approvals. The pro-

gram expands FDA review staff, supports timely

field inspections, and funds research on devel-

oping more complex generic dosage forms. One

result is the elevation of the relatively small

Office of Generic Drugs (OGD) in the Center

for Drug Evaluation and Research (CDER) into a

“super office” to accommodate a larger cadre of

scientists, reviewers, and policy experts to sup-

port new regulatory approaches.

GDUFA requires OGD to meet certain time

frames for assessing and approving ANDAs

and supplements, while also whittling away at

a massive application backlog. Specific goals

for reviewing ANDAs kick in this year, and

manufacturers have concerns about OGD

meeting the schedule. An unanticipated prob-

lem is that more than 1400 applications were

filed this past year, many more than pro-

jected, making it even more necessary for

OGD to implement a new review process that

sets priorities based on product risk, medical

importance, review goal dates, and internal

workload factors.

Chemistry reviewers will provide “appropri-

ate scrutiny” to high-risk areas, while stream-

lining the review of lower-risk products,

explained Susan Rosencrance, then acting

deputy director for generic drug chemistry in

CDER’s Office of Pharmaceutical Science (OPS),

at the FDA/PQRI conference in September 2014.

The risk-based review approach has already paid

New Era for Generic DrugsManufacturers face regulatory overhaul, while brand-generic debates escalate over biosimilars and labeling changes.

Jill Wechsler is BioPharm

International’s Washington editor,

chevy chase, Md, 301.656.4634,

[email protected].

read Jill’s blogs at

pharmtech.com/wechsler.

the emergence of

biosimilars continues

to fuel debate over the

assessment of similarity.



regulatory Beatregulatory Beat

off with a 50% reduction in chem-

istry review times this past year,

she noted.

A main strategy for speeding up

ANDA review and approval is to

reduce the number of application

review cycles. OGD is implement-

ing a “real-time communication”

program that allows staff to dis-

cuss minor deficiencies that can

be resolved quickly with manufac-

turers. The agency also is adopt-

ing a “block review” approach that

assigns a team to three or more

ANDAs with the same reference

listed drug or same drug mas-

ter file. This system moves away

from OGD’s random assignment

approach, established to avoid any

appearance of favoring one appli-

cation over another. Block reviews

aim to reduce repeated efforts, pro-

mote information sharing, and

produce more consistent decisions.

CDER also is working hard to

cut the massive backlog of some

5000 generic-drug manufactur-

ing supplements. An efficient sup-

plement review process is key to

encouraging product moderniza-

tion and quality improvements for

marketed drugs, and Rosencrance’s

office has almost halved the back-

log through a “strategic plan of

attack” by a special supplement

review team of external and inter-

nal chemistry reviewers.

Not all is rosy with FDA’s GDUFA

implementation process, though,

as seen in concerns raised by man-

ufacturers about still-slow ANDA

approvals at a GDUFA public hear-

ing in September. Small manu-

facturers asked FDA for reduced

annual facility and filing fees,

and several industry executives

urged more clarity in how new

guidance would be implemented.

They offered specific comments

on recent guidance documents

on ANDA content and format and

on the refuse-to-receive policy.

The loudest complaints focused

on OGD’s new communications

policy ending informal phone

conversations between FDA staff-

ers and industry representatives.

Manufacturers say such communi-

cation is key to resolving problems

quickly and helps them plan for

production changes and product

launches. FDA officials maintain

that constant queries are a burden,

lead to inconsistent practices, and

raise the specter of favoritism. But

they now plan to review and revise

the policy in response to industry

concerns.

liaBility and laBelsMeanwhile, the continued growth

in generic drug market share has

generated more legal challenges to

product development and market-

ing. Recent Supreme Court deci-

sions have raised questions about

the adequacy of safety information

in generic-drug labels, prompt-

ing FDA to propose a new rule

on labeling changes that generics

manufacturers strongly oppose as

likely to lead to different labels on

brands and generics. The Generic

Pharmaceutical Association (GPhA)

says FDA’s policy raises liability

issues that could curb development

of new low-cost medicines and

has sought Congressional support

for its position. The legal battle is

escalating as brand manufacturers

seek to avoid added liability for

patients harmed by generic drugs,

and generic-drug companies insist

they can’t have labels different

from the brand. GPhA has pro-

posed that FDA itself establish a

fast, efficient process for updating

labeling changes on both brand

and generic drugs, and to transmit

such updates electronically to pre-

scribers, dispensers, and patients.

Generic-drug makers also are

fighting innovators over allega-

tions that brands use risk evalu-

ation and mitigation strategies

(REMS) to block the development

and testing of new therapies.

GPhA backs legislation to make

it harder for innovator firms to

claim that a restricted distribu-

tion program required by a REMS

prevents it from making available

drug samples needed for bioequiv-

alence testing.

The emergence of biosimilars

continues to fuel debate over the

assessment of similarity between

reference products and follow-ons.

Although there is general agree-

ment that in-depth analysis of

product structure and function

plus pharmacology testing can

combine to document similarity,

there’s much disagreement over

extrapolation of data by a biosimi-

lar sponsor to support approval of

additional uses and over product

“naming” to distinguish innovators

from biosimilars, as brands look to

discourage interchangeability and

substitution of future biosimilars.

Successful biosimilar devel-

opment must consider manu-

fac t ur ing cost s and qua l it y

com m it me nt s , p o i nte d out

Parexel Vice-President Cecil Nick

at the September biosimilars con-

ference sponsored by the Drug

Information Association. In addi-

tion to assessing non-clinical and

clinical data requirements, spon-

sors must weigh the costs and effi-

ciencies of in-house production

versus contract manufacturing in

terms of production yield, media

costs, disposable versus fixed pro-

duction train, needed purification

steps, and fill/finish arrangements.

The generic-drug industry is “at

a crossroads,” commented Mylan

Senior Vice-President Carmen

Shepard at the FDLI conference.

GDUFA promises to provide more

predictable regulatory actions and

to encourage high quality pro-

duction. But manufacturers fear

that an over-emphasis on meeting

review goals could actually delay

final approvals and end up with

first filers losing exclusivity, under-

mining incentives for developing

new generic products. ◆




Perspectives on Outsourcing

Do

n F

arr

all/G

ett

y Im

ag

es

At the 2014 CPhI trade show, held Oct. 7–9

in Paris, executives from CDMOs and

contract labs whose operations are solely

in Europe expressed their desire to expand

their operations into North America. These

executives, however, were stymied about how

to do it.

Their interest in North America is not sur-

prising: opportunities there are much greater

than in Europe. There is far more venture

capital f inancing in North America than

in Europe and the level of drug develop-

ment activity is significantly greater. Many

European economies are contracting, and

government budgets to pay for drugs are

under stress. Further, with its large number

of former bio/pharma facilities converted to

contract services businesses, Europe experi-

ences price competition in the drug-devel-

opment market that seems more aggressive

than in North America.

Challenges in entering Us marketEuropean companies are challenged on sev-

eral levels to enter North America. For one

th ing , European cont rac tor s

don’t have a good understand-

ing of the North American mar-

ket. While some may have had

an FDA inspection, many haven’t

a nd don’t u nde r s t a nd F DA

requirements and how they differ

from European requirements.

Further, they have minimal

experience in trying to sell their

services in North America; some

may have one sales representa-

tive based in the US, but many

have none. Sales and marketing

in particular can be different in

North America versus Europe. For

instance, tradeshow marketing is important

in Europe and cold calling is uncommon, but

in North America it is the other way around.

Even if they have sales representation in

North America, European CDMOs suffer from

low brand recognition and can have a hard

time getting clients to travel overseas for ser-

vices that are readily available domestically.

Another cha l lenge for European con-

tractors is that there is a higher barrier to

market entry in North America than they

are used to. Most European CDMOs were

founded as buyouts of facilities that global

bio/pharmaceutical companies wanted to

get rid of. Facility closures are difficult in

Europe because of labor laws and because of

fears that mass layoffs could hurt companies

tendering for government drug supply con-

tracts. As a result, pharma companies have

been willing to offload unneeded facilities to

management teams or private equity inves-

tors at a fraction of their replacement value

and with contracts to continue to manufac-

ture legacy products for some period. This

has made it relatively easy to enter the con-

tract services business in Europe, although

the resulting overcapacity has hurt pricing

for contract manufacturing and development.

Opportunit ies to acquire faci l it ies on

such favorable terms are fewer and farther

sales and marketing in

particular can

be different in north

america versus europe.

Outside Looking In European CDMOs want into the US market, but entry options are limited.

Jim Miller is president of Pharmsource

information services, inc., and publisher

of Bio/Pharmaceutical Outsourcing

report, tel. 703.383.4903, twitter@

JimPharmsource, info@pharmsource.

com,www.pharmsource.com.


November 2014 www.biopharminternational.com BioPharm International 13

Perspectives on Outsourcing

bet ween i n Nor t h A mer ica .

Because North America consists

of just two large markets, ver-

sus the 20 -plus small to mid-

size markets in Europe, there

weren’t so many facilities built

in the first place, so there have

been fewer facilit ies to divest.

As result, European companies

looking to enter North America

may have to “pay reta i l” to

acquire a fac i l it y or serv ices

business. Acquisition valuations

of CDMOs in recent years have

been especially high.

European CDMOs a re a l so

hindered by a lack of capital

necessary to acquire their way

into North America. They are

often poorly capitalized, given

that their initial buy-in to the

indust ry d idn’t require a lot

of investment. Fur ther, their

low profit margins mean they

haven’t been able to accumulate

a significant amount of equity

t h roug h r e t a i ne d e a r n i ngs .

A lso, some European CDMOs

are employee-owned and may

have particular challenges rais-

ing additional capital without

threatening thei r ownership

structure.

OPPOrtUnities existThe barriers to European entry

i nto t he US CDMO ma rke t

are high but not insurmount-

able . E xamples of European

contractors that have success-

fully established themselves in

North America in the past 10

years include CDMOs Vetter and

Almac as well as contract labs

l ike SGS and Eurof ins. Those

companies, however, had favor-

able ownership structures (fam-

ily trusts or publicly-traded) that

gave them access to adequate

capital.

Fu r ther, it i s occasiona l ly

possible to acquire facilities in

North America under favorable

terms. In 2013, European CMO

Unither acquired a dose manu-

facturing facility with contracts

in Rochester, New York, f rom

UCB Pharma; and Fareva was

able to acquire a manufactur-

ing and packaging facility with

contracts in Richmond, Virginia,

from Pfizer in 2011.

It ’s a lso worth not ing that

Nor t h A mer ica n compa n ie s

have challenges similar to the

Europeans’ when consider ing

entry into Europe. A common

problem has been the fa i lure

to realize that Europe is not a

single market—not even the

European Union—but rather a

collection of more than 20 coun-

tr ies with different languages

and cultures, and a wholly dif-

ferent concept of distance. So,

for instance, North American

compa n ies have e s tabl i shed

facilities in Ireland intended to

serve all of Europe, only to learn

that continental companies view

the Ir ish facilit ies as far away

and foreign.

As the bio/pharmaceut ica l

and contract services industries

consol idate, hav ing a global

network of facilities, at least in

North America and Europe, has

become increasingly important

for competitive success. Mid-size

European CDMOs and contract

labs must figure out how to over-

come the barriers to their entry

into North America if they intend

to succeed over the long term. ◆

north american

companies have

challenges similar

to the europeans’

when considering

entry into europe.

Pfizer Ireland Plant Receives ISPE Award

The International Society for Pharmaceutical Engineers (ISPE) recognized

Pfizer Ireland as the overall winner in the 2014 Facility of the Year Awards

(FOYA) category at the society’s annual meeting in Las Vegas, Nevada. FOYA

acknowledges the pharmaceutical manufacturing industry’s accomplishments

in construction and facility design and the pursuit of new technologies.

The focus of Pfizer Ireland’s Network Strategy Implementation (NSI)

Capacity project was the addition of a new vaccine suite and a drug

substance bioprocess suite. The new manufacturing suites included the

latest technologies, including electronic batch records, process analytical

technology, and disposable bag processing. Pfizer Ireland conducted the

project using a lean management strategy, a 5S program in the design

process, and a Six Sigma toolkit. The Pfizer Ireland Grange Castle plant that

won the award is located in Clondalkin, South County Dublin.

“The society was impressed with the NSI Capacity Expansion project and

the company’s ability to effectively manage the challenges of maintaining

supply with the demolition of existing facilities, new construction, and start-

up and integration activities,” said Chair of the FOYA Judging Panel James

Breen in a press release.

—Randi Hernandez



RE

B Im

ag

es/

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y Im

ag

es

Gene- and cell therapy-based

medicines are experiencing

resurgence due to the introduc-

tion of “next generation” trans-

fer vectors, which have demonstrated

improved safety and efficacy. Patient sam-

ples are often extracted, expanded, and

transduced using gene-therapy vectors,

and the modified cells are re-implanted in

the patient for therapeutic applications.

In this circumstance, the modified cell

is the drug product rather than the gene-

transfer vehicle, and it carries with it dis-

tinct regulatory challenges. An increase

in the number of candidate molecules

is anticipated due to the interest in the

cancer treatments based on recent suc-

cesses seen with chimeric antigen receptor

(CAR)-based cell therapies. Although the

end product of the manufactured viral

vector is considered a drug substance, in

the case of cell therapies, the scrutiny for

testing for adventitious agents is high. As

in many cases, the transduced cell prod-

ucts possess short shelf lives, often before

all release testing can be completed. In

addition, the use of plasmids for genera-

tion of viral vectors adds another layer of

compliance and testing.

Given the complexities associated with

new technologies, especially with “first-in-

class” applications, the technical and scien-

tific input can be the deciding factor in the

success of a testing and/or manufacturing

program. Both the manufacturing pro-

cess and the performance of routine (e.g.,

adventitious agent testing, mycoplasma,

sterility) and custom-designed (e.g., iden-

tity, potency) assays need to meet clinical

and regulatory compliance standards.

The authors offer insight into cell-ther-

apy manufacturing, vector production, and

the regulatory requirements and safety

aspects of testing for characterization.

To illustrate the manufacturing and

testing strategies for a complex cell-ther-

apy production process, the multilevel

production required to generate a CAR T

cell therapy product can serve as a good

example. This production process starts

with generation of cell lines and trans-

fection of these cells with plasmids to

produce a viral vector, which is then used

to transduce patient T cells, before these

Vector Manufacturing and Testing for Gene and Cell Therapy Applications

Wolf Klump, Martin Wisher, Alison Armstrong,

and Audrey Chang

The authors offer insight into

cell therapy manufacturing,

vector production, and the safety

aspects of testing for

characterization.

Wolf Klump, PhD, is senior manager

of Technical Services at SAFC; Martin

Wisher, PhD, is senior director, Quality

Assurance & Regulatory Affairs at

BioReliance; Alison Armstrong,

PhD, is senior director, Development

Services at BioReliance; and Audrey

Chang, PhD, is senior director,

Development Services at BioReliance.

Gene and Cell Therapy


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AL

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HO

RS

are reintroduced into the patient.

This is a long and complicated path

that involves, in many cases, three

or more different manufacturers

(for cell banks, plasmids, lentiviral

vectors and patient cell manipula-

tion). The overall process is shown

in Figure 1.

In ex-vivo applications, gamma ret-

roviral vectors, derived from murine

leukemia virus (MLV), were the first

to be used; however, lentiviral vec-

tors, based on human immunode-

ficiency virus (HIV), have gained

attention due to their ability to

transduce non-dividing cells. While

MLV has a simple genome structure

(containing gag, pol, and env gene

sequences), lentiviruses have a more

complex one containing additional

accessory genes that are able to

manipulate host cell functions. The

general strategy in designing lentivi-

ral vectors for gene therapy is based

on the deletion and alteration of the

native viral sequences to prevent the

generation of replication-competent

retroviruses. To achieve this, the len-

tivirus components are segregated

into three or four different plasmid

constructs with the goal of pre-

venting the possibility of complete

recombination to a fully replication

competent lentivirus (RCL). The

viral vector genome contains at a

minimum the transgene expression

cassette, the long terminal repeats

(LTRs), and the packaging signal. In

most cases, three additional plasmids

provide the factors required for virus

production and packaging (e.g., gag,

pol, env). The envelope proteins are

typically replaced by a heterologous

viral glycoprotein, most commonly

vesicular stomatitis virus G-protein

(VSV-G), to modify the host range

of the vector. An important safety

feature is also the deletion of the

promoter-enhancer region from the

3’ LTR preventing transcription from

this region and subsequent viral rep-

lication (self-inactivating vector; SIN).

The essential steps of ex-vivo

gene therapy involve cell isolation

and in-vitro culture of the desired

cell type to allow the selection,

expansion, and differentiation

either before or after the cell has

been transduced with a viral vec-

tor. In the case of hematopoeitic

cells, most of these steps can be

performed in a closed system using

single-use blood collection and

processing bags.

For CAR T cell therapy, patient

blood cells are harvested, and the

desired T cell populations are selected

and grown to the required levels.

They are then transduced with a viral

vector carrying the CAR gene cassette,

followed by CAR T cell expansion to

the billion-cell level. Lentiviral vec-

tors have been shown to transduce T

cells more efficiently and are, there-

fore, the preferred vector for intro-

ducing CAR into patient target cells.

Expanded cells are then reintroduced

into the patient. To move quickly

into patients, the testing window is

relatively short, and administration

of cells may be initiated before all

testing is completed. This requires a

balance of product risk and timely

treatment of cancer patients.

LenTiViRAL VeCToR pRoDuCTion Lentiviral vector cGMP production

is frequently accomplished using

adherent HEK293 (human embry-

onic kidney cells immortalized

using sheared Adenovirus 5 DNA),

or HEK293T cells (HEK293 cells

containing the SV40 large T antigen

gene) transiently transfected with

plasmids providing the relevant vec-

tor components. The critical raw

materials usually needed for vector

production are the cells, medium

and serum, and the plasmids. Each of

these must be sourced from approved

suppliers and should have gone

through a rigorous testing program

to reduce the risk of introducing

adventitious agents into the produc-

tion process. Master and working cell

banks (MCBs and WCBs) and ani-

mal-derived media components are

also extensively tested.

If fetal bovine serum (FBS) and por-

cine trypsin are used in production,

they should be gamma irradiated to

reduce the risk of viral contamination.

FBS also carries the risk for bovine

spongiform encephalopathy (BSE)

contamination and, therefore, should

be restricted to negligible BSE risk

countries, such as the US, Australia,

and New Zealand. Plasmids being


Figure 1: Schematic of a representative manufacturing and testing strategy for a

cell therapy production process.

Identity

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Identity

Saftey

Purity

Identity

In-processtesting

Saftey

Purity

Identity

Saftey

Purity

Identity Saftey

Purity

Plasmids

Viralvector

Patientcell

Transducedpatient cell

Master cellbank (MCB)

Working cellbank (MCB)


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produced in bacteria are tested for ste-

rility and endotoxin levels. Similarly,

the vector product requires testing for

adventitious agents, purity, genetic

identity, as well as potency before its

release as a drug substance for trans-

duction of cells ex vivo.

For lentiviral vector current good

manufacturing practices (cGMP)

manufacturing at the SAFC Carlsbad

location, several approaches for scale-

up are being pursued, including use

of cell factories, Corning cellSTACK

or HYPERStack. Depending on the

size of the facility and the available

incubator space, 20 to 40 cellSTACKs

or up to 20 HYPERStacks can be

incubated in parallel and still allow a

consistent and reliable vector produc-

tion. To allow consistent productivity,

the plasmid transfections are done

with polyethylenimine (PEI) as the

transfection reagent, which does not

require as high scrutiny with respect

to pH and buffer consistency as the

calcium phosphate based precipita-

tion method. In many cases, the cells

used for production are still grown

in the presence of serum, which

requires a higher scrutiny in testing,

and efforts to implement serum-free

production should be undertaken in

sight of commercialization. Overall,

efforts should be undertaken to move

toward animal-free components,

which apply to media components as

well as cell propagation.

In comparison with other virus

productions, where cell lysis is

involved, retroviral or lentiviral vec-

tors are harvested from supernatant,

which may, dependent on the pro-

duction system, also allow multiple

harvests and thereby increase the

overall yield. Supernatant volumes

can reach 100 L or more, and require

first a clarification and concentration

step followed by column purification.

The main criterion for purification is

to obtain an acceptable vector con-

centration and assurance that the

vector product has high transduction

efficiency and does not compromise

target cell functionality due to the

presence of contaminants.

ReGuLAToRy ReQuiReMenTS Manufacture of viral vectors, includ-

ing control of critical raw materials,

is governed by regulatory guidelines

issued by agencies such as FDA, the

European Medicines Agency (EMA),

and the Japanese Pharmaceuticals &

Medical Devices Agency (PMDA).

EMA has produced specific guid-

ance on the development and manu-

facture of lentiviral vectors (1). FDA

has provided guidance for the manu-

facture and ex-vivo use of retroviral

gene therapy vectors (2, 3). General

guidance on the manufacture and

quality control of gene therapy viral

vectors is given in the United States

Pharmacopeia (UPS) (4) and European

Pharmacopoeia (Ph. Eur.) (5).

Rigorous testing of viral vector

product, and the critical materi-

als used in its manufacturing, are

required to ensure the viral vector

product is free of adventitious agents,

and is fully characterized for its iden-

tity, purity, and activity. While cell

banks and plasmids can be generated

at qualified manufacturers or in-

house under cGMP, other raw mate-

rials, like media, FBS, Benzonase,

and PEI, must be scrutinized as well.

Yet the viral vector manufacturer

does not directly control production

of these materials. Here, qualifica-

tion of the relevant manufacturers,

good supply chain control, and addi-

tional testing contribute to another

level of complexity. Table I provides

an overview of the testing required

for cell banks, viral vector, and cell-

therapy product.

ASpeCTS oF SAFeTy TeSTinGSafety for clinical use is paramount,

and lentiviral vector preparations

must be formally and extensively


Maintaining an Efficient and Safe Cell-Therapy Supply Chain during Scale-Up and Scale-Out

By Matthew Lakelin, chief scientific officer at TrakCel

Unlike traditional pharmaceutical products that have linear supply chains, autologous therapies have circular supply chains where

the first step is to obtain cellular starting material from the patient. Should an error occur in an autologous therapy supply chain,

resulting in a patient receiving a therapy manufactured from another individual’s cellular starting material, there is a significant

risk of graft versus host disease and other unwanted responses. Supply-chain complexity is exacerbated when considering the

time and temperature-sensitive nature of these products.

The manufacture of allogeneic products does not require harvesting of tissue or cells for processing from the therapy’s

recipient; however, regulations state that it must be possible to trace the therapy to the original donor of the cellular starting

material. Typically, manufacturing of cell therapy products is labor-intensive, and requires continuous communication between

treatment centers and manufacturers to coordinate manufacturing and treatment. Products tend to be separated so that only

one patient’s therapy is contained within a cleanroom to prevent cross contamination. To efficiently scale-up and scale-out cell-

therapy products, clear strategies need to be developed for scheduling management, logistics management, product stability, and

closed systems manufacturing.

To read more on the steps required to develop an efficient manufacturing and supply system for cell therapies, please visit

www.biopharminternational.com/TrakCel.


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tested to show they are absolutely

free of RCL. Various methods have

been proposed to detect RCL, which

report high specificity and sensitiv-

ity and can discriminate between

replication-defective virus and

RCL. Current testing recommen-

dations include testing of material

from multiple stages of the produc-

tion process and from transduced

patient cells. Both vector-producing

cells and supernatant from produc-

tion of an MCB should be tested for

RCL using a cell line permissive for

the RCL most likely to be generated.

Regulatory requirements are to test

1% of the total cells or 108 (whichever

is less) pooled vector-producing cells

by co-culture with a permissive cell

line. For supernatant, at least 5% of

the total production harvest must be

tested by amplification on a permis-

sive cell line. Infectivity assays on cell

supernatants or co-cultivation assays

for RCL require several passages of

detector cells and can take up to five

weeks to complete in the laboratory.

At present, most ex-vivo therapies

involve autologous donors where

no screening for adventitious agents

before transduction is done. After

transduction, cells are tested using

assays for sterility, absence of myco-

plasma, RCL, and endotoxin. If the

cell therapy product can be cryo-

preserved prior to administration

Table I: Assays to characterize cell lines and viral vectors. MCB is master cell bank. WCB is working cell bank.

AssaysHuman 293 producer cells Lentiviral

vector(Bulk harvest)

Lentiviral vector

(Purifed)

Ex vivo transduced

cellsMCB WCB

Identity

Isoenzyme analysis X X

DNA fingerprinting X X

Genetic identity by sequencing of transgene X

Genetic identity by restriction enzyme digest X

Absence of microbial contamination

Sterility assay X X X X x

Qualification of sterility assay X X X x

Mycoplasma assay X X X x

Qualification of mycoplasma assay X X x

Absence of adventitious viruses

In vitro assay for adventitious viruses (3 detector cell lines, 28-day assay)

X X X

In vivo assay for adventitious viruses (embryonated eggs, suckling and adult mice, GPs)

X X

Transmission electron microscopy X

PCR/RT-PCR assays for human viruses X

PERT assay X

Bovine virus assay X X X

Porcine virus assay X X X

Porcine circovirus X X X

Absence of replication competent vectors

Replication competent lentivirus X X X

Other tests

Titre of vector (infectivity and transducing efficiency)

X X X

Host cell DNA X

Host cell protein X

Residual bovine serum albumin X

Residual plasmids X

Osmolality X

pH X

Endotoxin X X


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back into the patient, classical assays

for sterility and mycoplasma (which

can take up to 28 days to perform)

can be used.

However, in many cases, it is not

possible to freeze cells, and in these

cases, rapid tests must be used. This

could be PCR (polymerase chain

reaction) for mycoplasma, and

rapid-cell-growth-based micro-

biological assays that can take

less than three days, rather than

the 14-day sterility assay. When

transduced cells cannot be frozen,

regulatory authorities have asked

manufacturers to use a rapid assay

for replication competent retrovirus

(RCR) or RCL, such as PCR or PCR-

based reverse transcriptase assays,

which can be completed in days.

The longer assays for sterility and

co-cultivation assays for RCL should

also be run for initial studies—even

if final assay results are only avail-

able after the patient has been

treated with the cell therapy.

TeSTinG STRATeGieSSafety and other testing for charac-

terization purposes can be done at

select testing laboratories. The qual-

ity standard under which testing is

performed varies with geographic

region and stage of clinical devel-

opment. In the US, the testing of

starting materials such as cell banks,

process intermediates, and drug sub-

stance for Phase I/II clinical trials

may be performed to good labora-

tory practice (GLP). In the European

Union, even for materials for early

clinical trials, all manufacturing

and quality control testing must be

performed in licensed premises to

cGMP standards.

Assays to detect adventitious agents

need to be at least generically vali-

dated. All assays used for quality con-

trol of clinical material must be fit for

purpose, and information about the

specificity, sensitivity, and reproduc-

ibility of the assay system should be

available. The extent of this qualifi-

cation/validation data will increase

to support later-stage clinical trials

and product licensure. To navigate

through the regulatory guidance and

to implement a suitable testing strat-

egy, the support of experienced test-

ing laboratories can be valuable.

Testing of master and working

cell banks is focused on safety and

identity. For safety testing, absence

of microbes is tested in sterility and

mycoplasma assays. Testing to show

absence of viruses requires the use

of a number of different assays:

broad specificity assays that detect

a broad range of viruses by exami-

nation for cytopathic effects and

haemadsorption in vitro; mortal-

ity/morbidity on embryonated eggs,

mice and guinea pigs; and trans-

mission electron microscopy.

PCR and reverse transcription PCR

(RT-PCR) assays are used to detect

viruses that are not detectable in

the cells used for the in-vitro assay,

and PCR-based reverse transcriptase

(PERT) assays are used for the detec-

tion of endogenous and adventi-

tious retroviruses. In addition, cells

are tested for identity by isoenzyme

analysis and DNA fingerprinting.

Plasmids used for transfections to

produce viral vectors require test-

ing for sterility and endotoxin to

assure removal of all microbes used

in their production. It is also crucial

to confirm the viral vector specific

sequences to assure generation of

a homogeneous vector population.

Plasmid purity, as well as stability, is

essential to enable consistent trans-

fection efficiencies.

Cell-bank and viral-vector test-

ing have a strong focus on adventi-

tious agent testing, specifically when

using FBS or other animal-based

materials in the manufacturing pro-

cess. In addition, testing for replica-

tion competent viruses is required

for manufactured viral-vector lots to

ensure no infectious lentivirus was

generated via recombination events

during the manufacturing process.

More recently, the emergence

of massive parallel sequencing

(MP-Seq) technology provides the

opportunity of sequencing total cell

genomes quickly. This allows screen-

ing for the presence of unknown

adventitious agents, as well as the

analysis of the homogeneity and sta-

bility of vector populations. Already,

these methods are applied in evalua-

tion of unexpected test results in col-

laboration with regulatory agencies.

As a cGMP requirement, all raw

materials used in production should

be tested for identity. Bovine serum

should be screened for growth pro-

motion ability, absence of adventi-

tious bovine viruses, and levels of

anti-BVDV neutralizing antibodies.

Porcine trypsin should be screened

for absence of stable viruses such as

porcine parvovirus, porcine circovi-

rus, and porcine hepatitis E virus.

ConCLuSionAs the fields of gene and cell therapy

continue to evolve, new vectors and

applications are being explored, and

new adventitious agents are being

discovered. The testing strategies will

require adjustments, and will become

even more complex. However, new

testing technologies like MP-Seq will

add to the repertoire of testing, and

will eventually make the advancing

gene and cell therapy products safer,

and product progression more effec-

tive. In the case of the emergence

of the CAR T cell therapies, devel-

opment of novel treatments will

provide more options and drive the

development of gene and cell therapy

forward to cure patients.

ReFeRenCeS 1. EMA, CHMP/BWP/2458/03 (May 2005).

2. FDA, Guidance for Industry: Guidance

for Human Somatic Cell Therapy

and Gene Therapy (March 1998).

3. FDA, Supplemental Guidance on Testing

for Replication Competent Retrovirus

in Retroviral Vector Based Gene

Therapy Products and During Follow-

up of Patients in Clinical Trials Using

Retroviral Vectors (November 2006).

4. USP <1047> “Gene Therapy

Products” USP 37.

5. European Pharmacopoeia, 5.14

“Gene Transfer Medicinal Products

for Human Use” Jan. 2010. ◆



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Cellular therapies are posi-

tioned to be the next revolu-

tion in the healthcare industry.

Disciplines such as bio-print-

ing and tissue engineering also require

high quality living cells and can be

considered a part of the overall cellular

therapy industry. Multiple diseases that

were traditionally incurable are being

addressed by cellular therapies with

promising early clinical results. Both

large and small companies are devel-

oping cellular therapies, and currently,

more than a thousand clinical trials are

being conducted (1).

Stem cells are unique in their ability

to divide and regenerate themselves and

in their ability to remain unspecialized

or differentiate into specialized cells

that can perform critical tasks in the

human body. Because of these unique

traits, these cells hold a great deal of

promise in helping researchers learn

about disease and develop treatments.

The regenerative properties of stem cells

are proving useful in developing treat-

ments for common conditions such as

diabetes, heart disease, Parkinson’s dis-

ease, spinal cord injuries, and strokes.

There are two primary categories of

cellular therapies: autologous and allo-

geneic. Autologous therapies are patient-

or donor-specific; allogeneic therapies

generally do not have a specific donor or

source requirement. Each therapy pres-

ents opportunities for treatments, but

also faces unique challenges to overcome

before it can get to the clinic. Autologous

therapies typically are not scalable; allo-

geneic therapies are scalable from a man-

ufacturing perspective. The number of

product doses that can be manufactured

or required for a single patient for an

autologous therapy are limited compared

to a scenario where multiple patients can

be treated using the same off-the-shelf

allogeneic therapy.

MANUFACTURING UNIT OPERATIONSAlthough recent scientific and techno-

logical advances in the cellular therapy

arena portend great therapeutic promise,

the final objective is to accelerate the

development path of these therapies to

the clinic and make them universally

available to all patients. Several steps

along the pathway are fraught with

challenges that institutions and bio-

pharma will face in the attempt to com-

mercialize these products.

One approach is to segment the

various steps of the development pro-

cess into discrete unit operations. This

approach has been successfully imple-

mented in the manufacture of chemi-

cals, automobiles, and food, as well as

other pharmaceutical industry sectors.

The lessons learned can be applied to the

development of cellular therapies. It is

here that cell biology meets engineering

with the application of sound manufac-

turing principles. These unit operations

range from science and discovery to

the successful execution of clinical tri-

als and commercialization of product.

This article focuses on the manufactur-

ing operations that include supply chain

management of raw materials, manufac-

turing processes with facility capabilities,

quality control, quality assurance release,

regulatory requirements, and shipping

and distribution.

Each unit operation needs to be scal-

able to effectively meet clinical demand.

The volume and complexity to make

product for an early-phase clinical trial

is different when compared to what is

required at commercial scale-up. There

is a need for process development

within each unit operation and while

Standardizing Practices for Cellular Therapy Manufacturing

Uplaksh Kumar and Naynesh R. Kamani

Cellular therapy

developers learn process development

strategies from pharma

industry experiences.

Uplaksh Kumar, PhD, MBA, is a cGMP

expert on the AABB Consulting Services

team. Naynesh R. Kamani, MD, is

the division director for the Center for

Cellular Therapies and Research at

AABB Center for Cellular Therapies.




the process starts out being flex-

ible, it needs to be locked in by

Phase III and before commercial

launch. An important component

of this overall strategy is to iden-

tify each of these requirements

early in the process.

Cost drivers increase as the

product moves through the dif-

ferent phases of clinical develop-

ment with the majority of the

costs closer to commercialization.

While safety and efficacy are pri-

mary drivers, the cost of the final

therapeutic product is also impor-

tant for therapies to be univer-

sally accessible; there should be no

limitations in getting these thera-

pies reimbursed and delivered to

patients (2).

Regulatory affairs

Regulatory requirements for dif-

ferent cell therapies are at differ-

ent stages of development, and

national and international regula-

tory agencies are discussing guid-

ance documents for the industry

to follow. The regulators are will-

ing to provide significant support

to drug developers and will work

with organizations to determine

the correct path forward, resulting

in a clear regulatory path to the

clinic. Japan’s regulatory agency,

for example, has recently retooled

its drug authorization framework

through legal reform to produce

the world’s fastest approval process

specifically designed for regenera-

tive medicine therapies (3).

Supply chain management

Supply chain management of key

materials is the first unit operation

within manufacturing. Cellular

therapies depend on the acquisi-

tion of the right source material

that, in most cases, is derived from

tissue or blood. A good donor

program needs to be established

to ensure that reproducible pro-

cedures are in place using stan-

dard methods to procure material.

While there are several options that

work well, there is limited stan-

dardization in approaches. Using a

standardized accreditation process

for blood and tissue sourcing, enti-

ties will help establish that the pro-

cess being followed is uniform and

consistent. Donor-to-donor vari-

ability will exist, so eliminating the

collection process as a variable will

improve reliability.

Another issue is a short supply

of serum, a critical raw material

in the supply chain. Projections

indicate that there is insufficient

serum to meet the commercial

demands for cell therapy (4). Using

synthetic biology approaches

with computational modeling can

identify substitutes to serum that

are more abundantly available. A

synthetic biology approach also

offers better characterization and

chemical definition, which will

help deliver a consistent prod-

uct and streamline the regulatory

pathway. Many media developers

have launched serum-free media,

which are also under evaluation to

address this bottleneck. Using raw

materials and consumables that

are well characterized and from

qualified suppliers is important.

Suppliers should have quality sys-

tems in place and open to an audit.

Facility design

The manufacturing facility needs

to be built and equipped with the

appropriate infrastructure and

environmental controls. Options

include building a facility, contract

manufacturing, and using modular

pods that are prefabricated and can

be implemented quickly to meet

requirements. Autologous cell-

therapy production may be biased

towards having a modular facility

for each product dose to minimize

cross contamination. Allogeneic

facilities can be designed in a ball-

room arrangement, as each pro-

duction lot represents multiple

doses made at larger scales.

Because terminal sterilization

for cellular therapies is limited, it

becomes important to minimize

open system processing where a

contaminant can be introduced

into the system and lead to failed

product batches. Open-system pro-

cessing requires a higher degree of

personnel training, aseptic process

validation, stringent environmen-

tal controls, and increased costs.

Using methods to ensure maxi-

mum closed-system manufacturing

with automation will reduce some

of the requirements on the facility.

Scale-up and manufacturing

Most manufacturing processes

start off being manual as they are

developed in a laboratory-based

environment with only small

quantities required for preclinical

testing. These processes are sel-

dom scale-up friendly and require

significant process development

efforts to get them ready for large-

scale production. Organizations

face this dilemma when they

review the process development

costs versus moving the process

as-is into clinical manufacturing.


Several steps along

the pathway are

fraught with

challenges that

institutions and

biopharma will face in

the attempt to

commercialize cellular

therapy products.



Technology transfer of the labora-

tory based process may work in the

short term, but creates issues when

the only option available is scale-

out to achieve required product

volumes.

Research and development scien-

tists require insight into what scale-

up options exist with protocols

and application notes. These proto-

cols will provide early opportuni-

ties to identify processes that can

be easily translated into large-scale

formats with some process devel-

opment. Process development and

technology transfer will always be

required but using standard meth-

ods will streamline the process.

When developers are working with

T-flasks, they seldom think about

transitioning into multi layers ves-

sels and bioreactors. Producing 10

million cells can be achieved in a

laboratory environment but when

cells have to be produced at the bil-

lion to trillion scale, technology

requirements are different. Some

of this development can be done

via computational modeling or

small-scale experiments using well-

characterized methods that have

been qualified for their scalability

potential. Large-scale experiments

are expensive to run and while large,

well-funded organizations have the

resources, smaller organizations

will find it cost prohibitive. Cost-of-

goods modeling is required as the

drug products approach commercial

launch. By understanding the driv-

ers of cost early in the development

phase, the process can be optimized

while there still is some flexibility.

Once the process is locked down,

much work and expense is required

to establish equivalence with the

previous process.

Automation options should also

be evaluated to determine which

steps of the process can be auto-

mated. Several automation options

can be plugged in without exten-

sive customization and process

development. For example, auto-

mated and semi-automated filling

systems for the final dose of the

product are not only a faster and

scalable than manual processes,

they also minimize the oppor-

tunity for contamination. Other

options from the pharmaceuti-

cal industry and other ancillary

industries can be leveraged. Several

academic and industrial consortia

are being created to generate stan-

dardized platforms and methods to

be used across a wide spectrum of

requirements.

Quality control/assurance

Intermediates used in the manu-

facturing process and the final

product must go through quality-

control testing prior to release.

Multiple assays and methods are

available to address sterility, safety,

and efficacy. Many assays may

seem relevant but have no conse-

quence on the drug product. The

development of the acceptance

criteria should be relevant. Doing

more assays does not necessarily

impact outcome but doing the cor-

rect assays with the relevant accep-

tance criteria is important.

Shipping and distribution

The drug product must reach clini-

cal sites without compromising its

sterility, safety, and potency; there-

fore, bio-preservation and cold

chain management need to be

addressed. Standard off-the-shelf

bio-preservation options have been

successfully used with support-

ing regulatory documentation (5).

Evaluating existing options from

the industry is recommended before

designing custom options and will

help in the regulatory submission.

Most cel lular therapies are

shipped and distributed under liq-

uid nitrogen at -80°C or -20°C con-

ditions. Many vendors and service

providers meet national and inter-

national requirements. In addition,

new technologies stabilize these

cells at higher temperatures with-

out compromising viability, shelf

life, and efficacy. Final shipping

and distribution costs can consti-

tute more than 25% of the product

cost, a factor that should not be

underestimated during the budget-

ing process.

ThE PATh FORWARDChallenges will always exist when

launching new therapies and tech-

nologies. Established expertise

from other fields can be leveraged

and applied to cellular therapies.

Options and tools are available to

address each of these challenges.

Execution of a commercialization

strategy can be done in multiple

stages over time and, most impor-

tantly, when required. In some

cases, the investment needs to be

made early enough to be ready for

the next stage.

Accelerating a cellular therapy to

clinic can be executed by identify-

ing the relevant unit operations;

identifying the major components

within the unit operation and

those that need the most atten-

tion; leveraging existing expertise

or standards; implementing the

right solution; and validating the

implementation.

It is only a matter of time before

treatments become available for

diseases that were considered

difficult to cure. The industry is

focused on the promise of deliv-

ering effective cellular therapies

worldwide.

REFERENCES1. Alliance for Rengerative Medicine,

Regenerative Medicine State of the

Industry briefing (January 2014), http://

alliancerm.org/sites/default/files/ARM_

SOTI_PPT_2014.pdf, accessed Oct. 15,

2014.

2. R. Shaw, B. Hampson, C. Betz,

Bioprocessing Journal, 13 (2), 26-31

(2014).

3. D. Cyranoski, Nature Medicine. 11 (9),

510-513 (2013).

4. S. Jung, K.M. Panchalingam, R.D. Wuerth,

L. Rosenberg, L.A. Behie, Biotechnol Appl

Biochem. 59 (2), 106-120 (2012).

5. AJ Mathew, Cryobiology. 67 (3), 412

(2013). ◆



PREPARING FOR THE NEW

ELEMENTAL IMPURITIES GUIDELINES(Original air date Tuesday, October 14, 2014) ON-DEMAND WEBCAST

For questions, contact Sara Barschdorf at [email protected]

EVENT OVERVIEW:

The bio/pharmaceutical industry has long anticipated revised

guidelines for elemental impurities limits and testing. While

many questions about the fnal guidelines, as defned in the

International Conference on Harmonisation (ICH) in Q3D

Guideline for Elemental Impurities and the United States

Pharmacopeia (USP) in General Chapters <232> and <233>

still remain, organizations should begin to initiate plans to

transition to these new guidelines now.

In this webcast, experts from pharmaceutical and excipi-

ent manufacturers and analytical testing services will discuss

key areas of concern including risk assessment, proposed

test methods, and sample preparation techniques. Audience

members will have the opportunity to ask questions about the

pending implementation.

Key Learning Objectives

n Review expected requirements for ICH Q3D and USP <232>

and <233>

n Understand key areas is a risk assessment and factors that

afect risk

n Learn appropriate methods and procedures for sample

preparation.

Who Should Attend

Presenters

John Glennon

Stability Lab Team Leader

Supply Chain Stability Testing Hub

ZEB Quality

NA, Japan & Global Pharma Supply

GSK

Nikki Schopp

Team Leader

Analytical Laboratory Services

SGS Life Science Services

Moderator

Rita Peters

Editorial Director

BioPharm International

Presented by

Sponsored by

Register for free at www.biopharminternational.com/elemental

n QA/QC personnel

n Laboratory managers

n Formulation scientists

n Production and process

development managers



Co

lin A

nd

ers

on/G

ett

y Im

ag

es

Using a design-of-experiment

(DoE) approach a l lows a

formulat ion development

scientist to examine the for-

mulation design space in a statistically

significant manner from the beginning

of experimentation. In addition, a DoE-

driven approach meets the International

Conference on Harmonization Q8

guidelines for multivariate design space

and the subsequent justification of for-

mulation components when develop-

ing a drug product, according to Steven

R. LaBrenz, scientific director, pharma-

ceutical development and manufactur-

ing sciences with Janssen Research &

Development. At the same time, DoE

results depend on the selected criti-

cal parameters and the sample mate-

rial used in the studies. In addition, a

large amount of data is generated.

Consequently, reaping the benefits

requires a significant commitment to

DoE, including the training of research-

ers in study design and data-processing

techniques.

The benefiTs of DoeOne of the major advantages of the

DoE approach is the ability to study

the effects of multiple excipients and

their interactions in a formulation

at the same time, unlike in the tradi-

tional one-factor-at-time approach,

which is inherently flawed and biased,

according to Mark Yang, director of

fill/finish development for Genzyme.

Phuong Nguyen, a senior scientist with

Millennium Pharmaceuticals (The

Takeda Oncology Company) agrees with

Doe Provides benefits, but Preparation is necessary

Cynthia A. Challener

Defining critical parameters

and processing large quantities of data can be

a challenge.

Cynthia A. Challener is a contributing

editor to BioPharm International.

formulation Development



this approach. “The quantitative

models for these multiple qual-

ity attributes can then be used for

global optimization of the formu-

lation, leading to more robust for-

mulation development,” she says.

Nguyen also notes that depend-

ing on the data that are generated

from an experimental design, it is

sometimes possible to gain some

mechanistic understanding of pro-

tein stabilization or behavior.

In addition, because multiple

variables can be explored at once,

fewer formulation studies are

required and, therefore, formula-

tion development is more efficient.

An added benefit of this efficiency,

Yang notes, is the reduced quantity

of material needed for formulation

development, which can be impor-

tant early in the development of a

biopharmaceutical product given

the limited availability of the bio-

logic API. Further, a DoE approach

can be particularly useful for com-

bination products that have device

attributes that must be considered

during formulation development,

says Nguyen.

The challenges of DoeWhile there clearly are numer-

ous advantages to using a DoE

approach in the formulation devel-

opment of biopharmaceuticals, it

is important to bear in mind that

there are also limitations to con-

sider with this method.

Two main challenges, asserts

LaBrenz, include the fact that sam-

pling of an adequate design space

is often difficult and there is an

overwhelming amount of data that

is generated with factorial design.

Yang agrees that the typical subset

of critical quality attributes of the

formulated product that are assayed

in a DoE study may not be com-

prehensive enough to cover some

of the quality changes that can

occur. Nguyen also warns that the

models used for DoE formulation

studies may include statistically

significant parameters that may

not be of any importance, such as

when the resulting change from an

input parameter range is within the

error of the method or is not large

enough to have a real effect.

In addition, Yang notes that the

API material used in DoE studies

comes from one or possibly a few

selected primary production lots

that are not necessarily completely

representative of later production

lots. “As a result, the conclusions

drawn based on DoE formula-

tion studies can be biased to some

degree,” he says.

LaBrenz believes that the chal-

lenges of a limited design space

and the management of large

quantities of data can be amelio-

rated with the adoption of high-

throughput sc reening (HTS)

techniques that provide both full

design space coverage and the abil-

ity to collect data in spreadsheets

and, eventually, databases.

Even with the use of HTS, how-

ever, implementation of DoE for

formulation development can be

time consuming and resource

intensive and can translate into

more extensive exper imenta-

tion than planned, according to

Nguyen. “It is a challenge to bal-

ance the number of experiments

required for a statistically robust

DoE study with the available sup-

plies, personnel, resources, and

time,” she says. In addition, user

training is a must, according to

Yang. “DoE study design and data

processing requires an understand-

ing of statistics theory and mod-

els, which can be challenging for

many new users,” he comments.

obTaining relevanT DaTaIn most DoE formulations studies,

data related to the critical quality

attributes and the stability of the

API, such as the protein melting

temperature, secondary or tertiary

structure, or other biochemical/

biophysical characteristics, are

generated. The ultimate goal for

formulation development is to

maintain the API in a stable state

with respect to both structure and

function during processing and

storage, according to Yang. Nguyen

points out that all of the previously

mentioned parameters may serve

as indicators for a stable state.

It is also important to reduce

the data to single-value results

as often as possible, such as the

percent monomer or aggregate as

determined using size exclusion

chromatography-high performance

liquid chromatography (SEC-HPLC),

or the percent purity. For spectral

data from characterization assays,

Janssen calculates the Center

of Spectral Mass Wavelength (or

Mean Center Mass), which allows

the creation of a relative stability

profile for a given spectrum-based

assay. “This single-point, continu-

ous, data-point strategy is readily

testable using most statistical meth-

ods,” LaBrenz explains. In addition,

Nguyen notes that the generated

stability data can be reduced down

to a reaction rate constant or an

output parameter used to develop

statistical models. “Overall,” she

summarizes, “data on quality attri-

butes are generated that will pro-

vide an understanding of how the

excipient or formulation within the

design space affect these attributes.”

Because DoE studies lead to the

production of large quantities of

data, it is important to ensure

that all of the data that are col-

lected are actually relevant. “A

thorough understanding of the

API and desired formulation char-

acteristics is necessary before ini-

tiating a DoE study,” says Yang.

“With such knowledge, a scientist

can make sound scientific judg-

ments and consider the potential

impact of new factors or excipi-

ents when designing a DoE study.”

formulation Development

Contin. on page 40



We

st

en

d61P

re

miu

m/G

et

ty

im

aG

es

Manufacturers exploring

opportunities in global

markets face dynamic

demographic and disease

trends, changing market demands, and

evolving regulatory requirements—all

of which differ from one country to

another. While emerging markets con-

tinue to represent a new channel of

demand for pharmaceutical products,

manufacturers have quickly realized

that significant attention must still

be given to more established markets,

such as Germany. It’s no longer suf-

ficient to expect that regulatory data

from prospective randomized clinical

studies alone will be enough to con-

vince payers to provide a price pre-

mium for new products. In this article,

the authors take a look at some of the

recent developments in the German

pharmaceutical market, identify pric-

ing and reimbursement challenges, and

discuss strategies manufacturers should

consider for sustainable success.

Overview Of German market and amnOG Germany is the third largest phar-

maceutical market worldwide and

accounts for approximately 23% of

the European pharmaceutical market

(1). Of equal importance to manufac-

turers, drug prices in Germany are

often used as reference prices in 19

other countries. Taken together, gain-

ing access to this market at an accept-

able price has major implications

for long-term success. In a cost-con-

strained economy, the German gov-

Germany Post amnOG: insights for BioPharma

Jill E. Sackman andMichael J. Kuchenreuther

The authors take a look at some of the recent

developments in the German pharmaceutical

market.

Jill E. Sackman, DVM, PhD, is a

senior consultant, and Michael

Kuchenreuther, PhD, is a

research analyst, both at numerof

& associates, inc., St. Louis, mO,

www.nai-consulting.com.

european market report



ernment has taken steps to

reduce healthcare spending, and

unfortunately for manufactur-

ers, one way they have sought to

do this is through The Act on the

Reform of the Market for Medical

P roducts (A rzneimit te lmarkt-

Neuordnungsgesetz—AMNOG).

This piece of leg islat ion was

enacted in 2011 and mandates a

more rigorous benefit evaluation

procedure for new pharmaceuti-

cals (and their subsequent label

expansions), thereby adding sig-

nificant challenges to the market

access process.

In AMNOG’s new system, manu-

facturers continue to set the ini-

tial price for new prescription

drugs after regulatory approval.

This price is valid for one year.

During this time, the manufac-

turer’s value dossier is reviewed


Table I. Decision criteria for G-BA’s/IQWiG’s beneft assessment.

Input CategorizationFactors shown to impact categorization decision

Qualitative

certainty of results

Proof, indication,

hint or no proof

Number of appropriate clinical studies available; use

of valid measurement instruments; risk of bias (e.g.,

non-blinding); endpoint type (e.g., hard, surrogate)

Quantitative extent

of added benefit

Major, considerable,

minor, non-quantifiable,

no added benefit, or

reduced benefit

Effect size at outcome level, confidence

interval associated with effect

Table II. G-BA decision breakdown on “Degree of Added Beneft” for new

pharmaceuticals within a specifc patient subpopulation (N=169).

Degree of added beneft Percent of cases

Major 0%

Considerable 10%

Minor 25%

Not quantifiable 7%

Lower 1%

Not proven 57%

For exhibit & sponsorship opportunities, contact:

Companies A-K:

Jason Gerardi

781-972-5452

[email protected]

Companies L-Z:

Carol Dinerstein

781-972-5471

[email protected]

Cambridge Healthtech Institute’s 14th Annual

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January 19-23, 2015

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Be a Part of It!



AL

L F

IGU

RE

S A

RE

CO

UR

TE

SY

OF

TH

E A

UT

HO

RS

by the Federal Joint Committee

(G-BA), which represents the

se l f-governance st r uc ture of

the German healthcare system.

With the help of the Institute for

Quality and Efficiency in Health

Care (IQWiG), an expert Health

Technology Assessment (HTA)

body, the G-BA determines the

level of added benefit of the new

drug relative to the appropriate

comparative therapy (ACT) cho-

sen by the G-BA as well as the

certainty of evidence presented

by the manufacturer. A br ief

description of these two inputs

that go into the G-BA’s final deci-

sion is included in Table I. Patient-

relevant criteria for additional

medical benefit include improv-

ing health, extending survival,

shortening the burden of i l l-

ness and reducing side effects, or

improving quality of life, and are

outlined in the IQWiG method-

ology paper (2). Originally, the

law was written to include the

possibility that patented products

already on the market would have

to undergo retrospective benefit

assessments; however, manufac-

turers were recently spared from

this potential headache (3).

Once the G-BA reaches a final

conclusion, pricing negotiations

begin with the statutory health

insurance (SHI) umbrella orga-

nization, GKV–SV (Gesetzliche

K r a n k e n v e r s i c h e r u n g –

Spitzenverband), which nego-

tiates on behalf of all SHIs and

also private sickness funds in

Germany. It is important to high-

light that the ACT is not only

used by the G-BA in its assess-

ment, it is also the price anchor

for these negotiations. For drugs

found to have no added benefit,

their price is capped in reference

to the price of the comparator.

Reference pricing to the compara-

tor can be either advantageous if

the ACT is already a high-priced

therapy or devastating if the ACT

is a generic drug. Thus, manu-

facturers looking to enter break-

through therapeutic areas where

the current standard treatment

is a generic will be particularly

challenged. Therapeutic prod-

ucts that demonstrate added ben-

efit are priced above the ACT but

may still face a minimum price

reduction of 7% (formerly 16%)

by law, unless it has been replaced

as part of the price negotiations.

Unfortunately for manufactur-

ers, while the number of prod-

ucts that have gone through the

entire assessment and pricing pro-

cess remains small since the law

was enacted three years ago, early

evidence suggests only limited

correlation exists between ben-

efit ratings and price reductions.

Rather, G-BA’s benefit rating has

primarily served as a door opener

for price negotiations (4).

SnaPShOt Of Benefit aSSeSSmentS and PricinG neGOtiatiOnS under amnOGAs of May 2014, 79 products have

been assessed by the G-BA within

169 patient subpopulations. More

than 50% of these early benefit

assessments have led to ‘no added

benefit’ rulings by the G-BA (see

Table II) (5). Not surprisingly, there

has been considerable variance

observed in the levels of addi-

tional benefit reported by phar-

maceutical manufacturers and the

G-BA. In contrast, the G-BA’s deci-

sions have more closely resembled

IQWiG’s recommendations with a

few notable exceptions (e.g., beli-

mumab, cabazitaxel, eribulin) (6).

Reasons the G-BA has offered for

‘no proven added benefit’ include

inadequate comparator, lack of

a relevant study to back claims

of benefit, lack of data on poten-

tial harms, and omission of data

for relevant patient subpopula-

tions. A more detailed breakdown

of the G-BA’s negative rulings as

of October 2013 is presented in

Figure 1 (7).

As Figure 1 i l lustrates, even

though the outcome of bene-

fit assessment is a key driver of

price negotiations, manufactur-

ers have not always prepared dos-

siers adequately. This, in turn,

compromises the outcome of the

assessment and subsequent price

that is agreed upon. Such prob-

lems with incomplete or inade-

quate evidence may be overcome


Figure 1. Reason for no proof of added beneft ruling for new pharmaceuticals

within a specifc patient subpopulation (N=113).

32%38%

20%

10%

Evidence inappropriate

Appropriate comparatornot considered

No beneft shown

Evidence incomplete




as drug makers gain better under-

standing of the requirements.

To this end, the Federal Joint

Committee offers consultation

opportunities for manufacturers

to give advice on trial design (e.g.,

patient segmentation, compara-

tor selections, and endpoints). Not

all manufacturers, however, have

communicated with the G-BA to

discuss the technical issues and

challenges around preparation of

the benefit dossier, or earlier to

discuss the clinical trial (6).

Despite the market access

challenges that manufacturers

have experienced so far, only a

few products have been pulled

despite negative G-BA rulings and

demands for substantial rebates.

Novartis became the most recent

manufacturer to do this, with-

drawing its oral anti-diabetic

Galvus from the German market

after failing to secure a mutually

beneficial price with payers (8).

Given the size and revenue poten-

tial associated with this market-

place, the fact that few products

have been pulled is not surprising.

However, Hagen Pfundner, the

chairman of Germany’s pharma

lobby VFA and head of Swiss

drugmaker Roche’s German unit,

believes that a recent update to

the AMNOG legislation could lead

to “an increasing number of opt-

out decisions” (9). In the past, a

product’s original launch price in

Germany served as the published

list price for other markets. This

approach is no longer the case.

Since April 2014, the newly nego-

tiated reimbursement amounts

are published as visible ex-factory

prices, effectively replacing the

original list prices as source for

referencing. Drug makers fear the

information could challenge the

entire pricing framework within

Europe (and globally) either caus-

ing a downward spiral in reim-

bursement across the reg ion

or heavy parallel exports from

Germany to other countries. If

this new law is not overturned, it

poses a significant risk to profits

in the industry, especially consid-

ering that price discounts have

been as high as 70% following

G-BA’s benefit assessment and

range on average between 16–30%

(10). More broadly, the new rule

reinforces the importance of

manufacturers understanding the

nuances of this market and hav-

ing strategies in-place to achieve

successful market access.

recOmmendatiOnS fOr manufacturerSWhile Germany is certainly not

the only market that is enforc-

ing more stringent pricing and

reimbursement policies for new

therapeutic products, it is per-

haps scrutinizing the quality and

appropriateness of clinical data

more so than any other country.

Taken together with the fact that

other markets look to Germany to

determine pricing, manufactur-

ers should place a greater empha-

sis on G-BA’s recommendations

when structuring clinical studies.

To date, the majority of AMNOG

submissions did not have much

guiding input from the G-BA prior

to clinical study design and were

based on evidence generated on

Figure 2. Case summary of IQWiG’s beneft assessment of Kadcyla.

Drug

Indication

Subgroupsassessed by

G-BA

Comparatordefned by

G-BA

G-BA resolution

Notes

Kadcyla (trastuzumab emtansine, Roche)

Patients with unresectable, locally advanced or metastatic breast cancer that is HER2+

A. Patients with HER2+,locally advanced,unresectable breast cancer

Radiotherapy

No additional beneftproven (no relevantdata were available)

The company deviated from the G-BA’s specifcation by considering the total target population, for which it used lapatinib + capecitabine as comparator therapy.Thus, no added beneft was found for subpopulations A, C and D. For subpopulation B, there were positive effects in the outcome categories “mortality”, “health-related quality of life” and “serious/severe AEs”, and negative effect in the outcome category “non-serious/non-severe AEs.

No additional beneft proven(no relevant data were available)

No additional beneft proven(no relevant data were available)

Lapatinib + capecitabine

Indication of a major added beneft

Anthracycline (doxorubicin, epirubicin) Individual treatment under consideration ofthe respective approval of the drugs used

B. Patients with HER2+, metastaticbreast cancer, with prior treatmentwith anthracyclines, taxanes andtrastuzumab

C. Patients with HER2+, metastatic breastcancer, with prior treatment with taxanesand trastuzumab, but withoutanthracyclines

D. Patients with HER2+, metastatic breastcancer, with prior treatment with taxanesand trastuzumab, for whom treatment withanthracyclines is not an option



a pre-AMNOG world. Moving

forward, proact ively consult-

ing with the G-BA to define the

comparator(s), clinical endpoints

and patient cohorts will be essen-

tial. Manufacturers need to do

this early in product development,

especially prior to starting Phase

III trials. Internally, manufactur-

ers should also enhance commu-

nication between regulatory and

market access teams to strategi-

cally plan for both market autho-

rization requirements and G-BA’s

requirements.

Even before G-BA consulta-

tions, manufacturers need to give

greater consideration to the prod-

uct’s indication. While the indica-

tion does not determine how the

benefit assessment is conducted,

completed assessments indicate

that it can influence the G-BA’s

comparator choice and a pivotal

trial’s relevance. For products with

broad indications, IQWiG and the

G-BA are demanding clinical data

for multiple patient subpopula-

tions and against multiple ACTs.

For example, these commission-

ing bodies recently distinguished

between four subpopulat ions

and ACTs for Roche’s Kadcyla

(see Figure 2) (11). Manufacturers

that have failed to anticipate and

include such data are seeing a

significant reduction in the over-

all level of added benefit granted

to their products (e.g., Pixuvri

and Inlyta) (12). Moving for-

ward, manufacturers will need to

ensure that all relevant subpopu-

lations have robust and statisti-

cally significant clinical endpoints

to support reimbursement, with

increasing demand for quality of

life data. If the resources required

to study multiple populations

using multiple comparators are

too great, pursuing a narrower

indication for a clearly defined

patient population and against a

single comparator serves as a via-

ble alternative.

Manufacturers will also have to

keep in mind that every new indi-

cation for a product will trigger

another round of benefit assess-

ment and a new price negotia-

tion. Here, attempts to negotiate

a higher price with subsequent

indications may be met with resis-

tance by the GKV-SV and prove

to be a significant challenge for

manufacturers. Thus, drug makers

should give greater consideration

to the trade-off between a fast

product launch and the highest

value launch.

Aside f rom data col lect ion

and defining a product’s indica-

tion, manufacturers must also

develop a solid pricing strategy

earlier on in the product devel-

opment process and have capa-

bilities to better predict a products

negotiated price. There is cur-

rently no formula regarding the

rebate amount the pharmaceuti-

cal company has to grant on its

retail price. Furthermore, while

evidence demonstrating added

benefit is required to avoid refer-

ence pricing, it is by no means the

sole determinant of pricing deci-

sions. Rather, the extent to which

a product’s price will be marked

down following a positive benefit

assessment is largely dependent

on its original launch price as well

as the market size and price of

the appropriate clinical compara-

tor. As more products go through

the product review and pricing

process and as more data become

available, manufacturers should

consider developing algorithms

to forecast the benefit assessment

outcomes and the product’s final

net price.

The f irst three years of the

AMNOG reform have proven that

demonstrating added benefit is

no small feat for manufacturers,

and while complaints continue

to be heard from pharmaceutical

stakeholders, the law shows no

signs of slowing down. AMNOG

has not only set new rules for

reimbursement and pricing of

pharmaceuticals in Germany, it

also forces the industry to adapt

at a global level, rethinking how

it brings new products to market.

Manufacturers that prepare thor-

oughly for benefit assessment and

the negotiation processes within it

will be best positioned for success.

aknOwLedGementThe authors would like to thank

Stefan Seliger, PhD, for his review

and insights.

referenceS 1. German Pharmaceutical Industry

Association/BPI, based on IMS World Review 2012.

2. IQWiG, General Methods Version 4.1. (Nov. 28, 2013).

3. G. Collier, A tweak or an outrage? Germany passes new pricing law. March 24, 2014, www.scripintelligence.com/home/A-tweak-or-an-outrage-Germany-passes-new-pricing-law-350844, accessed Aug. 8, 2014.

4. IMS Consulting, Pricing and Market

Access Outlook–2013 edition. 5. LEO Pharma Germany, It´s difficult to

meet HTA criteria according AMNOG – reason why? (June 10, 2014).

6. J. Ruof, et al., Eur J Health Econ. 15, pp 577–589 (2014).

7. PRMA Insights, PRMA Insights Focus:

Pricing and Reimbursement Success in

Germany under AMNOG (2013) 8. F. Kermani, “Novartis Pulls Galvus

From Germany After Failed Price Negotiations,” The Pink Sheet Daily (June 19, 2014).

9. L. Burger and T. Severin, “Germany’s stance on pricing threatens drug firm profits,” Reuters, Feb. 18, 2014, http://uk.reuters.com/article/2014/02/18/us-germany-drugs-analysis-idUKBREA1H09E20140218, accessed Aug. 14, 2014.

10. D. Bahr and T. Huelskoetter, “Comparing the Effectiveness of Prescription Drugs: The German Experience” (May 21, 2014), www.americanprogress.org/issues/healthcare/report/2014/05/21/90120/comparing-the-effectiveness-of-prescription-drugs-the-german-experience/, accessed Aug. 14, 2014.

11. Institute for Quality and Efficiency in Health Care, Trastuzumab emtansine – Benefit assessment according to §35a Social Code Book V

12. C. Henry, “Oncology drugs under AMNOG,” PMLive (May 7, 2014). ◆




Yuji

Sakai/G

ett

y Im

ag

es

The past decade has seen con-

siderable growth in the Indian

pharmaceutical industry. India

has emerged as a key sup-

plier of high quality and affordable

medicines not only to the developing

world, but also to developed economies

as well (Figure 1A) (1). This sector has

recorded a compound annual growth

rate (CAGR) of 13.5% over the past five

years and is projected to reach $45 bil-

lion in 2020 (2). With the ongoing shift

from small molecules to biologics, the

Indian biopharmaceutical industry is

also set to replicate the success received

by the Indian pharmaceutical compa-

nies (Figure 1B) (1). The biopharmaceu-

ticals market has witnessed the fastest

growth in the 2013 financial year as

compared to other biotech markets

(e.g., Bio-Agri, Bio-Services, and Bio-

Informatics).

Growth in this sector has also bur-

dened the public institutions that

are responsible for ensuring that the

marketed products are safe and effica-

cious. In India, the Drug Controller

General of India (DCGI)-led Central

Drugs Standards Control Organization

(CDSCO) together with the State

Author it ies are pr imar i ly respon-

sible for ensuring the quality of bio-

tech therapeutics post-approval. The

Indian Pharmacopoeia Commission

(IPC), which creates and publishes

the Indian Pharmacopoeia (IP), how-

ever, plays a key role. The IP, as per

the Drugs and Cosmetics Act of 1940,

prescribes the standards for drugs pro-

duced and/or marketed in India and,

Setting Standards for Biotech Therapeutics in India

Anurag S. Rathore, Renu Jain, M. Kalaivani,

Gunjan Narula, and G. N. Singh

The authors take a look at the

past and future impact of the

Indian Pharmacopoeia

Commission.

Anurag S. Rathore* (pictured) is a

professor, Department of Chemical

Engineering, Indian Institute of

Technology, New Delhi, India. Renu

Jain is a scientist at National Institute of

Biologicals, NOIDA, India. M. Kalaivani

is a scientific assistant, Gunjan Narula

is a pharmacopoeial associate, and

G. N Singh is Secretary-cum-Scientific

Director at the Indian Pharmacopoeia

Commission, Ghaziabad, India.

*To whom all correspondence

should be addressed.

Global Perspective: Indian Pharmacopoeia Commission



therefore, plays a significant role

in the control and assurance of

the quality of the pharmaceu-

tical products (3). Unlike a lot of

developing and developed coun-

tries, the standards stated in the

IP are authoritative and legally

enforceable by the Indian regu-

latory authorities (CDSCO and

State Drug Regulators). In this

31st article in the “Elements of

Biopharmaceutical Production”

series, the authors report on the

evolution and future of IPC. The

focus of the article is on biotech

therapeutics.

INDIAN PHARMACOPOEIA COMMISSIONThe IPC was constituted in 1948

with publication of IP defined as

its primary function. The first IP

was published in 1955 followed by

a supplement in 1960. This phar-

macopoeia contained both western

and traditional Indian pharmaceu-

tical products commonly used in

India.

Thereafter, the IP has been pub-

lished at frequent intervals. The

frequency has increased with time

due to the phenomenal growth

in the number of pharmaceutical

products over the past five decades

as well as the diversity in their ori-

gin and content. Over time, the

IP committee has deleted mono-

graphs for products that have

become obsolete and added mono-

graphs based on the therapeutic

merit and medical need (3).

The IPC was established in 2005

and the first addendum, which was

published by IPC in 2005, included

a large number of antiretroviral

drugs and raw plants commonly

used in making medicinal prod-

ucts not covered by any other

pharmacopoeias, which attracted

much global attention. Similarly,

IP 2007 contained 271 new mono-

graphs with focus on those drugs

and formulations that cover the

National Healthcare Programs

and the National List of Essential

Medicines. The addendum in 2008

contained 72 new monographs (4).

The commission had become fully

operational as an autonomous

body under the Ministry of Health

and Family Welfare, Government

of India in 2009 and released IP

2010 (5). IP 2010 contained mono-

graphs on antiretroviral, antican-

cer, antituberculosis, and herbal

drugs. It also included monographs

of biologically derived products

such as vaccines, immunosera for

human use, blood products, and

other biotech and veterinary (bio-

logical and non-biological) prepa-

rations. Addendum 2012 to the IP

2010 incorporated 52 new mono-

graphs (Table I) (3).

The primary objectives of IPC

include the following:

• Develop comprehensivemono-

graphs for drugs and upgrade

them as needed

• Accord pr ior it y to mono -

graphs of drugs included in

the National List of Essential

Medicines

• Collaborate with other phar-

macopoeia (e.g., United States

Pharmacopeia [USP ], Br it ish

Pharmacopoeia [BP], Chinese

Pharmacopeia [ChP], European

Pharmacopoeia [Ph. Eur.], World

Health Organization [WHO],

and Japanese Pharmacopeia [ JP])

to attempt harmonization with

global standards

• Prepare,certify,anddistributeIP

Reference Substances

• PublishNational Formulary of

India

• Organize educational programs

and research activities to gener-

ate awareness about the need for

quality standards for drugs and

related articles/materials (3).

MONOGRAPHS OF BIOTECH THERAPEUTICSThe scope of IPC has been

extended to include products of

biotechnological origin, indig-

enous herbs and herbal products,

veterinary vaccines, and additional

antiretroviral drugs and formula-


Table I. Evolution of India Pharmacopoeia (IP) over the past fve decades. Source: Indian Pharmacopoeia (5).

IP Editions (By IP Committee) IP Editions (By IP Commission)

Year Edition Year Edition

1955 I 2005 Addendum

1960 Supplement 2007 V

1966 II 2008 Addendum

1975 Supplement 2010 VI

1985 III 2012 Addendum

1989 & 1991 Addendum 2014 VII (Recent)

1996 IV 2015 Addendum (To be published)

2000 Addendum

2000 Vet supplement

2002 Addendum



Al

l f

Igu

rE

S c

ou

rt

ES

y o

f t

hE

Au

th

or

S

tions, inclusive of commonly used

fixed-dose combinations. IP 2014

had 577 new monographs and

included monographs of API [134],

formulations [161], excipients [18],

new drug substances [43], antivi-

ral [11] and anticancer [19], anti-

biotics [10], herbal [31], vaccine

and immunosera for human use

[5], insulin products [6], and bio-

technology products [7]. IP 2014

also included 19 new radiopharma-

ceutical monographs and a general

chapter on radiopharmaceutical

preparations (4). Table II presents a

comparison of monographs related

to biotech therapeutics across the

different international pharmaco-

poeial bodies. It can be seen that IP

compares well with other leading

global agencies. Figure 2 illustrates

the evolution and key milestones

of IPC since formation.

CHALLENGES AND POSSIBLE SOLUTIONSWhile significant advancements

have been made in the past decade

by the IPC since its formation, the

complexities of dealing with bio-

tech therapeutics raise the bar fur-

ther. The following are some of the

key challenges IPC faces today with

respect to successful creation and

implementation of monographs of

biotech therapeutic products.

• Li m i t e d e x p e ri e n ce w i t h b i o -

te c h pr o ce ss e s an d pr o duc t s .

Limited experience with bio-

tech processes and products is

a challenge faced by many gov-

ernment organizations in India

and across the world. Approval

of the first recombinant DNA

pro duc t , hu m a n i n s u l i n ,

occurred only in 1982. The

experience is even more lim-

ited in India. The government,

through agencies such as the

Department of Biotechnology,

actively funds events that allow

for training and sharing of best

practices and lessons learned.

Such activities are essential

for gradually building a strong

foundation of in-house experts.

For the interim, IPC will con-

tinue to rely on the scientific

panels that presently provide

scientific and technical super-

vision (6).

• L a c k o f i n - h o u s e l a b o r a t o r y.

While IPC has a laboratory for

characterization of reference

standards related to pharma-

ceutical products, it is in the

process of creating a state-of-

the-art laboratory for biotech

products. At present, IPC relies

on the National Institute of

Biological (NIB) for this set of

activities.

• Creation of reference standards

for biotech therapeutics. Biotech

products are complex in nature

and, therefore, no two products

are exactly the same (7). This

really complicates the task of

creating a reference standard

for a biotech therapeutic. So far

such reference standards are

offered for only a handful of

simpler biotech products, such

as interleukin and insulin. IPC,

together with NIB, is working on

creating a robust strategy for cre-

ation, characterization, storage,

and distribution of these stan-

dards to support the domestic

biotech industry.

• Collaborations with other global

pharmacopoeial agencies. The

scope of activities at IPC along

with the complexities associ-

ated with biotech therapeutics

make it a necessary require-

ment that the various pharma-

copeial agencies work together

with a col laborat ive spir it.

IPC and USP have been work-

ing closely together and orga-

nize an annual conference to

share updates and ideas. Similar

relationships need to be pur-

sued with other global agen-

cies such as National Institute

of Biological Standards and

Control (NIBSC), and European


Figure 1. growth of the Indian (A) pharmaceutical industry and (B) biopharmaceutical industry.

50

45

40

35

30

25

20

15

10

5

0

1.4

1.2

1

0.8

0.6

0.4

0.2

0

2008 2009 2010 2011 2012 2013F

2003

-04

2004

-05

2005

-06

2006

-07

2007

-08

2008

-09

2009

-10

2010

-11

2011

-12

2012

-13

2014F2015F2016F2020F

USD

(B

illio

ns)

USD

(B

illio

ns)

YEARSYEARS

A BCAGR till now

CAGR expected

Export (billion dollars)

Domestic (billion dollars)




Directorate for the Quality of

Medicines (EDQM). As the IPC

grows in its capabilities, such

meaningful collaborations will

be mutually beneficial.

FUTURE PERSPECTIVEThe primary responsibil ity of

the IPC has been towards pub-

l ishing the IP at a f requency

that meets the requirement of

the industry and the country. IP

2014 included several biotech

monographs, and the next IP is

likely to include many new bio-

tech monographs as well in view

of the increasing dominance of

biotech therapeutics in the phar-

maceutical marketplace. IPC is in

the process of monograph verifi-

cation stage for rituximab drug

substance and drug product and

teriparatide drug substance and

drug product monographs. Many

new general chapters pertain-

ing to topics such as therapeu-

tic monoclonal antibodies, host

Table II: comparison of the status of monographs of biotech therapeutics across the various leading pharmacopeial

organizations across the world (8-12). IP is Indian Pharmacopoeia. chP is Chinese Pharmacopeia, uSP is United States

Pharmacopeia. BP is British Pharmacopoeia. Ph. Eur. is European Pharmacopoeia. JP is Japanese Pharmacopeia.

Biotech Monographs IP 2014 ChP 2010 USP 2013 BP 2014 Ph. Eur 2014 JP 2011

Erythropoietin Concentration Solution √ X X √ √ √

Erythropoietin for Injection √ √ X √ X X

Erythropoietin Injection √ √ X √ X X

Filgrastim Concentrated Solution √ √ X √ √ √

Filgrastim Injection √ X X X X √

Interferon Alpha 2 Concentration Solution √ X X √ √ X

Interferon Alpha 2a Injection √ √ X √ X X

Interferon Alpha 2b Injection √ √ X X X X

Interferon Beta 1a Concentration Solution √ X X √ √ X

Recombinant Streptokinase Bulk Solution √ X X X X X

Recombinant Streptokinase for Injection √ √ X X X X

Insulin Aspart √ X X √ √ X

Insulin Aspart Injection √ X X √ X X

Biphasic Insulin Aspart Injection √ X X X X X

Insulin Lispro √ X √ √ √ X

Insulin Lispro Injection √ X √ √ X X

Biphasic Insulin Lispro Injection √ X X X X X

Human Insulin √ X √ √ √ √

Insulin Injection Biphasic Isophane √ X √ √ √ X

Insulin Injection Isophane √ X √ √ √ X

Insulin Injection Soluble √ X √ √ √ X

Insulin Zinc Suspension √ X √ √ √ X

Insulin Zinc Suspension (Amorphous) √ X √ √ √ X

Insulin Zinc Suspension (Crystalline) √ X √ √ √ X

Insulin Glargine X X X X √ √

Human Glucagon X X √ √ X X

Human Glucagon for Injection X X √ X X X

Somatropin X X √ √ √ X

Somatropin Concentrated Solution X X X √ √ X

Somatropin for Injection X X √ √ √ X

Somatropin Injection X X X √ X X

Interferon Gamma 1b Concentrated Solution X X X √ √ X

Molgramostim Concentrated Solution X X X √ √ X




cell proteins and DNA, and viral

safety are in the works for the

next IP edition.

As mentioned previously, cre-

ating and implementing a pro-

cess for producing, storing, and

distributing reference standards

for biotech therapeutic products

is a key focus for IPC at present.

To establish these standards, can-

didate materials can be sourced

from multiple Indian manufactur-

ers (with certificate of analysis)

and calibrated against the origi-

nator product. Development of

reference standards for biotech

therapeutics can be done by col-

laborative studies involving the

manufacturers and other govern-

ment agencies such as the NIB.

The WHO International Standard

(WHO IS) could be considered

at the highest level of hierarchy

(primary standard) of reference

standard. The reference standard

should have the following key

components:

• Candidate materials sourced

from the manufacturers must

comply with the acceptance

criteria provided in the IPC

monograph. The cert i f icate

of analysis should be submit-

ted and should include the

critical quality attributes with

respect to identity, content,

and potency of the product.

Stability of the material should

be already established with

its formulation/presentation

defined by the manufacturer.

• Assessment of suitability of the

candidate material should be

evaluated by IPC with respect

to the content, formulation, and

final presentation of reference

standard material.

• A multi-centric collaborative

study should be planned to

verify the IP reference stan-

dard. The detailed study testing

protocol should include vali-

dated method to be followed

for analytical testing, storage,

and handling along with the

procedures for reporting and

submission of results.

Another major initiative for IPC

is establishing a laboratory for

verification of biological mono-

graphs and characterization of

the reference standards for bio-

logical products. The laboratory

will have state-of-the-art analyti-

cal instrumentation for testing/

analysis of biotechnology ther-

apeutics. The scope of the lab

includes:

• Development/verif ication of

methods and limits for biologi-

cal monographs

• Development of IP reference

standards for biotech therapeu-

tics

The success of these two initia-

tives is crucial for IPC to make a

meaningful contribution to the

Indian biotech industry.

SUMMARYWith biotechnology based thera-

peutics becoming increasingly

important to India, organizations

such as the IPC will need to evolve

to effectively do their part in the

process of bringing safe and effica-

cious therapeutic products to the

market. This article presents an

update on the challenges faced by

Figure 2. Evolution of Indian Pharmacopoeia commission over the past decade.

IP 2007(14 Monographs)

IP 2014(24 Monographs)

Next editionof IP

IP 2010

Addendum 2012(15 Monographs)

• Erythropoietin drug substance• Filgrsatim drug substance• Interferon alfa 2 drug substance• Streptokinase drug substance• Human insulin drug substance and drug products

• Erythropoietin drug substance• Filgrsatim drug substance• Interferon alfa 2 drug substance• Streptokinase drug substance• Human insulin drug substance and drug products

• Emphasis on Therapeutic Monoclonal antibodies and PEGylated products

• Erythropoietin drug substance and drug products• Filgrsatim drug substance and drug products• Interferon alfa 2 drug substance and drug products• Streptokinase drug substance and drug products• Human insulin drug substance and drug products• Insulin aspart drug substance and drug products• Insulin lispro drug substance and drug products



LaBrenz adds that developing the

proper experimental design space

before sett ing up DoE experi-

ments ensures that the parameter

critical for the stability of an API

is identified. More specifically,

conducting a screening DoE to

determine which product quality

attributes (and the corresponding

output parameters used to rep-

resent them) are relevant in the

design space is helpful, accord-

ing to Nguyen. Accelerated stabil-

ity studies can also be performed

to determine relevant output

parameters.

Another key to generat ing

appropriate and relevant data is to

make sure that normal-distributed

data, obtained either directly or

after transformation, are used. If

there is a major process change,

it is necessary to evaluate and

understand any impacts on the

protein and the formulat ion,

according to Yang, which may

mean conducting comparability

or bridging studies.

MANAGING THE DATAFor DoE studies to be useful, the

generated data must not only be

relevant, but manageable. There

are different approaches to address-

ing this problem.

The solution for LaBrenz is

to use an open, read-only data-

base that can be shared between

mult iple groups, such as pre -

formulation, formulation, and

analytical development groups,

so that each unit can focus on

particular aspects of interest in

a DoE. “While a formulat ion

scientist needs to know where

the most stable space for an API

resides, an analytical chemist

may be more interested in the

variability and reproducibility

of results, both of which can be

obtained from a well-designed

DoE,” he says.

Nguyen remarks that using soft-

ware to automate data collection

and extraction of the relevant out-

put parameters for statistical analy-

sis is important. She also stresses

that having an understanding of

which output parameters to col-

lect and limiting the excipients

examined to a subset of approved

parenteral excipients can reduce

the amount of data that must be

analyzed.

Training on data processing is

also crucial, regardless of what

approach is used. LaBrenz uses

many different tools depending

on the level of complexity required

for a given project, and often the

choice of software is determined

by collaborators. “It isn’t the soft-

ware package that actually mat-

ters. It is all of the extra training

to develop my applied statistics

skills, including six-sigma training

and seminars, that helps me on the

job,” he states. ◆

Formulation DevelopmentÑContin. from page 29

the IPC and some of the significant

initiatives that the organization is

pursuing.

ACKNOWLEDGEMENTSThe authors would like to thank

the members of the IPC’s Expert

Committee on Biologicals and rDNA

Products. These include Dr. S.S.

Jadhav and Dr. Sunil Gairola (Serum

Institute of India), Dr. Venkata

Ramana (Reliance Life Sciences), Dr.

Anil Kukreja (Roche Products Pvt.

Ltd), Dr. Sriram Akundi (Biocon

Foundation), Dr. Jaideep Moitra

(Gennova Biopharmaceuticals),

Dr. Rahul Kulkarni (Gennova

Biopharmaceuticals), Dr. Himanshu

Gadgil (Intas Biopharmaceuticals),

Mrs. Kinnari Vyas and Dr. Susoban

Das (Intas Biopharmaceuticals), Dr.

Satyanarayana Subrahmanyam

(Dr. Reddy’s Laboratories Limited),

Dr. Sanjeev Kumar (Zydus Cadilla)

Dr. M. Kalaivani (IPC), Ms. Gunjan

Narula (IPC), and Dr. Renu Jain

(NIB). Prof. Anurag S. Rathore

(IIT Delhi) is the Chairman of the

Committee. Dr. G. N. Singh is pres-

ently the Drug Controller General

of India (DCGI) and is also the

Scientific Director of IPC.

REFERENCES 1. Association f Biotechnology

Led Enterprises, Industry

Insight, Biospectrum Asian

Edition, Vol. 1 (June 2013).

2. PricewaterhouseCooper, India Pharma

Inc.: Capitalizing on India’s growth

potential (PWC, November 2010).

3. Indian Pharmacopoeia (Ministry

of Health & Family Welfare),

Govt. of India (2014).

4. R.M. Singh, “Role of Indian

Pharmacopoeia for Quality Medicines

in India,” Spinco Biotech Cutting

Edge, 1 (6) (December 2013).

5. IPC, Indian Pharmacopoeia,

6th Edition (September

2010), www.ipc.gov.in.

6. A. S. Rathore, BioPharm Inter.

24 (11) (November 2011).

7. A. S. Rathore and I. S. Krull, LC

GC North America 28 (2010).

8. Pharmacopoeia of the People’s

Republic of China, 2010, The

state Pharmacopoeia Commission

of P.R. China, China Medical

Science Press, Beijing, China.

9. USP, USP 37 NF 32, United States

Pharmacopoeia Commission (Unite

Book Press Inc., Baltimore, MD 2014).

10. BP, British Pharmacopoeia, 2014

by The Stationary office on behalf

of The Medicines and Healthcare

Products Regulatory Agency (MHRA),

(London SW1W9SZ 2013).

11. Ph. Eur., The Europoean

Pharmacopoeia 8.0, Directorae

for quality of medicines and

healthcare of the Council of Europe

(EDQM), Council of Europe, 67075

Strasbourg, Cedex, France (2013).

12. JP, The Japanese Pharmacopoeia,

16th Edition, Pharmaceutical

and Medical Devices regulatory

Science Society of Japan,

Tokyo 150-002, Japan. ◆



For questions, contact Kristen Moore at [email protected]

Presenter:

Ken CookEU Bio-separations Support ExpertThermo Fisher Scientifc

Moderator:

Mike TracyGroup PublisherBioPharm International

Sponsored by

Presented by

Who Should Attend: n Biopharmaceutical research

and development chemists and

laboratory managers

n Biopharmaceutical QC chemists and

laboratory managers

n Protein characterization chemists

n Fermentation production analysts

n Biotherapeutic protein clone

selection chemists

EVENT OVERVIEW:

Over the past decade, the number of monoclonal antibodies

(mAb) candidates entering the clinical pipeline has

grown signifcantly. In addition, the number of antibody

drug conjugates that use mAb specifcity to carry drug

payloads to target sites has increased. As a result, analytical

characterization is in high demand.

This webinar will discuss new innovations in sample

preparation, column technology, UHPLC, and high resolution

mass spectroscopy (HRMS) that allow the development of

analytical methods with run times of less than 5 minutes for

all routine methods.

Orbitrap technology has been established as the most

powerful MS technology for protein characterization. How

the new ultra high resolution Orbitrap technology can

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LIVE WEBCASTThursday, November 13, 2014 at 8:00 am PST/ 11:00 am EST/ 4:00 pm GMT/ 5:00 pm CET

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Key Learning Objectives:

n Fast method development for charged variant analysis

and ADC characterization

n Rapid sample preparation for increased throughput and

precision

n Integration of ultra-high resolution LC-MS into the routine

biotherapeutic protein analysis workfow



Sve

ta D

em

ido

ff/G

ett

y Im

ag

es

Troubleshooting

Removal and inactivation of adventi-

tious and endogenous viruses have tra-

ditionally been achieved during the

downstream purification of biologics. Viral

clearance is assessed in small-scale tests, and

regulatory guidance documents provide a gen-

eral framework for how these tests should be

performed (1). Even with guidance, however,

demonstrating an appropriate level of viral

clearance can be challenging for biologics

manufacturers.

Upstream viral clearance Using media with a low level of viral contami-

nation can lead to major problems in biolog-

ics manufacturing. Cell-culture media and

other raw materials, particularly those derived

from animals, should be subjected to rigor-

ous testing and viral inactivation treatments,

according to S. Steve Zhou, director of virology

and molecular biology with the MicroBioTest

Division of Microbac Laboratories. In addi-

tion to treatment with heat and ultraviolet

radiation, virus retentive filtration is recog-

nized as one of the most efficient and robust

virus removal steps, and implementation in

the media feeding process could decrease the

risk of contamination significantly, accord-

ing to Horst Ruppach, senior director, viral

clearance with Charles River Biologics Testing

Solutions. “Current filters can be used in this

application, but they were not designed to

run under continuous and high throughput

conditions like those required for media sup-

ply,” he observes. Filter vendors are currently

being asked to modify the filter design for

this specific approach. Viral clearance stud-

ies will also need to be designed differently in

order to address the specific condi-

tions associated with media supply,

Ruppach adds.

Facility design and process monitoring Conditions throughout the commercial manu-

facturing process must be constantly monitored

to avoid viral contamination events. One major

concern for biologics production is the entry

of a small, non-enveloped, chemically resistant

virus into the manufacturing system, accord-

ing to Zhou. “Good facility design and strict

compliance with good manufacturing practice

is the best approach to avoiding this problem,”

he says. Equipment and process failures, such as

inadequate raw material screening or failure of

an upstream inactivation method, particularly

those that go undetected, are also a concern

with respect to potential viral contamination.

In these cases, close monitoring of the process,

preferably using automated systems, and a good

quality assurance/quality control program are

essential for preventing such problems, accord-

ing to Zhou.

minimizing manUFactUring costAs purification templates are established, the

cost of goods is of particular importance

because there is often pressure to limit oper-

ations to those that are necessary for bio-

therapeutic purification rather than include

operations that confer a marginal improve-

ment of product quality, according to Trish

cell-culture media and other

raw materials should be sub-

jected to rigorous testing and

viral inactivation treatments.

Viral Clearance Challenges in Bioprocessing Challenges remain for virus removal and validation.

Cynthia A. Challener is a contributing

editor to BioPharm International.



troubleshooting

Greenhalgh, virology manager for

EMD Millipore. Processes with

fewer purification steps present

a challenge to virus clearance,

however, because higher removal

claims are expected with indi-

vidual unit operations. “Access to

high titer virus preparations in

testing labs is one way to achieve

high clearance levels, and i f

complete clearance is observed

across the unit operations, high

log reduction values (LRVs) will

be obtained,” says Greenhalgh.

“Meeting clearance targets by eval-

uating a minimal number of steps

that each deliver high removal

can be a risky approach, and a

more thorough evaluation of addi-

tional purification steps expected

to contribute to virus removal is

preferred by regulatory agencies,”

she continues.

More recently, there has been a

focus on understanding the impact

of small changes in the operating

window of individual unit opera-

tions on product quality. “There

is an expectation that the impact

of these changes on the virus

clearance capabilities for unit

operations, particularly chromato-

graphic purification steps, will be

understood,” Greenhalgh explains.

Historical virus clearance data with

the same template can be invalu-

able in setting realistic expecta-

tions for unit operation clearance.

Ideally, however, she notes that

clearance studies should also evalu-

ate conditions outside the process

center to more fully understand

the robustness for virus removal.

Comprehensive risk analysis is

often effective for highlighting

and prioritizing such evaluations

to streamline costly virus testing,

according to Greenhalgh.

process representationAnother challenge for viral clear-

ance validation is accurate process

representation. “In order to perform

high-quality viral clearance studies

and avoid unreliable, inaccurate, or

outdated viral clearance data, it is

necessary to regularly review the

manufacturing process and ensure

that the current manufacturing

process matches what was tested in

the viral clearance study,” accord-

ing to Zhou. A thorough definition

of full-scale process conditions is

particularly important so that they

can be assessed in small-scale viral

clearance tests.

These tests should also consider

process excursions, including inter-

ruptions, depressurization events,

and minor changes in feed quality

from chromatographic unit oper-

ations, according to Greenhalgh.

Zhou agrees: “In addition to hav-

ing a thorough understanding of

the process steps, particularly the

process parameters that are critical

for robust viral clearance, it is nec-

essary to consider worst-case sce-

narios in order to accurately define

the design space for viral clearance

testing.” He also believes that it

is important to update the design

space as new knowledge develops.

These assessments of process excur-

sions require open communication

between the biologics manufac-

turer and the testing laboratory to

develop comprehensive evaluation

plans, according to Greenhalgh.

For scale-down tests to provide

reliable viral clearance data, the

actual challenge feed must be rep-

resentative of that in the full-scale

process. Achieving this goal can be

difficult, because the test material

is typically frozen for shipping to

the testing lab, potentially leading

to changes in the process interme-

diates due to aggregation or prod-

uct degradation, which can result

in different performance for indi-

vidual unit operations compared

to that observed during process

development. “Understanding the

impact of shipping and extended

storage on performance and the

development of mitigation strat-

egies are important for ensuring

accurate virus clearance assess-

ments,” Greenhalgh says.

continUoUs processingInterest in continuous processing

of biologics using single-use sys-

tems is gaining traction because this

approach can significantly reduce

production costs, particularly for

smaller-volume APIs. Viral clear-

ance becomes even more impor-

tant under continuous production

conditions, according to Ruppach.

“Contaminants typically detected

during the fermentation process

may enter the purification process

under fully continuous produc-

tion conditions. Other questions

must also be addressed: How can

a potential contamination best be

mimicked in a process where virus

contaminants enter the downstream

process under a constant flow?

Will continuous processing impact

the viral inactivation and removal

capacities of downstream process

steps for which effective inactivation

or removal could be demonstrated

under standard conditions like low

pH inactivation, anion exchange

(AEX) chromatography, or virus-

retentive filtration? Further stud-

ies need to be performed to answer

these questions,” he states.

model virUs selectionPresently, according to Ruppach, the

same set of model viruses (murine

leukemia virus [MuLV], pseudora-

bies virus [PRV], reovirus [Reo-3],

and minute virus of mice/porcine

parvovirus [MVM/PPV]) is applied

for the viral clearance validation of

cell line-derived recombinant prod-

ucts. The achieved single reduction

factors are summed up to an overall

reduction factor that describes the

general virus inactivation/removal

capacity of the downstream pro-

cess. For instance, he notes that it is

accepted that AEX chromatography,



troubleshooting

when run under certain conditions,

is highly effective in removing

this set of model viruses. It is also

known that low pH inactivation is

an effective inactivation step for

enveloped viruses when high reduc-

tion factors are demonstrated for

the two enveloped viruses MuLV

and PRV. “It is also known, however,

that other model viruses behave dif-

ferently. The Poliovirus, for instance,

is not effectively removed by AEX

chromatography under the same

conditions, and HIV-1 and bovine

viral diarrhea virus (BVDV) are

much more resistant to low pH

inactivation compared with MuLV

and PRV. These varying responses

raise questions about using the

same model viruses for all steps,

and a discussion should be initiated

regarding how robust viral clear-

ance can better be demonstrated,”

Ruppach asserts.

In addition, because nanofiltra-

tion is known to be the most effec-

tive virus removal step and can

remove both large (MuLV, PRV)

and small (MVM, PPV) viruses,

there is some discussion about the

use of these small model viruses

as surrogates for the larger viruses,

according to Ruppach. He points

out that some companies have in

fact claimed MVM removal data

as indicative of MuLV removal via

virus-retentive filtration or used

a fixed-reduction factor based on

internal experiments. “This practice

is not in full compliance with cur-

rent guidelines, but some agencies

have accepted this type of data for

IND applications of mAbs [mono-

clonal antibodies] derived from

CHO [Chinese hamster ovary] cell

lines. It remains uncertain, however,

whether all agencies will accept this

practice and if it can be applied for

late-stage viral clearance studies and

other products,” he comments.

Another issue with viral clear-

ance testing is the variable and often

unknown quality of the virus prep-

arations or spikes that are used in

these tests, according to Greenhalgh.

The Parenteral Drug Association

Technical Report 47 (2) provides a

framework for the preparation and

characterization of virus prepara-

tions, and individual testing labs

have developed their own descrip-

tions for virus preparations of differ-

ing purities. Generally, Greenhalgh

notes that virus purity has the big-

gest impact on the virus filtration

step: less purified preparations are

more likely to negatively impact the

virus filter performance by reduc-

ing the volumetric throughput and

ultimately resulting in over-sizing of

the filtration area and an increased

cost of goods for this dedicated virus

removal step. “Pre-studies to opti-

mize both the feed and the virus

spike level are critical prerequisites

for ensuring that expected perfor-

mance targets are met,” she states.

glp and/or gmp?Viral clearance studies, when per-

formed by contract research orga-

nizations (CROs), are frequently

performed following good labo-

ratory practices (GLP) principles.

Recently, however, the question

of whether viral clearance studies

should follow GMP rather than

GLP principles has been raised.

“Audits performed by customers at

CRO sites more often follow GMP

rather than GLP processes, and

typical GMP requirements, such

as corrective action and preven-

tive action (CAPA) procedures, are

requested,” says Ruppach.

This discussion is additionally

stimulated by the fact that viral

clearance studies are required at

different stages of the product

lifecycle, from before the clinical

phase through more comprehen-

sive studies for marketing autho-

rization. In the first case, a fully

validated production process is

typically not in place. In the lat-

ter case, a fully GMP-compliant

validated production process must

be in place. Accordingly, a GMP-

compliant viral clearance study

is more important for the late

stage rather than the early stage

of the product development pro-

cess, according to Ruppach. “It is

important, therefore, that CROs

offering viral clearance services

following GMP principles must

not apply all of the measurements

that are important for a production

site that manufactures and releases

pharmaceuticals for human use,”

he asserts.

importance oF commUnicationMeeting regulatory requirements

for virus safety depends on well-

designed studies that demonstrate

virus clearance across multiple

orthogonal steps with accurate

scale-down conditions, according

to Greenhalgh. “Comprehensive

test design resulting from thor-

ough process understanding and

communication between the bio-

logics manufacturer and the virus

clearance testing lab is essential to

meeting these goals.”

reFerences 1. ICH, Q5A. Guidance on Viral Safety

Evaluation of Biotechnology Products

Derived From Cell Lines of Human or

Animal Origin (1998).

2. Parenteral Drug Association,

Technical Report No. 47: Preparation

of Virus Spikes Used for Virus

Clearance Studies (2010). ◆

the question of

whether viral clear-

ance studies should

follow gmp rather

than glp principles

has been raised.



Analytical Best Practices

Developing Representative Sampling Plans for Development, Problem Solving, and Validation The ability to define a scientifically justified and statistically sound sampling procedure is a fundamental skill in modern systematic drug development.

In all product and process development and

in all validation activities, developing a

representative sample and the correct and

defendable use of the statistical method used

are crucial. In all sampling activities, a scien-

tifically sound sampling plan should be devel-

oped, justified, and implemented. Sampling

activities include clinical trials, formulation,

stability (long term and accelerated), process

characterization, analytical method develop-

ment, method validation, process validation,

and release testing.

International Conference on Harmonization

(ICH) Q8, Q9, Q10, and Q11 (1–4) all require sta-

tistically valid sampling procedures in test and

product and process development. Specifically

Q8, Q9, and Q10 Questions and Answers (R4),

states (5):

“Q6: Do traditional sampling approaches apply to real

time release (RTR) testing?

A6: No, traditional sampling plans for in-process and

end-product testing involve a discrete sample size

that represents the minimal sampling expectations.

Generally, the use of RTR testing will include more

extensive on-line/in-line measurement. A scientifically

sound sampling approach should be developed, justi-

fied, and implemented. (Approved April 2009) process-

ing, in-process materials, and drug product quality can

provide an opportunity to shift controls upstream and

minimize the need for end product testing.”

The purpose of this paper is to organize

a logical framework and identify the appro-

priate tools that aid in the development of

a statistically valid sampling protocol. Due

to the complexity of the kinds of issues and

the types of problems to be solved, each sam-

pling procedure will be somewhat unique;

however, there are common issues and ques-

t ions that each sampling pro-

tocol will need to consider and

address.

sTATIsTIcAL MeTHODs fOR PRODUcT DeVeLOPMenTThe following are generally key steps for using

statistical methods for problem solving and

product development.

Define the business case

The business case explains the development

objective, how each activity relates to qual-

ity objectives, quality target product pro-

f i les (QTTPs), cr it ical quality attr ibutes

(CQAs), timelines or product development

requirements, and why the activity needs to

be completed. The business case gives con-

text to development and validation activities

and helps CMC teams understand how each

activity fits into overall business and qual-

ity imperatives. Failure to understand the

business case for development and validation

activities causes discontinuity in development

activities and the logic of what, why, and how

much becomes hard to justify and or file to the

appropriate health agencies.

Define the problem

Problem definitions describe what we don’t

know and or what is wrong with our current

performance. Problem definitions are essen-

tial for problem sampling plan development

and rationalization. Limitations and/or scope

failure to understand the

business case for develop-

ment and validation activi-

ties causes discontinuity.

Thomas A. Little is president of Thomas

A. Little Consulting, [email protected].




ALL F

IGU

RE

S C

OU

RT

ES

Y O

F T

HE

AU

TH

OR

associated with each problem

definition is critical in defining

the associated population of units

associated with the problem.

Also associated with the problem

definition, there should be clar-

ity on what is the sampling unit

(batch, vial, drum etc.)

Define all objectives,

goals, and study questions

From the problem def init ion,

objectives, goals and study ques-

t ions must be def ined. Goals

come in four forms: maximize,

minimize, match target, and

none. Limits and acceptance cri-

teria should also be defined. The

sampling plan will be designed

to ensure all study questions are

answered, goals are achieved, and

questions are sufficiently precise

and accurate relative to the limits

and tolerances of the acceptance

criteria.

D e t e r m i n e a l l f a c t o r s a n d

responses and analytical methods

Based on the study questions and

goals, what must be measured to

meet the business case and solve

the problem? All factors that

influence the problem and study

questions must be defined. All

responses and analytical meth-

ods associated with the problem

need to be clarified. In many cases,

the factors and/or responses that

are currently measured in batch

records or in on-line data systems

do not address the problem to be

solved or the process to be charac-

terized. Care should be exercised

to assure there are no missing mea-

surements or the business case will

not be met or the problem will not

be addressed correctly.

Define the population

Based on the study questions,

unit def init ion, and problem

statement, what is the popula-

t ion of units that need to be

understood? Population defini-

tion is crucial prior to sampling

plan formalization. For R&D, the

population is often a function

of formulation and or configura-

tion. Another term that is often

associated with the population is

“volume.” How will the product

perform in volume and at scale

versus the limited product test-

ing that is performed in small-

scale studies?

Define the sample that will rep-

resent the population, study

quest ions , and t he de f ine d

problem

A sampling plan needs to be for-

mally defined and scientifically

justified to assure it is representa-

tive of the population and it meets

the all defined study objectives

and acceptance criteria.

Figure 1: Partition of variation analysis for sampling method determination.

Partition of varation (POV) crossed, dependent analysis

. . . . .Between total 0.000021 4.55 0.004601 0.5900 0.9622 Between sublot-fill/orientation 0.000002 0.43 0.001422 0.2498 0.9721 Between lot number 0.000016 3.41 0.003981 1.1415 0.3247 Between sublot-fill/orientation*lot number 0.000003 0.71 0.001814 0.2370 0.9964 . . .Within total 0.000444 95.45 0.021080 Within sublot-fill/orientation 0.000107 22.94 0.010334 Within lot number 0.000253 54.27 0.015895 Within sublot-fill/orientation*lotnumber 0.000042 9.01 0.006476 Common 0.000043 9.24 0.006559 . . .Total 0.000466 100.00 0.021577

PopVariance

Sqrt(varComp)% of TotalComponent F Ratio

Perc

en

t o

f to

tal

vari

ati

on

100

80

60

40

20

0

Variance components

Wit

hin

lo

t n

um

ber

Wit

hin

su

blo

t-fi

ll/o

rien

tati

on

Co

mm

on

Wit

hin

su

blo

t-fi

ll/o

rien

tati

on

*lo

t n

um

ber

Betw

een

lo

t n

um

ber

Betw

een

su

blo

t-fi

ll/o

rien

tati

on

*lo

t n

um

ber

Betw

een

su

blo

t-fi

ll/o

rien

tati

on

Prob>F Sig.

2 Level POV analysis: sublot-Fill/orientation, lot number




WHO guidelines for representa-

tive sampling state (6): “Representat ive sample, Sample

obtained according to a sampling pro-

cedure designed to ensure that the dif-

ferent parts of a batch or the different

properties of a non-uniform material

are proportionately represented.”

The FDA process validation

guideline states (7):

“The sampling plan, including sampling

points, number of samples, and the

frequency of sampling for each unit

operation and attribute. The number of

samples should be adequate to provide

sufficient statistical confidence of qual-

ity both within a batch and between

batches. The confidence level selected

can be based on risk analysis as it

relates to the particular attribute under

examination. Sampling during this

stage should be more extensive than is

typical during routine production.”

All statistically justifiable sam-

pling plans require two primary

considerations: sampling method

and sample size.

Define the sampling method

The sampling method is defined

to clarify “how” samples are taken,

“where” they are taken, and “how

often.” How many samples are taken

is sample size. To determine the sam-

pling method, care must be exer-

cised to assure the samples are taken

from the primary sources of varia-

tion. Partition of variation (POV) or

components of variation (COV) anal-

ysis are used to determine the pro-

portion of variation within/between

batch for example. In Figure 1, 54%

of the variation occurs within the lot,

so at least 54% of the measurements

need to be allocated to the within lot

sampling to be representative. The

batch-to-batch variation is only 3%

so many batches are not needed in

this example. If 90% of the variation

was between batches, then 90% of

the samples should be from multiple

batches.

Define the sample size

Sampling method must be defined

first, then sample size. There are

many International Organization

for Standardization (ISO) standards

for variables and attributes sam-

pling for lot acceptance (8-10), and

there are also the National Institute

of Standards and Technology

(NIST) standards for determining

the sample size (11). SAS/JMP and

other statistical packages have their

own sample size and power cal-

culators. Every sampling protocol

involves risk. The risk should be

known rather than unknown.

To use a sample size calculator, the

confidence interval (1-alpha), the

power of the test, how reliably you

want to detect a change (1-beta), and

the practical change to observe (delta)

must be known. For example: alpha =

0.05, the power =0.95, and the delta

in pH that we want to detect is 0.2

and the standard deviation of pH at

the point of evaluation is 0.125 from

historical measurements. What is the

sample size? Eight samples will do

it. Sample size does not address sam-

pling method. Sampling method tells

you how to take the sample; sam-

ple size tells you how many. Power

curves are used when the delta is

unknown (see Figure 2).

Collect data per the sampling plan

Follow the sampling plan and col-

lect data and all associated data

tags (e.g., time, date, analyst, etc.)

during sampling.

Summarize data into statistics for

the sample and confidence inter-

vals for the population

Statistics and graphs are used to

summarize and aggregate the data.

The statistics describe the sample,

and the confidence intervals are

used to describe the population.

Confidence intervals control for

risk (95%, for example), varia-

tion in the data, and sample size.

Confidence intervals should be in

every graph and in every table.

Draw conclusions and inference

Based on the data and all associ-

ated confidence intervals, models,

and graphs, draw conclusions rela-

tive to acceptance criteria, limits,

CQAs, and the business case.

Verify conclusions, solve the prob-

lem, meet quality requirements,

and achieve the business case

Verify the conclusions and pre-

diction made from the sample

are subsequently observed in the

population. Demonstrate that

solutions are generally applica-

ble though on-going longitudi-

nal monitoring and continuous

validation protocols. Verification

Figure 2: Sample size and power curve.

Sample sizeOne mean

Difference to detect 0.2

Sample size 8

Power 0.95

Testing if one mean is different from

the hypothesized value.

Alpha 0.05

Std Dev 0.125

Extra Parameters 0

Supply two values to determine the

third.

Enter one value to see a plot of the

other two.

One mean

Sam

ple

siz

e

Difference

0.125

0.00 0.05 0.10 0.15 0.20

100

80

60

40

20

0

0.95 0.05

Sample size

PowerError

Std Dev Alpha




indicates earlier estimates taken

from the representative sample

are correct. Failure to verify con-

clusions and inferences generally

indicates additional uncontrolled

factors are at play and need to

be understood and/or controlled

before the business case can be

achieved.

Summary

The ability to define a scientifi-

cally justified and statistically

sound sampling procedure is a

fundamental sk i l l in modern

systematic drug development. It

impacts every aspect of devel-

opment and validation. A struc-

tured approach using the key

considerations outlined in this

paper will aid in assuring it has

a defendable technical basis for

sampling method and sample

size selection and controls and

addresses risk relative to a clearly

def ined business cases, CQAs,

problem statements, and study

questions.

RefeRences 1. ICH, Q8 Pharmaceutical

Development (ICH, August 2009).

2. ICH, Q9 Quality Risk Management

(ICH, Nov. 9, 2005).

3. ICH, Q10 Pharmaceutical Quality

System (ICH, June 4, 2008)

4. ICH, Q11 Development and

Manufacture of Drug Substances

(Chemical Entities and

Biotechnological/Biological Entities)

(ICH, May 1, 2012).

5. ICH, Q8, Q9, and Q10 Questions and

Answers (R4) (ICH, November 2011).

6. WHO, Annex 4, WHO Guidelines for

Sampling of Pharmaceutical Products

and Related Materials (WHO, 2005).

7. FDA, Guidance for Industry, Process

Validation: General Principles and

Practices (January 2011).

8. ISO, ISO 10725, Acceptance

sampling plans and procedures for

the inspection of bulk materials

(ISO, 2000).

9. ISO, ISO 3951:1989, Sampling

procedures for inspection by

variables (ISO, 1989).

10. ISO, ISO 2859-1, Sampling

procedures for inspection by

attributes. Sampling schemes

indexed by acceptance quality limit

for lot-by-lot inspection (ISO, 1999).

11 NIST, “Sample Sizes Required,”

Engineering Statistics Handbook,

www.itl.nist.gov/div898/handbook/

prc/section2/prc222.htm, accessed

Oct. 16, 2014. ◆

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Verification

indicates earlier

estimates taken from

the representative

sample are correct.



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THE WORD

INDUSTRY BRIEFS

• FDA’s Dermatologic and Ophthalmic Drugs Advisory

Committee voted 7-0 to recommend approval of Novartis’

AIN457 (secukinumab) for the treatment of plaque pso-

riasis for patients who are candidates for systemic therapy

or phototherapy. The panel determined the drug was

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provide the greatest benefit to patients. When compared

with Enbrel (etanercept) in a head-to-head trial last year,

secukinumab demonstrated significantly superior efficacy

over Enbrel in patients with moderate-to-severe plaque

psoriasis.

• Pall ForteBio announced the launch of a new solution

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ForteBio Octet Platform.

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MOST TWEETED

• How scientists are harnessing the power of modified T

cells to treat cancer. bit.ly/ZIjPzS

• Novartis announced positive results for secukinumab in

Ankylosing Spondylitis trials. bit.ly/ZP8rSS

• EMA encourages companies to apply for orphan-drug

status for Ebola treatments. bit.ly/1x1k3ge

EVENTS

2014 Lyophilization WeekDecember 1–4, 2014Bethesda, MD Risk-based Qualif cation of Sterile Drug Product Manufacturing SystemsDecember 8–10, 2014

Bethesda, MD

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