volume 27 number 7 biopharmfiles.pharmtech.com/alfresco_images/pharma/2018/09/11/1c07e3fd … ·...

BioPharmThe Science & Business of Biopharmaceuticals

INTERNATIONAL

www.biopharminternational.com

INTERNATIONAL

Bio

Ph

arm

Intern

atio

nal

JULY 2

014

M

on

oclo

nal A

ntib

od

ies I P

rote

ins I H

um

an

Erro

r V

olu

me 2

7 N

um

ber 7

July 2014

Volume 27 Number 7

SECURING THE BIOPHARMACEUTICAL SUPPLY CHAIN

BUSINESS

INNOVATION INVESTMENTS

HEALTH SYSTEMS RAISE

THE BAR ON REIMBURSING

NEW DRUGS

REGULATIONS

INDUSTRY SEEKS

CLEARER STANDARDS

FOR TRACK AND TRACE

PROTEIN

CHARACTERIZATION

ANALYZING PROTEINS

USING SEC, MALS,

AND UHPLC

ES458361_BP0714_CV1.pgs 06.25.2014 01:44 ADV blackyellowmagentacyan ES456315_BP0714_CVTP1_FP.pgs 06.23.2014 17:36 ADV blackyellowmagentacyan

CHT™ Ceramic HydroxyapatiteThe direct path to puri�cation success.

To meet the demands of an increasingly diverse pipeline and compressed development timelines, you need a

polishing step that can effectively clear aggregates and other impurities. Why spend time experimenting to �nd the

right selectivity when you can use CHT Ceramic Hydroxyapatite? CHT has a proven track record of signi�cantly

reducing the full range of impurities in a single polishing step that is easy to develop for a wide range of proteins

and expression systems. Why take the long road? Discover for yourself how direct the path to purity can be.

Learn more at bio-rad.com/info/directpath

ES456314_BP0714_CVTP2_FP.pgs 06.23.2014 17:36 ADV blackyellowmagentacyan


INTERNATIONAL


INTERNATIONAL

Bio

Ph

arm

Intern

atio

nal

JULY 2

014

M

on

oclo

nal A

ntib

od

ies I P

rote

ins I H

um

an

Erro

r V

olu

me 2

7 N

um

ber 7

July 2014

Volume 27 Number 7

SECURING THE BIOPHARMACEUTICAL SUPPLY CHAIN

BUSINESS

INNOVATION INVESTMENTS

HEALTH SYSTEMS RAISE

THE BAR ON REIMBURSING

NEW DRUGS

REGULATIONS

INDUSTRY SEEKS

CLEARER STANDARDS

FOR TRACK AND TRACE

PROTEIN

CHARACTERIZATION

ANALYZING PROTEINS

USING SEC, MALS,

AND UHPLC

ES458361_BP0714_CV1.pgs 06.25.2014 01:44 ADV blackyellowmagentacyan

www.tosohbioscience.com

Tosoh Bioscience and TOYOPEARL are registered trademarks of Tosoh Corporation.

TOSOH BIOSCIENCE LLC • Customer service: 866-527-3587 • Technical service: 800-366-4875, option #3

TOYOPEARL® NH2-750F

A NEW salt tolerant Anion Exchange Resin

from Tosoh Bioscience

High salt increasing

your blood pressure?

ES458089_BP0714_CV2_FP.pgs 06.24.2014 23:21 ADV blackyellowmagentacyan

INTERNATIONAL


EDITORIALEditorial Director Rita Peters [email protected]

Managing Editor Susan Haigney [email protected]

Scientific Editor Adeline Siew, PhD [email protected]

Community Editor Melanie Sena [email protected]

Art Director Dan Ward [email protected]

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

Publisher Mike Tracey [email protected]

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]

Market Development, Classifieds, and Recruitment Tod McCloskey [email protected] 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 Florio, Chief Executive Officer Fashion Group, Executive Vice-President; Tom Ehardt, Executive Vice-President, Chief Administrative Officer & Chief Financial Officer; Georgiann DeCenzo, Executive Vice-President; Chris DeMoulin, Executive Vice-President; 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

ES458364_BP0714_003.pgs 06.25.2014 01:44 ADV blackyellowmagentacyan

4 BioPharm International www.biopharminternational.com July 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


INTERNATIONAL


INTERNATIONAL

July 2014

Volume 27 Number 7

Securing the Biopharmaceutical Supply chain

BuSineSS

INNOvATION INvEsTmENTs

HEALTH sysTEms RAIsE

THE BAR ON REImBuRsINg

NEw DRugs

regulationS

INDusTRy sEEks

CLEARER sTANDARDs

fOR TRACk AND TRACE

protein

characterization

ANALyzINg PROTEINs

usINg sEC, mALs,

AND uHPLC

Cover: -Oxford-/E+/Getty Images

Social Media

Follow us on Twitter@BioPharmIntl

Join our BioPharmInternational Group

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

biopharminternational.com/subscribe

Online Exclusive Optimizing Human Performance, Part I, is the first in a three-part series on minimizing human error in biopharma manufacturing. Visit BioPharmInternational.com/HumanError to read the article in full.

6 From the Editor FDA draft guidances seek to maintain accurate drug information in new media. Rita Peters

8 Global News

12 US Regulatory Beat Stakeholders face challenges and benefits from a more secure pharmaceutical supply chain. Jill Wechsler

16 Perspectives on Outsourcing As payers refuse to cover new drugs, CMOs take a hit.Jim Miller

18 Burrill on Biotech Gene therapy, immune-oncology, and digital healthcare technologies offer promise for innovation investments.G. Steven Burrill

45 Product Spotlight

45 Ad Index

48 New Technology Showcase

50 Final Word Human error reporting and investigations should be deep and lead to effective, lasting solutions. Gerry McAuley

SUPPLY CHAIN

Ensuring a Robust Raw-Materials Supply ChainMartin VanTriesteWith the increasing globalization of the

biopharmaceutical industry, companies must

establish strategies to minimize vulnerabilities

in the raw-materials supply chain. 22

Challenges in Securing the Biopharma Supply ChainIndustry experts discuss the

unique challenges of securing the

supply chain for biopharmaceuticals. 26

PROTEIN CHARACTERIZATION

Analyzing Proteins Using SEC, MALS, and UHPLCCynthia A. ChallenerLight scattering analysis combined with more

rapid size exclusion chromatography improves

protein characterization. 30

MONOCLONAL ANTIBODIES

Defining Critical Quality Attributes for Monoclonal Antibody Therapeutic ProductsAnurag S. Rathore, Andrew Weiskopf, and Andrew J. ReasonAn approach for establishing the CQAs of

a mAb product by evaluating impact and

uncertainty during risk assessment. 34

Volume 27 Number 7 July 2014

FEATURES


METHOD

DEVELOPMENT

Many of the world’s most ground-breaking pharmaceuticals are made with the

help of methods developed using Waters Chromatographic Solutions. More proof

that world-class drug development demands world-class method development.

So if you want to get there first, partner with Waters at waters.com/methods

THE LATEST DISCOVERIES.

THE

PHARMACEUTICAL n HEALTH SCIENCES n FOOD n ENVIRONMENTAL n CHEMICAL MATERIALS

ES458110_BP0714_005_FP.pgs 06.24.2014 23:23 ADV blackyellowmagentacyan


From the Editor

FDA draft

guidances seek to

maintain accurate

drug information

in new media.

Benefits and Risks of Drug Information on Social Media

Social media has changed the way people and organizations communicate.

Platforms like Twitter and Facebook have demonstrated that they can be

effective tools for widespread communication of emergency instructions

during natural disasters and in organizing political change in countries with

censored media. Social media outlets, however, have limitations when asked to

deliver complex, technical information. In addition, the open platform nature

of the Internet presents challenges for companies trying to maintain correct

information about their products online.

FDA in June proposed two draft guidances that share the agency’s current

thinking about how drug and medical device manufacturers can accurately

communicate about their products online.

Guidance for Industry, Internet/Social Media Platforms with Character Space

Limitations—Presenting Risk and Benefit Information for Prescription Drugs and

Medical Devices (1) provides recommendations for conveying information

about a drug on social media platforms such as Twitter or paid search results

links. While the 140-character limit of Twitter may be enough for the latest life

updates from figures in popular culture, it will be difficult for drug companies

to use the platform under FDA’s proposed guidelines.

In the guidance, FDA notes: “… regardless of the platform, truthful, accurate,

non-misleading, and balanced product promotion best serves the public health.

For some products, particularly those with complex indications or extensive

serious risks, character space limitations imposed by platform providers may

not enable meaningful presentations of both benefit and risk … If an accurate

and balanced presentation of both risks and benefits of a specific product is not

possible within the constraints of the platform, then the firm should reconsider

using that platform for the intended promotional message.”

In the draft guidance, FDA indicates that a drug’s risk information must be pre-

sented with benefit information in the same limited-character message, such as a

tweet. The risk information should include the most serious risk associated with the

drug. In addition, a mechanism, such as a hyperlink, must direct people to more

information about risks. That is a lot of information to get into 140 characters.

In Guidance for Industry, Internet/Social Media Platforms: Correcting Independent

Third-Party Misinformation About Prescription Drugs and Medical Devices (2), FDA

explains that drug companies generally are not responsible for comments from

third parties who are independent of the drug company that are posted on the

company’s website forum, an independent website, or in social media. If a firm

voluntarily and truthfully undertakes the correction of misinformation that is

within the scope of the guidance, “FDA does not intend to object if these volun-

tary corrections do not satisfy otherwise applicable regulatory requirements, if

any,” the draft guidance reads.

FDA cites the growing the role of social media and notes that the guidance

was developed with the best interests of the patient in mind. However, the task

of maintaining proper information about regulated products in an unregulated

environment may be too great a challenge for FDA or drug companies to manage.

References

1. FDA, Guidance for Industry, Internet/Social Media Platforms with Character Space

Limitations—Presenting Risk and Benefit Information for Prescription Drugs and

Medical Devices, Draft Guidance (Rockville, MD, June 2014).

2. FDA, Guidance for Industry, Internet/Social Media Platforms: Correcting Independent

Third-Party Misinformation About Prescription Drugs and Medical Devices, Draft

Guidance (Rockville, MD, June 2014). ◆

Rita Peters is the editorial director of

BioPharm International.


© 2014 Thermo Fisher Scientifc Inc. All rights reserved.

All other trademarks are the property of Thermo Fisher Scientifc

and its subsidiaries.

Analysis

1

Analysis 2

Analysis

3

Analysis

n

Analysis

2

Analysis 3

Analysis

n

Analysis

1

Our award winning fritless SPE technology removes variability and optimizes

your high throughput laboratory workflow. Thermo Scientific™ SOLAµ™ plates

are designed for bioanalytical and clinical research analysts who consistently

require cleaner, highly reproducible and robust sample extraction at very low

sample volumes.

No variability

Greater sample success at low

elution volumes due to high

reproducibility

Providing confidence in your

analytical results

just consistency

mA

U

Time (min)

5

0.0

0

100

1015

2025

3035

4045

10

20

30

40

50

60

70

80

90

ANALYSIS 1

ANALYSIS 2

ANALYSIS 3

ANALYSIS n

• When your sample volume is critical visit: thermoscientific.com/sola-spe


Glo

be im

ag

e: C

ha

d B

ake

r/G

ett

y I

ma

ge

s; P

ho

to C

red

it:

Glo

be im

ag

e: C

ha

d B

ake

r/G

ett

y I

ma

ge

s; P

ho

to C

red

it: L

elia V

ald

ug

a/M

om

en

t O

pe

n/G

ett

y I

ma

ge

s

Brazil’s PhytotherapicDrug Market and RegulationIt is well known that Brazil has an immense biodiversity and

that the Amazon is the largest tropical rainforest in the world.

Traditional Brazilian medicines include African elements,

rooted on indigenous groups. Few pharmaceutical companies,

however, know at what level phytotherapic drugs are

commercialized in the country, how much regulation is

imposed for herbal medicines, and if there are any

opportunities in this unspoken, mysterious market in Brazil.

Dozens of studies link Brazil’s herbal medicines to

successful treatments and cures of various ailments. According

to Japanese scientists, there is strong anticancer activity in

certain Brazilian traditional medicines (e.g., basic and applied

studies for physiological activities of Brazilian traditional

medicine). Another study analyzed antifungal properties of

plants used in Brazilian traditional medicine against clinically

relevant fungal pathogens. One more study made a

comparison between ethnopharmacology in traditional

Chinese medicine and Brazilian popular phytotherapy.

One would suppose that due to the potential of the market,

there would be dozens of companies investing in the sector.

This potential, however, is not translating into market growth,

according to industry sources.

So why is the herbal drugs market in Brazil almost

completely undiscovered and profoundly undeveloped? Is

there any real potential for new or existing companies to enter

this market?

There are few figures available on the local herbal drugs

market, and its evolution is not officially followed, according

to the Brazilian Health Surveillance Agency (Anvisa) . It

appears that most of the investment in the Brazilian herbal

market has come from the cosmetics sector and not directly

from the pharmaceutical industry.

A December 2011 study conducted by the University of São

Paulo concluded that the number of patents filed at the

Brazilian patent bank (76 patents) was much lower than that

observed in its American (279) and European (328)

counterparts and did not show clear signs of growth (1). The

study was based on Brazilian, European, and American patent

banks, with the objective of evaluating herbal extracts applied

in cosmetics.

Alexandros Botsaris, president of the Brazilian Phytotherapy

Association (Abfit), stated in an interview with BioPharm

International that there are various barriers in Brazil related to

registration, environmental legislation, and local production

of raw materials, which end up slowing down the availability

of quality products in the local market. “Without a proper

supply of products, no market is able to grow consistently,”

said Botsaris.

Anvisa has imposed regulation processes that include the

registration of herbal medicines, according to Abfit.

“However, Anvisa was excessively strict regarding safety and

efficacy criteria, which

caused many smaller

laboratories that produced

traditional products to shut

down,” said Botsaris, adding

that was the main reason

why the volume of herbal

drugs available in the local

market reduced significantly

in the past 15 years.

Botsaris adds that another issue is which products should be

named “phytotherapic” as the term could include herbal

extracts; ‘in natura’ products, or even items sold though

network/pyramid marketing. “Brazil’s herbal industry is in a

very early stage if compared with other developed countries,”

says Botsaris. Brazil tends to follow guidelines published in the

US, which could influence the Brazilian herbal market in the

long term, he adds.

Also, according to Botsaris, environmental legislation made

the use of Brazilian biodiversity extracts on commercialized

products or research more complicated. “The CeGen (Cultural

and Genetics Heritage Council) aggressively fined researchers

and companies that invested in plants considered of Brazilian

heritage, which has greatly inhibited the production of herbal

medicines made with Brazilian plants,” said Botsaris.

Legislation

According to Ana Cecília Carvalho, phytotherapic coordinator

for the Brazilian Health Surveillance Agency (Anvisa), difficulties

in the production of herbal remedies may arise due to

legislation, which may not be changed by Anvisa. According to

Carvalho, there are new norms being edited aiming at meeting

other points not foreseen by the Brazilian Law to harmonize the

legislation with international standards of quality, safety, and

efficacy control.

“We hope these changes will make it possible for more herbal

remedies to be available in the market and [guarantee] that

every product will meet current international quality standards,”

Carvalho told BioPharm International.

The local legislation for herbal drugs has evolved since 1967

in a few aspects to level itself a little more with international

standards. In the past eight years, Brazil expanded its regulation

principles regarding raw materials and created its good practice

rules and other specific rules for herbal remedies to standardize

the sector.

Since then, Anvisa updated and re-edited rules such as the

Guideline to Herbal Medicine Registration (Director’s Collegiate

Resolution [RDC] 14/10) and the Good Manufacturing Practices

Guideline (RDC 17/10), among others. “This is the fifth time the

Herbal Medicine Registration is being re-edited ... the last

version was RDC 14/2010,” said Carvalho.

According to Carvalho, one of the main changes to the rules

is related to the splitting of herbal products into two classes:

one that passes all clinical studies needed for the new drugs


Global News


registration to be granted and another for lower-risks products.

“Lower-risk products do not need complete testing,” she said,

adding that the data from more than 30 years of usage on

human beings is considered.

According to Carvalho, this makes approval of lower-risk

herbal drugs a quicker process, with follow-up control by Anvisa

itself. “The legislation update is needed in order to make sure

that the consumer understands how the product purchased

was registered … if it was through standardized clinical trials or

safe and effective usage, which is not clear today,” said Carvalho.

To re-edit the rules, Anvisa analyzed various points of the

international legislation from the World Health Organization

(WHO), European Community, Canada, and Australia and

extracted “the best” safety, efficacy, and quality principals from

each, Carvalho said. According to Anvisa, various associations,

scientists, and communities participated in the process.

Botsaris, however, states that Abfit was not happy with the

process. “We have sent various suggestions to Anvisa and never

had any idea actually used by them. We currently do not feel

any type of proximity with the agency,” he said.

“Abfit favors legislation and market systems similar to the ones

found in Europe, where the government is active in validating

traditional products, while there is also more flexibility for

registration and prescription of [herbal] products,” Botsaris added.

Growth and Opportunities

Brazil’s pharmaceutical market has grown in the past years as

the volume of products available increased and new products

emerged, especially those that were patent-protected,

according to Abfit data. The association estimates, however,

that the herbal drugs market has not followed the same trend.

According to Abfit, the number of new registrations dropped

by 50% at Anvisa in the past 14 years.

Anvisa also confirmed to BioPharm International that there

has been a reduction in the number of registered herbal drugs

from manufacturers. “However, we have no means to offer

[comparative] information on whether [the drop] was related

with herbal drugs sales or financial values as Anvisa does not

follow herbal drug sales and finances [/figures],” said Carvalho.

Despite the lack of statistics, it is possible to notice that the

growth of herbal medicines in Brazil did not follow the evolution

of the regular pharma market. On the other hand, according to

Botsaris, Brazil historically follows international trends in this

sector and the search for natural drugs is increasing locally and

worldwide so there are various good reasons to believe that the

herbal industry in Brazil will offer great opportunities ahead and

should receive more investments in the years to come.

Reference 1. W. Magalhães et al., “Patenting in the Cosmetic Sector: Study of

the use of herbal extracts,” Brazilian Journal of Pharma. Sciences, 47 (4), University of São Paulo (October/December 2011).

—Hellen Berger is a business news

correspondent based in São Paulo, Brazil.

Brazilian herbal-drugs market growth

Alexandros Botsar is , president of the Brazi l ian

Phytotherapy Association, stated the following in an inter-

view with BioPharm International as reasons for growth in

the Brazilian herbal drugs market:

• Brazil has a consistent and persistent market demand

for natural, herbal remedies, especially aimed at treating

simple health ailments or to promote wellbeing.

• Brazil possesses an enormous herbal biodiversity and

the possibility of discovering various drugs and

molecules with market potential as more investments

are made in research and development.

• All needed resources are available such as workers,

technology, farmland, and industrial complexes for

establishing organized production chains.

• Brazil’s natural drugs market offers limited availability of

herbal products, while hundreds of herbal extracts with

market potential are waiting to be discovered and

launched.

• The recent regulation of the herbal-drugs market as well

as the growth of phytotherapic health practices will

generate prescriptions and increase demand for herbal

medicines.

FDA Issues Guidance on Identifying Suspect DrugsFDA has issued a draft guidance document on how to

identify suspect drug products in the supply chain. Drug

Supply Chain Security Act Implementation: Identification

of Suspect Product and Notification, developed under

the Drug Supply Chain Security Act, describes potential

signs that drug supply-chain stakeholders can look for to

identify suspect drugs, including product labeling that

may contain misspelled words or looks different than the

standard labeling; packaging that has missing lot numbers

or expiration dates or has been opened, damaged, or

altered; or a change in shape or color from the standard

product.

Supply-chain stakeholders are encouraged by FDA

to be cautious when purchasing drugs from a new or

unknown source, from the Internet, or purchasing drugs

on the drug shortage list. Unsolicited offers for lower-

priced drugs should also be avoided. The draft guidance

provides supply-chain stakeholders with information on

how to notify FDA of illegitimate products and details

a process for stakeholders to follow when terminating

previously made notifications.

—Susan Haigney

July 2014 www.biopharminternational.com BioPharm International 9

Global News


FDA Licenses First US Facility for Cell–Culture Influenza VaccinesFDA has licensed the Novartis

manufacturing facility in Holly

Springs, N.C. for the commercial

production of cell-culture influenza

vaccines. The site, the first US facility

of its kind, will produce seasonal and

pre-pandemic influenza vaccines,

and has the capacity to significantly

ramp up production in the event of a

pandemic, the company reports.

Novartis uses cell-culture

technology to produce Flucelvax

(influenza virus vaccine), the first

FDA-approved seasonal influenza

vaccine not manufactured

with chicken eggs. Cell-culture

technology offers several potential

benefits over traditional influenza

vaccine production in chicken eggs,

Novartis reports. The manufacturing

process can be controlled more

easily and is more flexible, enabling

the potential to scale up production

quickly to develop large quantities of

vaccines in the event of a pandemic.

Using the cell-culture technology,

Novartis has developed a vaccine

candidate for the H7N9 avian

influenza virus, which was first

reported in China in March 2013. This

facility supplied a stockpile of H7N9

vaccine to the US government prior

to the second wave of the outbreak

in January 2014.

The Holly Springs facility is a

result of a joint partnership between

Novartis and the US Department

of Health and Human Services,

Biomedical Advanced Research

and Development Authority (HHS,

BARDA). The facility was the overall

winner of the ISPE Facility of the Year

Award in 2013.

—Rita Peters

NIH and NSF Collaborate on Biomedical InnovationsThe National Institutes of Health (NIH) and

the National Science Foundation (NSF) have

collaborated on the I-Corps at NIH, a pilot

program of the NSF Innovation Corps tailored

for biomedical research. The program will

train NIH-funded researchers to evaluate the

commercial potential of scientific discoveries to

further biomedical innovation.

I-Corps is a nine-week boot camp where

researchers are paired with instructors

that have biomedical business experience

and take a scientific method approach to

customer discovery. Academic researchers and

entrepreneurs with Small Business Innovation

Research and Small Business Technology

Transfer (SBIR/STTR) Phase I awards from

participating NIH institutes will be eligible

to apply to I-Corps at NIH. Participating NIH

institutes include the National Cancer Institute;

the National Heart, Lung and Blood Institute;

the National Institute of Neurological Disorders

and Stroke; and the National Center for

Advancing Translational Sciences.

“I-Corps will help teach NIH-funded start-

ups how to build scalable business models

around new technologies they’re developing

for the detection and treatment of disease. The

program sheds new light on how companies

can deal with important business risks such as

protecting intellectual property and developing

regulatory and reimbursement strategies,” said

Michael Weingarten, director of the NCI SBIR

Development Center, in a press release.

“This new collaboration with NIH is further

evidence of the flexibility and efficacy of the

I-Corps model,” said Pramod Khargonekar, NSF

assistant director of engineering, in a press

release. “Translating basic biomedical research

to the marketplace has its own particular set of

challenges, which we recognize. By focusing

and adapting the I-Corps curriculum to the life

sciences, we expect biomedical researchers will

be better-equipped to enter the business arena.”

“This pilot will leverage NIH’s robust SBIR/

STTR program and further NIH’s mission to

advance our understanding of human illness

and treatment of disease and disability,” said

NIH SBIR/STTR program coordinator Matthew

Portnoy, in the press release. “We look forward

to this collaborative endeavor with NSF.”

—Susan Haigney

Traditional Big Pharma Jobs Shrink; Biotech, Smaller Players BoomsA new jobs report published by EP Vantage revealed that Big Pharma

employment dropped by 3% between 2003 and 2013, relieving fears

that industry consolidation and restructuring would lead to significantly

reduced headcounts and payrolls.

The new report shows that when it comes to pharmaceutical industry

jobs, big biotech and specialty drugmakers are growing in significance,

more than offsetting the loss of jobs in Big Pharma.

Headcount more than doubled over the past decade at companies

with market capitalizations of more than $30 billion, but who are not

traditionally considered Big Pharma. Some of those gains were the result of

acquisitions, such as Valeant, but groups like Novo Nordisk, Gilead Sciences,

and Regeneron have seen their staff double, triple, or even quadruple

based primarily on organic growth, the report finds.

“Large drug makers like Gilead are now not only outperforming Big

Pharma, but are outhiring it,” said Lisa Urquhart, EP Vantage editor. “With

the focus still on cost-cutting in Big Pharma, if you want a long-term career

in the industry you might be better off with a smaller player.”

The report also found: Novartis is the biggest employer in the pharma

sector, with a workforce of more than 135,000 people; Bristol-Myers Squibb

and Pfizer topped the industry in terms of shrinking headcount, each firing

36% of their employees; and the biggest hirer of 2013 in percentage terms

was Pharmacyclics, which more than doubled its headcount to 484 to

support the launch of cancer drug Imbruvica.

—Melanie Sena


Global News


Before saving the day, even superheroes need to clean their rooms.

EMD Millipore is a division of Merck KGaA, Darmstadt, Germany

EMD Millipore and the M logo and are trademarks of Merck KGaA, Darmstadt, Germany. Clarisolve is a registered trademark of Merck KGaA, Darmstadt, Germany.

© 2013 EMD Millipore Corporation, Billerica, MA USA. All rights reserved.

The first step in purifying a life saving drug is Clarification.

To get this step done right and to ensure successful

downstream purification, you need a partner who will

provide you with products, services and expertise you can

rely on. With the help of EMD Millipore clarification products,

you’ll know your purification process is off to a clean start

so you can move on to bigger things — like saving the world.

Learn more about our new Clarisolve® Depth Filters

for primary clarification of pretreated feed streams

visit www.emdmillipore.com/clarisolve

ES458103_BP0714_A11_FP.pgs 06.24.2014 23:22 ADV blackyellowmagentacyan


Regulatory Beat

Vis

ion

so

fAm

eri

ca

/Jo

e S

oh

m/G

ett

y I

ma

ge

s

Beginning Jan. 1, 2015, manufacturers

and distributors will need to have in

place systems able to transmit informa-

tion on prescription drug movement in the

United States from plant, to packagers and

various wholesalers and distributors, and ulti-

mately to dispensers. FDA is charged by the

Drug Supply Chain Security Act (DSCSA), a key

component of the Drug Quality and Security

Act (DQSA) of 2013, to issue guidance and rules

for establishing such a process and is consulting

with all stakeholders on viable approaches and

policies (1).

FDA held a public workshop in May 2014 (2)

to gain input from manufacturers and other

supply-chain parties on developing standards

for what eventually will be an interoperable

tracking system for prescription drugs. FDA

officials and industry leaders further reviewed

DSCSA requirements, along with broader

supply-chain security issues, at a June confer-

ence in Washington, D.C. sponsored by the

Parenteral Drug Association (PDA).

The larger aim of drug tracking is to pre-

vent drug diversion and to keep counterfeit

and substandard products out of

the US supply chain, observed Janet

Woodcock, director of the Center for

Drug Evaluation and Research (CDER),

in opening the FDA workshop (2).

Woodcock cited the recent discov-

ery in the US of counterfeit drugs

to treat cancer, hypoglycemia, and

hormone replacement, and noted the

dangers of stolen or diverted prod-

ucts entering the distribution system.

Electronic tracking, Woodcock noted,

also would help manage product

recalls, prevent shortages, and deter

criminal elements from introducing

substandard drugs into the US market.

Seeking guidanceFDA is working with supply-chain parties to

tackle its multiple assignments under DSCSA,

starting with guidance on how manufacturers

and distributors should identify suspect prod-

ucts and then notify other parties that such

products are not legitimate. More challenging

is a November 2014 deadline for draft guidance

that sets standards for interoperable exchange

of required information. That includes transac-

tion information (TI), transaction history (TH),

and transaction statements (TS)—the “3Ts”—

every time a product changes hands. Initially,

data will apply to drug lots, as opposed to indi-

vidual packages, and can be provided via paper

or electronic systems. Supply-chain participants

have to maintain data records for six years, and

they have to be able to provide drug transac-

tion information fairly quickly when requested

by FDA or other agencies or is needed to notify

trading partners when illegitimate products

are detected. By 2017, manufacturers will need

unique identifiers on drug packages and elec-

tronic data transmission. A fully electronic

package-level tracing system is set for 2023,

most likely based on the Electronic Product

Code Information Services standard.

There is broad agreement among supply-chain

parties that clear standards are crucial to success,

but considerable debate about crafting the spe-

Industry Seeks Clearer Standards for Track and TraceStakeholders face challenges and benefits from a more secure pharmaceutical supply chain.

Jill Wechsler is BioPharm

International’s Washington editor,

chevy chase, Md, 301.656.4634,

[email protected].

Read Jill’s blogs at

PharmTech.com/wechsler.

Fda is working with

supply-chain parties to

tackle its multiple assign-

ments under dScSa.



Regulatory Beat

cifics. Woodcock noted at the FDA

workshop that it’s difficult to reach

agreement on standards, formats,

and practices because that usually

requires some parties to change

what they’re doing. Workshop

participants indicated a need for

clearer definitions of basic concepts,

such as “efficient interoperability”

and “electronic data interchange.”

There was discussion about use of

packing slips to identify the con-

tents in shipments, which is com-

mon practice for manufacturers,

but raised objections from whole-

salers that reliance on packing slip

information would slow down the

distribution process.

There also was debate over using

email to send transaction informa-

tion, an approach that seems simple

and direct to some parties, but raises

concerns about security and data

control for others. Similarly, partici-

pants considered whether transmis-

sion of a PDF document constitutes

dissemination of an electronic or

paper document. Electronic transac-

tions that disclose product prices are

a concern for manufacturers, who

fear that such information could

encourage pilferage or theft and

undermine rate negotiations.

Some stakeholders questioned the

viability of the envisioned step-wise

data transmission system called

for by the legislation. An alterna-

tive suggestion was for all parties

to submit information to a central-

ized data hub, which could provide

records to determine if the prod-

uct is legitimate when a problem

arises, instead of each supply-chain

partner passing and accepting thou-

sands of product transaction reports.

There also was a proposal that FDA

limit its standards to what infor-

mation has to be transmitted, and

leave it to trading partners to figure

out how to send data and messages.

FDA officials agreed on the need

for flexibility but also noted that

the legislation requires the agency

to issue standards for the program.

Overall, stakeholders expressed

strong interested in seeing FDA’s

policy earlier than November to

help them meet the January 2015

implementation deadline.

coSTS and BeneFiTS While FDA crafts further guid-

ance, manufacturers are preparing

for both short-term and long-term

changes, which are laid out in a

DSCSA implementation timeline pre-

pared by The Pew Charitable Trusts

(3). Manufacturers already have

spent millions of dollars on technol-

ogy to implement drug serialization

systems and anticipate that it will

be costly and challenging to inte-

grate new technologies with existing

operations, according to stakeholder

perspectives on drug serialization

and traceability, prepared for the Pew

by Booz Allen Hamilton (4).

Pharmaceut ica l companies

report that off-the-shelf software

often is suitable to support data-

bases and communication systems,

although customization is needed

to meet individual business needs.

Most pharma companies plan to

outsource systems development

and implementation, and a host

of IT consultants and vendors have

emerged to tackle such projects.

Despite notable costs associated

with serialization and tracking,

there is optimism that such initia-

tives will translate into important

gains for the industry. Not only will

improved supply-chain visibility

help block distribution of counterfeit

or compromised pharmaceuticals,

there is the potential for added busi-

ness benefits, according to respon-

dents to the Pew/Booz Allen study

(3). In addition to facilitating drug

recalls and enhancing cargo security,

manufacturers anticipate gaining

more timely and accurate produc-

tion and shipping information. This

information could help reduce pro-

duction lead times, enhance inven-

tory control, process returns more

efficiently, prevent distribution of

expired goods, help manage supplies

for clinical trials, and improve track-

ing of drug samples. More detailed

information on product movement

through the supply chain, moreover,

could help manufacturers ensure

the accuracy of sales and charge-

backs and support drug rebate rec-

onciliation. Future gains might

extend to improved accuracy in

drug-reimbursement systems, better

medication adherence by patients,

and support for FDA reporting

requirements for high-risk products.

All together, these developments

could support efforts to prevent

drug shortages.

As standards emerge for a drug-

tracking system in the US, policy

makers are looking to facilitate

policy harmonization with the

European Union, China, and other

nations. A broad goal is to agree

on barcodes on pharmaceuticals

that are acceptable in all markets.

European governments are estab-

lishing unit-level tracking policies,

with requirements for anti-tam-

pering features on packages and

guidelines for serialization and

authentication. Most countries

are adopting two-dimensional

barcodes, although China may

opt for a linear barcode require-

ment. Different requirements and

implementation timelines in other

regions, unfortunately, would add

to the complexity of establishing

pharmaceutical traceability systems

that gain international acceptance.

ReFeRenceS 1. J. Wechsler, Pharm. Tech., 38 (4) (2014)

p. 14–16.

2. FDA, FDA DSCSA Public Workshop

Summary–May 8–9, 2014 www.fda.gov/

downloads/Drugs/NewsEvents/

UCM399693.pdf, accessed June 3, 2014.

3. The Pew Charitable Trusts, Timeline for the

Drug Supply Chain and Security Act, www.

pewhealth.org/reports-analysis/data-

visualizations/timeline-for-the-drug-supply-

chain-and-security-act-85899544324,

accessed June 1, 2014.

4. The Pew Charitable Trusts,

Implementing a Pharmaceutical

Serialization and Traceability System in

the U.S., www.pewhealth.org ♦


Product & Service Innovations Advertorial

Company DescriptionVetter is a leading contract development and manu-

facturing organization (CDMO) that specializes in

the aseptic filling of syringes, cartridges, and vials.

The company has extensive experience with biolog-

ics and other complex compounds, including mono-

clonal antibodies, peptides, interferons, and vaccines.

Collaborating with pharma/biotech clients worldwide,

Vetter supports products from preclinical develop-

ment through global market supply. Through its US

and European facilities, Vetter Development Service

provides state-of-the-art support for early-stage prod-

ucts, with seamless transfer at Phase III to Vetter

Commercial Manufacturing for large-scale production.

The company offers state-of-the-art technology and

innovative processes to promote product quality and

maximize API yield.

Vetter Development Service: Filling your clinical development needsVetter Development Service provides expert support for

your drug-development projects, from inception to mar-

ket launch. Our services include state-of-the-art clinical

manufacturing at our facilities in Chicago and Europe,

with scale-up and transfer to our large-scale manufactur-

ing facilities. Thanks to the latest technology and innova-

tive processes, we help increase your API yield.

Early planning can help save costs. Together, we

work with you to develop the appropriate delivery sys-

tem for your drug, starting in early development. In

addition to matching all components to your product’s

specifications, we replicate commercial manufactur-

ing processes in our laboratories, which can prevent

surprises when your drug reaches market production.

Once products reach Phase III, we provide seamless

transfer to our large-scale manufacturing facilities

in Europe for late-stage and commercial production.

Simultaneous activities, coupled with expertise and

foresight, reduce time to market. To help prolong your

success, Vetter also offers support on product lifecycle

management, which ideally begins in the preclinical

phase and becomes an integral part of the drug devel-

opment process.

International production facilitiesVetter’s manufacturing facilities include:

• Europe: Three commercial aseptic filling facilities

and state-of-the-art secondary packaging facility.

• US: Small-batch clinical manufacturing facility

in Chicago. Supports preclinical through Phase II

products. At Phase III, products are transferred to

Vetter’s commercial manufacturing facilities.

Vetter Pharma International

Vetter Pharma International

For US inquiries please contact:

Phone: 847.581.6888

Email: [email protected]

For EU inquiries please contact:

Phone: +49-751-3700-0


www.vetter-pharma.com



It takes a unique blend of expertise

to deliver the right results

From clinical development to commercial production

At Vetter, we look at your product from every angle. And help you

find answers that make a difference in efficiency, productivity, safety,

quality, and growth. From initial process design through high-speed

fill and finish, learn how a partnership with Vetter will keep your

product moving smoothly towards success.

• More than 35 years of experience in aseptic filling

• Expertise with many compound classes, including biologics

• Highly trained experts in key technical areas

• Integrated life cycle management

• Innovative drug delivery options

• State-of-the-art cGMP manufacturing

• Excellent global regulatory support

Vetter

Development Service

Vetter

Commercial Manufacturing

Vetter

Packaging Solutions

For US inquiries please contact [email protected] • For EU, Asia and other international inquiries, please contact [email protected]

Answers that work

www.vetter-pharma.com

Dual-chamber syringes vs. vials: Join our free webinar on July 16. www.bpiseminars.com/live



Perspectives on Outsourcing

Do

n F

arr

all/G

ett

y I

ma

ge

s

The value of the customer relation-

ship to a CMO is a function of two

variables: unit volume and price per

unit. Both variables are contentious issues:

bio/pharmaceutical companies are putting

enormous pressure on their CMOs for lower

prices, while their inability to deliver fore-

casted volumes often means lost revenues for

CMOs as reserved capacity goes unutilized.

The resulting low margins depress CMO prof-

itability and threaten their ability to raise

capital and invest in replacement equipment

and new facilities.

While low prices and missed forecasts

often undermine the CMO-customer rela-

t ionsh ip, they re f lec t rea l cha l lenges

in the macro bio/pharma env ironment.

Governments and private payers in North

America and Europe are increasingly unwill-

ing or unable to afford escalating expendi-

tures on drugs. In Europe, governments have

either pledged to reduce drug expenditures

by national health plans or limit the growth

of those expenditures to less

than 5% annually. To ensure that

budget targets are met, drug com-

panies are forced to rebate some

of the revenue rea l ized f rom

sales to national health programs

when those purchases exceed tar-

geted levels.

In the US, there has been

much press attention to the rapid

rise in list prices for drugs, but

the reality is that those list prices

do not reflect what drug compa-

nies actually receive from their

sales. A recent analysis by invest-

ment firm Credit Suisse found

that major bio/pharma com-

panies must give back 25-50%

of the drug price in the form of discounts

or rebates (1). Health insurance companies

are getting tougher when negotiating pric-

ing and are pushing more of the costs onto

patients in the form of higher co-pays.

A growing risk for bio/pharma companies

is that a drug won’t get covered at all. Payers

are increasingly asking whether the incre-

mental benefit of a new treatment is worth

the high prices that bio/pharma companies

are asking for new medications, especially

cancer treatments. This development directly

threatens the revenues and profits that bio/

pharma companies expect their new product

pipelines to be generating in the future.

Europe, especially the UK and Germany,

is leading the way in restricting formulary

access for new drugs. The leader in this pro-

cess has been the UK’s National Institute

for Clinical Excellence (NICE). NICE evalu-

ates drugs for inclusion on the approved for-

mulary of the UK’s National Health Service

based on an analysis of clinical benefit rela-

tive to cost.

A recent PharmSource Trend Report found

that NICE rejected 50% of the new oncology

drugs it reviewed in the 2009–2013 period.

Another th i rd of oncolog y drugs were

granted “Condit ional Recommendation,”

meaning they would be reimbursed only

for limited indications and/or with substan-

tial discounts. Only 17% of oncology drugs

reviewed during the 2009-2013 period were

Decisions limiting or

rejecting coverage for new

drugs have hit CMOs hard.

Health Systems Raise the Bar on Reimbursing New Drugs As payers refuse to cover new drugs, CMOs take a hit.

Jim Miller is president of

PharmSource Information

Services, Inc., and publisher of Bio/

Pharmaceutical Outsourcing Report,

tel. 703.383.4903,

Twitter@JimPharmSource,

[email protected],

www.pharmsource.com



Perspectives on Outsourcing

granted a full recommendation.

A mong non- oncolog y d r ugs ,

one-third received an outright

recommendation for coverage

but over half received a condi-

tional recommendation (2).

While NICE does not set actual

prices in the UK, its counterpart

in Germany, the Inst itute for

Quality and Efficiency in Health

Care (IQWIG), does. Drugs that

are deemed not to deliver addi-

tional clinical benefit are priced

at the level of the comparator

drugs a lready on the market,

which are often generics. Bio/

pharma companies have with-

drawn some innovator drugs

from the German market after

receiving an evaluation of no

additional benefit because they

were unwill ing to accept pay-

ment at generic-drug price levels.

Eva luat ions of new d r ugs

by IQWIG have been similar

to those by NICE. During the

per iod 2011–2014 (f i rst three

months), IQWIG determined that

50% of the new drugs presented

to it offered no additional ben-

efit relative to drugs already on

the market. A third were deemed

to offer minor or non-quantifi-

able benefits, and only 10% were

found to offer considerable ben-

efit (2).

CMOS TAKE A HITDecisions limiting or rejecting

coverage for new drugs have hit

CMOs hard. PharmSource analy-

sis found that the nearly 60%

of the rejected or limited drugs

use a CMO for drug manufac-

ture, and a similar percentage

use a CMO for API manufacture.

PharmSource estimates the lost

CMO revenues amount to at least

$250 million per year, and prob-

ably more: NICE and IQWIG

evaluations are referenced by

most other European countries,

and even by Japan.

Drug companies and CMOs

will take an even bigger hit as

the US catches up with Europe

in the evaluation of comparative

effectiveness. The furor over the

cost of Gilead’s Hepatitis C treat-

ment Sovaldi (contract manufac-

tured by Patheon) has focused

heightened at tent ion on the

cost/benefit trade-off. In recent

months, the American Society

of Clinical Oncology has begun

its own initiative to evaluate the

cost effectiveness of alternative

cancer therapies as guidance for

oncologists.

In the face of this increasingly

d i f f icult macro env ironment,

how shou ld CMOs respond?

Their f irst response should be

defensive by doing r igorous

due dil igence when determin-

ing pricing and contract terms

for new drugs, especially new

molecular entit ies. They need

to u nder s t a nd whet he r t he

sponsor’s expectations regard-

ing price and volume are realis-

tic given the high performance

benchmarks erected by payers.

They should be familiar with

the coverage decisions that have

been made regarding similar

drugs, and they need to satisfy

themselves that sponsors have

ref lected pharmaco-economic

factors in clinical tr ial design

and marketing plans.

W here cove rage r i sk s a r e

high, CMOs may want to insist

on take-or-pay or volume-based

tiered pricing schemes to assure

themselves a level of protection

against adverse coverage deci-

sions. They must also be relent-

less in their efforts to drive down

their operating costs to protect

their margins.

Price pressures and coverage

limitations are immutable ele-

ments of the bio/pharma indus-

try’s macro environment. CMOs

need to reflect those realities in

their processes and operations if

they are to succeed.

REFERENCES 1. S. King, “FirstWordLists: Which

companies pay the highest US

rebates and which companies are

most dependent on US drug price

increases?” www.firstwordpharma.

com, May 11, 2014.

2. PharmSource, “Not So NICE: How

Market Access Schemes in Europe

are Impacting the CMO sector,” (May

2014). ◆

Drug companies

and CMOs will take

an even bigger hit as

the US catches

up with Europe

in the evaluation of

comparative

effectiveness.

Join the discussion

Is drug pricing affecting your CMO’s bottom line?

Post your comments on www.biopharminternational.com/linkedin.



Burrill on Biotech

Dig

ita

l V

isio

n/G

ett

y Im

ag

es

The promise of precision medicine is

beginning to bear fruit as deadly dis-

eases are made treatable, doctors use

genetic information to guide treatment deci-

sions, and the convergence of information,

communications, and biological technology

reinvents the practice of medicine. The arrival

of this new age of medicine has captured the

imagination of investors, who are pouring

record investments into these emerging areas.

Privately held life-sciences companies have

raised $7 billion through the first five months

of 2014, representing a 36.2% increase com-

pared to the same period last year. Investment

in early-stage companies drove the increase as

seed, series A and series B investment jumped

182% during the period to $2.9 billion. The

surge in funding is going into innovative areas

such as gene therapy, immune-oncology, and

digital healthcare technologies that promise

to move the needle on the delivery of care

and improve outcomes for patients with once-

intractable diseases.

As Big Pharma shifts its resources away from

internal R&D to externalizing innovation,

investors see opportunities in backing compa-

nies with cutting-edge technologies. And ven-

ture investors, boosted by liquidity

from the robust capital markets,

are backing startups up with ade-

quate funding to allow them to

validate their technologies rather

than needing to constantly seek

new capital.

Over the past year, investors

have pumped more than $2 billion

into gene therapy, immunothera-

pies, and digital-health companies,

including more than $1.3 billion

invested in startups and $819 mil-

lion raised by nine companies

through initial public offerings (see Table I).

Almost every big pharmaceutical company

with an oncology program is developing cancer

immunotherapies, while companies focused

on genetically inherited diseases are exploring

gene-therapy solutions.

Investments In Gene therapyVenture investors and Big Pharma took notice

of the potential of gene therapy after a team of

researchers at the University of Pennsylvania,

led by Carl June, published results of a small

trial of their chimeric antigen receptor T-cell

(CART) cancer-killing cell therapy in August

2011 that showed complete remission from

chronic lymphocytic leukemia in three patients

who no longer responded to chemotherapy.

That led to a historic partnership between

Novartis and the University of Pennsylvania

aimed at bringing the new personalized immu-

notherapy approach to patients with various

forms of cancer. Novartis invested $20 million

for the construction of a new research center

in Philadelphia as part of the pact, and gained

an exclusive worldwide license to the technol-

ogy developed at Penn that uses manipulated

immune-system cells to kill cancer cells. Using

genetic engineering, June’s team manipu-

lated T cells extracted from leukemia patients

into recognizing and attacking leukemia cells.

These altered T cells were re-injected, using

a deactivated HIV-1 virus, into the patients

Investors see opportunities

in backing companies with

cutting-edge technologies.

Moving the Needle on HealthcareGene therapy, immune-oncology, and digital healthcare technologies offer investors promise for innovation investments.

G. Steven Burrill is chief executive

officer at Burrill equities, san

Francisco, Ca, 415.341.3870,

[email protected].


July 2014 BioPharm International www.biopharminternational.com 19

Burrill on Biotech

where they proliferated until they

destroyed the cancer cells.

At the time, June told report-

ers that multiple drug makers and

many venture investors were inter-

ested in the “ultra-personalized”

therapy. He chose to work with

Novartis because he felt the therapy

was likely to reach patients faster

with an already existing company.

June isn’t the only scientist

experimenting with CART ther-

apy to attack cancer. In early

December 2013, th ree lead-

ing cancer centers—The Fred

Table I: Select fnancings of innovative companies 2013 to date.

Venture

COMPAnY FInAnCInG rOunD rAISeD (uSD M) PrInCIPAL FOCuS

Juno Therapeutics Series A 176.0 CART-cell cancer therapies

Spark Therapeutics Series A and B 122.8 Gene therapies

Avalanche Biotechnologies Series B 55.0 Ophthalmic gene therapies

Kite Pharma Mezzanine convertible notes 50.0 CART-cell cancer therapies

uniQure (Netherlands) Strategic investment 46.0 Cardiovascular gene therapies

Voyager Therapeutics Series A 45.0 Gene therapies

Editas Medicine Series A 43.0 Gene editing

GenSight Biologics (France) Series A 41.6 Ophthalmic gene therapies

Audentes Therapeutics Series A 30.0 Gene therapy to treat rare muscle disease

CRISPR Therapeutics (Switzerland) Series A 25.0 Gene therapies

Lysogene (France) Series A 22.0 CNS gene therapies

NightstaRx (United Kingdom) Series A 19.8 Gene therapies for retinal dystrophies

AAVLife (France) Series A 12.0 Gene therapies for rare diseases

Immune Design Series C 48.5 Cancer immunotherapies

Jounce Therapeutics Series A 47.0 Cancer immunotherapies

Kinex Pharmaceuticals 40.0 Cancer immunomodulators

Argos Therapeutics Series E 37.5 Cancer immunotherapies

Isarna Therapeutics (Germany) 25.4 Cancer immunotherapies

Jennerex 21.6 Cancer immunotherapies

Apexigen Series A 20.0 Cancer immunotherapies

CoStim Pharmaceuticals 10.0 Cancer immunotherapies

Flatiron Health Series B 130.0 Cloud-based platform to improve cancer care

Nant Health, LLC Series B 135.0 Integrated healthcare

Proteus Digital Series G 120.0 Wearable and injectable sensors

IPOs

COMPAnY tICKer rAISeD (uSD M) PrInCIPAL FOCuS

bluebird bio BLUE 116.1 Gene therapies for genetic diseases

Celladon CLDN 50.6 Gene therapy for heart failure

UniQure (Netherlands) QURE 91.8 Gene therapies for rare diseases

Horizon Discovery (United Kingdom) LSE:HZD 66.0 Gene editing platform

Applied Genetic Technologies AGTC 50.0 Ophthalmic gene therapies

Agios Pharmaceuticals AGIO 121.9 Cancer immunotherapies

Argos Therapeutics ARGS 45.0 Cancer immunotherapies

Castlight Health CSLT 178.0 Healthcare IT

Everyday Health EVDY 100.0 Digital Health



Burrill on Biotech

Hutchinson Cancer Research

Center, Memorial Sloan-Kettering

Ca ncer Cente r, a nd Seat t le

Children’s Research Institute—

joined forces to launch Juno

Therapeutics in Seatt le. Arch

Venture Par tners and A laska

Permanent Fund pledged an ini-

tial investment of $120 million,

with Amazon’s Jeff Bezos and oth-

ers adding another $56 million

in 2014, making it perhaps the

largest series A funding of a life-

sciences company to date.

Juno’s cofounders inc lude

R icha rd K lausner, a for mer

director of the National Cancer

Institute, and Juno CEO Hans

B i shop, who he lp e d b u i ld

Dendreon’s process of using a

patient’s own T cells to induce

an immune response in cancer.

Other companies in the space

include Bluebird Bio and Kite

Pharma.

Investor s a re a l so launch-

ing companies developing gene

therapies using adeno-associ-

ated vectors to modify genetic

defects to treat otherwise irre-

versible conditions. In October

2013, the Children’s Hospital of

Philadelphia (CHOP) commit-

ted $50 million in seed funding

to launch Spark Therapeutics to

advance its gene therapy clini-

cal trials and commercialize its

technology. The financing came

after more than a decade of work

at CHOP perfecting the necessary

tools to allow routine translation

of gene therapy from bench to

clinic: the gene delivery vector

itself, and the manufacturing of

clinical-grade vector using good

manufacturing practices.

Besides its agreement with

CHOP, Spark is working with

other academic institutions to

assemble the technology, pro-

grams, and capabilities needed

to deliver its first gene therapy

products. These include gene

therapy to correct the gene for

clotting factor IX, defective in

patients with hemophilia B, for

use in an early-stage clinical trial.

They are also pursuing a gene

therapy to correct a gene defec-

tive in one form of inherited reti-

nal degeneration that ultimately

causes irreversible blindness, for

use in a late-stage trial. In late

May, Spark raised another $72.8

million in a series B round from

venture investors and several

healthcare funds.

Resea rchers a re a lso work-

ing with bacterial proteins that

allow them to cut DNA in spe-

cific places to edit disease-causing

genes. Cambridge, Massachusetts-

based Editas Medicine launched

in November with $43 million

in a series A financing to trans-

late its genome editing technol-

ogy into therapeutics. Genome

editing technology has come a

long way, making it now pos-

sible to precisely modify almost

any gene in the human body

with the ability to directly turn

on, turn off, or edit disease-

causing genes, says the com-

pany, whose f ive co-founders

include Harvard’s George Church,

MI T’s Feng Zhang, Ha r va rd

University’s David Liu, Harvard

Medical School’s Keith Joung,

and the University of California,

Berkeley’s Jennifer Doudna.

Further InnovatIve InvestmentsInvestment is also ramping up in

innovative digital technologies

that aim to transform the delivery

of healthcare. Three recent financ-

ings attest to what investors see as

the power of technology to modify

health.

Flatiron Health, a company

developing an oncology platform

to improve cancer care, raised $130

million in a series B financing

round led by Google Ventures. Its

cloud-based platform aggregates

and transforms clinical and finan-

cial data from electronic medi-

cal records and billing systems in

real-time, allowing the industry to

have a comprehensive view of a

patient’s experience in the oncol-

ogy office as it happens.

NantHealth, launched by bil-

lionaire Patrick Soon-Shiong, raised

$135 million from an undisclosed

sovereign wealth fund in a series B

financing round. NantHealth says

it is in the intersection of innova-

tion and connectivity, building a

platform that will integrate data

streams to allow for better health-

care delivery and outcomes.

And Proteus Digital Health, a

maker of digital pills—miniature

ingestible sensors that track vital

signs, raised $120 million from

undisclosed global institutional

investors. These digital medi-

cines integrate drugs with ingest-

ible, wearable, mobile devices, and

cloud computing in order to deliver

solutions that enable patients, their

families, and their doctors to make

better decisions about their health.

These are a number of the inno-

vative, precision technologies

that likely will be coming onto

the market over the next few years

that have the capability of improv-

ing how health decisions are made,

how care is delivered, and how

patients are medicated, all with

the potential of transforming

healthcare. ◆

Investment is ramping

up in innovative

digital technologies

that aim to trans-

form the delivery

of healthcare.


The Parenteral Drug Association presents the...

2014 PDA/FDAJoint Regulatory

ConferenceConnecting Regulatory, Quality, Science & Compliance: Assuring

Customer-Focused Outcomes throughout the Product Lifecycle

September 8-10, 2014RENAISSANCE WASHINGTON HOTEL | WASHINGTON, DC

At the 2014 PDA/FDA Joint Regulatory Conference learn about how the quality culture of a company is a

foundational cornerstone to attaining successful business goals and objectives.

Conference highlights include:

• Analytics & Manufacturing of the Future: This session

will focus on how companies are changing the old

manufacturing and analytical models to new, cost

effective and compliant models.

• The Cost of Poor Quality: The consequences of short-

sighted decisions that do not support quality will be

discussed (in context of cost of ownership) and will

be contrasted with the benefi ts of quality assurance

to both drug quality and the business.

• Patient Perspective: You will hear how innovative

medical products touch the lives of patients in past,

current and future settings and drive the future for

development of innovative medicines.

• FDA Panel Discussions: Compliance Update and

Center Initiatives: Popular sessions where Compliance

Directors from the FDA’s Centers and Offi ce of

Regulatory Affairs provide an update on current hot

topics in the compliance and enforcement areas and

hear directly from agency leaders on their Center’s

current and future initiatives. Immediately following the conference:

• On September 10-11, the 2014 PDA Drug Shortage Workshop will provide you with the opportunity to hear

about technological improvements that can have a positive impact on preventing drug shortages.

• PDA’s Training and Research Institute (PDA TRI) will be hosting six stand-alone

training courses on-site from September 11-12.

Visit www.pda.org/pdafda2014 for more information & to register.EXHIBITION: SEPTEMBER 8-9 | POST CONFERENCE WORKSHOP: SEPTEMBER 10-11 | COURSES: SEPTEMBER 11-12

Register by July 29 and Save

FDA’s Views on Manufacturing of the Future: The Conference will start off with a look at what

manufacturing in the future might look like as doctors, researchers and healthcare practitioners advance

healthcare to the next level.



-Oxfo

rd-/

E+

/Gett

y Im

ag

es

Globalization is impacting most

industries, and the pharma-

ceutical industry is no excep-

tion. On the positive side,

globalization has enabled the industry

to enter markets all over the world and

provide life-changing medicines to mil-

lions of patients. With the benefits of

globalization, however, come significant

challenges and responsibilities.

One unintended consequence to

globalization is the creation of drug

shortages. Even though new drug short-

ages have been on the decline since a

peak in 2011, the issue of drug short-

ages remains a serious one: when drug

shortages occur, some of the most vul-

nerable among us—sick patients—are

profoundly affected.

How do drug shortages affect patients?

Most commonly, they result in patients

using alternative medications or treatment

delays. Drug shortages also can lead to

longer hospitalizations, treatment failure,

and even death (1).

Simply put, the human cost of drug

shortages is unacceptably high. The indus-

try must do more to ensure there are ade-

quate supplies of medicines for patients

when they need them.

Many factors contribute to drug short-

ages. These include manufacturing delays,

quality problems, loss of a manufactur-

ing site, and issues with raw materials (2).

Raw materials issues, including shortages,

account for 9% of all drug shortages (3).

Factors affecting the quality and avail-

ability of raw materials include natural

Ensuring a Robust Raw-Materials Supply Chain

Martin VanTrieste

With the increasing

globalization of the biopharma-ceutical indus-

try, companies must establish

strategies to minimize vulner-abilities in the raw-materials supply chain.

Martin VanTrieste, R.Ph., is senior

vice president of quality at Amgen. He

is the founder and first chairman of

Rx-360 and is currently on its board

of directors, [email protected].

Supply Chain



disasters, geopolitical movements,

and variability. Variability in raw

materials is a key issue in the supply

chain. Inconsistencies such as raw

material solubility, bioburden, and

residual metals and impurities in

animal-derived excipients can lead

to manufacturing delays, impact

product quality and immunogenic-

ity, and, ultimately, affect the safety

and supply of medicines. Even the

smallest change in a raw material

can have a measureable impact.

Another crucial factor affect-

ing the supply chain is adultera-

tion, or the deliberate or accidental

contamination of materials, which

was the case in 2008 when more

than 12 manufacturers unknow-

ingly purchased contaminated hepa-

rin, an anticoagulant that had been

sourced in China (4). There were 246

reported deaths in the United States

following use of heparin between

Jan. 1, 2007 and May 31, 2008 (5).

Adulterated materials not only

can have a devastating impact on

product safety, but also can affect

patients in other ways. Poor manu-

facturing and quality along with

inadequate preparation for events

that affect the supply chain can

cause increased competition for

inventory, capacity, and freight

lanes, leading to customer ship-

ment delays. When companies

take a proactive approach, they

can minimize the response time

and investment required to miti-

gate supply-chain issues and also

reduce the downtime that results

from those issues.

EffoRtS to AddRESS SuPPly-CHAin iSSuES The Drug Quality and Security Act

(HR 3204) was signed into law on

Nov. 27, 2013 and outlines steps to

build an electronic, interoperable

system to identify and trace certain

prescription drugs in the US. The

act, which will be phased in over

10 years, includes requirements for

product identification, tracing, veri-

fication, detection, and response

notification systems, wholesaler

licensing and third-party logistics

provider licensing (6). Ultimately,

the electronic system will provide

information at the individual pack-

age level about where a drug has

been in the supply chain. Despite

this, no pedigree requirements for

upstream supply-chain security

have been implemented.

Rx-360, a not-for-profit phar-

maceutical and biotech industry

consortium, formed an Upstream

Supply Chain Security working

group in June 2013 to educate

and inform policy makers, regu-

lators, and industry profession-

als about supply-chain security

issues. Rx-360 conducted a sur-

vey in August 2013 to understand

Supply Chain

Supplier Audit Program Marks Progress

The Rx360 pharmaceutical supply chain consortium was launched in 2009 in response to the heparin adulteration crisis, which

raised broad concerns about inadequate monitoring of the pharmaceutical supply chain by manufacturers. Since then, Rx360

has attracted more pharmaceutical and biotech companies to support its efforts to enhance supply-chain security. The group

has expanded to conduct approximately 25-30 joint audits a year, a collaborative process that can lower audit costs, expand

the audit process, and reduce suppler “audit fatigue.” Joint audits coordinate the assessment of a particular supplier of APIs,

excipients, container/closure systems, packaging materials, and other raw materials. All sponsors of the joint audit gain access

to the resulting report, which then can be purchased by other parties.

To improve this program, Rx360 established a “strategic partnership” with BSI Supply Chain Solutions to handle joint audit

scheduling and management. The goal is to conduct more than 100 joint audits in the coming year, said Martin VanTrieste,

senior vice president at Amgen and founding chair of Rx-360. While the audit volume so far is respectable, he believes

that there are thousands of suppliers that could benefit from this collaborative program. “But we’re not close to that,” he

commented. Not all suppliers have bought in to the joint audit process, he notes, some due to fears the process could damage

their relations with customers. VanTrieste also sees a reluctance within leading manufacturers to shift from doing audits

themselves. The group’s shared audit program has developed more slowly, but now has more than 200 audits available to

members. Drug manufacturers and suppliers tend to feel more proprietary about their own reports on key suppliers, even with

the ability to redact confidential information.

Rx-360 has formed an Asia Working Group to develop its program in China, primarily to audit API producers. And it has

developed vendor assessment templates to streamline how manufacturers gather information on new suppliers. Supplier

audits involve ensuring that these firms have their own security processes to prevent quality problems. The consortium tracks

supply-chain policies and provides members with reports on the latest developments, but does not comment on specific

rules or policies. A main goal is to identify and support opportunities for regional and international cooperation in addressing

pharmaceutical supply chain threats.

—Jill Wechsler, Washington editor



Supply Chain

the industry’s concerns related to

upstream supply-chain security (4).

Survey respondents represented

more than 80% of the largest

global pharmaceutical companies

by revenue.

The survey showed that while 75%

of respondents have a formal supply-

chain security focus, as many as 44%

do not use supply-chain mapping

documentation for some or all of

their materials to make sure these

materials are not adulterated or mis-

branded. Supply-chain mapping is

an important tool to understanding

the origins of raw materials, particu-

larly given the international scope of

supply chains.

Nearly one-third of the respon-

dents reported they do not feel

there is alignment between phar-

maceutical manufacturers and

their suppliers. Furthermore, only

45% of those surveyed go as far

back as their supplier’s supplier

when ensuring supply-chain safety.

MitigAting SuPPly-CHAin RiSkCompanies must increase their

understanding of the total supply

chain. Leveraging best practices

from other industries such as the

automotive industry, biopharma-

ceutical companies should develop

processes that ensure both optimal

quality materials for medicines

and a company’s ability to quickly

respond to issues. The following

three key areas may be focused on

to increase understanding of the

total supply chain and help miti-

gate risk.

Organization

A cross-functional team comprised

of dedicated leaders for each cat-

egory (such as basic chemicals and

pharmaceutical glass containers)

drives strategies linked to the spe-

cific needs of that category, pri-

oritizes based on those strategies,

and unifies supplier direction and

management. The team also inte-

grates approaches to specific cat-

egory risks, provides oversight to

all suppliers, and increases knowl-

edge management capability and

expertise. Category leaders are

supported by a core team of staff

from supplier quality management,

product development, global stra-

tegic sourcing, and manufacturing

departments. These cross-func-

tional teams are built for key sup-

pliers to focus on technical issues,

optimize the supply chain and

product quality, and build long-

term relationships.

Process

Focused work streams by cate-

gory—similar to the approach used

successfully by the auto industry—

help to improve quality, increase

reliability, and decrease variability.

The work stream framework con-

sists of intense technical engage-

ment to increase understanding of

the attributes, manufacture, use,

and interactions of raw materi-

als, to optimize the transparency

and synchronization of the supply

chain. The goals of the focused

work streams are to improve line

of sight, lot definition, reliable sup-

ply, plus optimize inventory, and

reduce waste. Close collaboration

with well defined teams and con-

tinued engagement of executives

results in robust relationships with

suppliers. Paramount to the suc-

Regulating the Supply Chain

The recent and upcoming changes to the FDA Safety and Innovation Act (FDASIA) have added a number of requirements

intended to ensure a safe supply of medicines. Many of these enhancements are included in Title VII of the act, parts 701-

718. The changes outlined in Title VII are important because they allow the agency to collect more comprehensive, accurate,

and timely information about the pharmaceutical supply chain. In addition, FDASIA helps establish the same requirements

for foreign and domestic manufacturers and allows the agency to work more effectively with their overseas counterparts.

The Act also endows FDA with new tools to protect the integrity of the global supply chain. Specifically, FDA can collect and

analyze product data to enable risk-informed decision making on incoming products. FDA may now partner with foreign

authorities to leverage resources through information sharing and recognition of foreign inspections of facilities. These

changes have already resulted in two draft guidance documents: Specification of the Unique Facility Identifier (UFI) System for

Drug Establishment Registration and Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection.

FDA’s Supply Chain Pilot Program is designed to help in addressing the increasing issues and problems associated with

importations that have arisen from the globalization of the pharmaceutical supply chain. The goal of the program is to

expedite the importation of legitimate materials, APIs, and product coming from abroad. The pilot program will collect data

from 2014-2016. At the end of this period, the data will be evaluated to establish a system where there is an efficient use

of time and resources to evaluate items of importation. The system would rely on specific code numbers that would require

little human intervention. Instead, time can be spent on evaluating the questionable materials that require a more detailed

human review. —Susan Schniepp

Continued on page 28


Time (min)

0 0.5 1.0 1.5 2.0 2.5 3.0

10

20

30

40

50

60

70

80

90

100

Rela

tive A

bundance

1.33

1.35

1.361.361.381.310.96 1.48 1.81 2.281.960.730.51 2.510.22 2.77

1.33 1.341.331.360.970.52 2.161.31 2.24 2.531.55 1.880.75 2.820.270.14

10

20

30

40

50

60

70

80

90

100

20-fold increase

in concentration

SOLAµ plates

Thermo Scientifc™ SOLAμ™ plates are designed for bioanalytical and

clinical research analysts who require cleaner, highly reproducible

and robust sample extraction at very low solvent elution volumes

in high-throughput workfows. SOLAµ achieves this due to the

unique and innovative frit-less SPE technology.

Sensitivity counts

Thermo Scientifc SOLAµ plates allow users to pre-concentrate up

to 20 times prior to injection, allowing greater limits of sensitivity

to be achieved.

Precision matters

The application of award winning Thermo Scientific™ SOLA™

technology to micro-scale elution provides improved flow

characteristics, which gives users the confdence in results, time

after time.

SOLAμ provides reproducibility, robustness and ease of use

at low elution volumes by utilizing the revolutionary SOLA

Solid Phase Extraction (SPE) technology. This removes the

need for frits, delivering a robust, reproducible format which

ensures highly consistent results at low elution volumes.

SOLAμ delivers:

• Robust sample processing

• Capacity for clinical scale sample volumes

• Lower sample failures due to high reproducibility at low

elution volumes

• Increased sensitivity due to lower elution volumes

• The ability to process samples which are limited in volume

Figure 1: Shows how SOLAμ allows users to pre-concentrate the sample up to 20 times

prior to injection

© 2014 Thermo Fisher Scientific Inc. All rights reserved. All trademarks are the property of Thermo Fisher Scientifc and its subsidiaries. Specifcations, terms and pricing are subject to change. Not all products are available in all countries. Please consult your local sales representative for details.

0.00

5.00

10.00

15.00

20.00

25.00

0 5 10 15 20 25 30 35

SOLA Competitor (i) Competitor (ii)

Sample number

Air flo

w m

L/m

in

Figure 2: SOLA provides more uniform fow through characteristics compared to loose

packed SPE products

Introducing an award winning approach to micro-scale elution.

To download the full application note

SOLAμ for Pre-analysis Sample Concentration

visit: www.thermoscientifc.com/sola-spe



Supply Chain

Challenges in Securing the Biopharma Supply Chain

To gain insight on the unique challenges of securing

the supply chain for biopharmaceuticals, BioPharm

International spoke with Manja Bouman, president, BIO

at Patheon and Susan Schniepp, vice-president Quality

Regulatory Affairs at Allergy Laboratories about the

management of the biopharmaceutical supply chain.

Biopharma Supply Chain Challenges

BioPharm: What top challenges do biopharmaceutical

companies face when managing the supply chain?

Schniepp (Allergy Laboratories): There are a number

of challenges facing biopharmaceutical companies

with respect to managing their supply chain. Today’s

supply chain is quite complex and involves transport of

ingredients and final product through multiple countries

and touch points. Biopharmaceutical companies must

understand the culture and dynamics in multiple regions

in order to protect their product from theft, diversion,

and counterfeiting. Understanding and managing the

complexity of their supply chain is probably the biggest

challenge facing companies today.

Bouman (Patheon): Lead time for production

consumables and materials can be several weeks

to months for some custom-made cell culture

media. Lead time to manufacture, test, and release

a biopharmaceutical drug substance typically takes

15-20 weeks from initiation of batch manufacturing

to release of an drug substance for filling. Drug

substances and finished biopharmaceuticals are

typically cold chain, and there are risks of temperature

deviations during transport. The supply chain will likely

involve multiple parties and providers so there is a

inherent complexity, resulting in a need for planning

and project management.

Multiple quality agreements and manufacturing

agreements are in place, [and it is] highly desirable to

align these requirements and combine all activities as

much as possible. For example, have the drug substance

manufacturer and final dosage manufacturer in one

agreement and under one project manager. Contractors

need to be flexible and able to address needs of

customers, such as shifting timelines due to delays in

other areas of the manufacturing chain, for example.

Ensuring Quality

BioPharm: What specific steps should companies take to

ensure the quality of a product when dealing with multiple

biopharmaceutical material suppliers?

Bouman (Patheon): The specific steps are essentially

around cGMP compliance but with special attention to

mitigating cross-contamination risks in a multi-product

environment. [There should be] a fully defined supply

chain and agreement on how and when product moves

from supplier A to supplier B. [Companies should] try to

build in flexibility [and have] excellent planning, including

risk mitigation and ‘what if’ scenario planning.

Schniepp (Allergy Laboratories): At the recent PDA/

FDA/Rx360 conference on the Pharmaceutical Supply

Chain (Expanding Your Quality System [Q10] for a Robust,

Reliable, and Secure Supply Chain), there were a number

of suggestions for protecting products that were offered

to attendees, among which were tracking and tracing

devices, bar coding of product, hiring of firms that monitor

the product and raw materials through shipment. Of

all the suggestions offered, the one endorsed the most

frequently was that companies needed to accurately

map their supply chain and identify the areas where

the greatest risk could occur. Once the supply chain is

accurately mapped and risks identified, the next step is to

try and mitigate the identified risks. If done correctly, the

supply chain mapping identifies all the transfer points in

the supply chain. It is most often at these transfer points

where the product is most vulnerable of being stolen.

Bottom line, creating and maintaining a detailed mapping

of your supply chain is paramount to understanding your

vulnerabilities. When you understand your vulnerabilities

you can take steps to mitigate them.

Best Practices

BioPharm: From a risk-management and risk-mitigation

perspective, what are some key best practices in

maintaining security and integrity of biopharmaceuticals

in the supply chain?

Bouman (Patheon): [Companies should] implement

a rigorous supplier qualification and requalification

process [and] develop and scale-up GMP compliant

manufacturing bioprocesses. Particular attention should

be paid to minimizing process variability and exclusion

of extraneous agents. [Companies should] validate the

supply chain, particularly cold-chain and frozen-chain

components; safety, integrity and security of drug product

shipments through validation and constant monitoring

post-validation. Conduct thorough FMEA on all aspects

of the supply chain through from DS/API to shipment

to clinic/pharmacy. Involve contractors in this exercise.

Identify potential weak points and establish mitigation



Supply Chain

Challenges in Securing the Biopharma Supply Chain (continued...)

strategies. Where feasible, establish second suppliers.

Manage contractor-contractor to contractor interface

closely. Be proactive as far as possible with the issues.

Schniepp (Allergy Laboratories): There were a

number of suggestions made [at the 2014 PDA/FDA/

Rx360 supply chain conference] for maintaining the

security and integrity of the supply chain, but one

recommendation stood out as number one: know

who you are doing business with. All of the speakers

agreed that knowing who you are doing business

with is essential to securing the supply chain. They

recommended facility audits and personal visits to your

product transporters to establish a business relationship

and an understanding about expectations for securing

the product. They also recommended having a single

point of contact, if possible. It was the majority opinion

that nothing takes the place of a good working business

relationship. When a relationship is open and trusting, the

communication is meaningful and immediate because

both parties have a vested interest in the outcome.

This [relationship] is critical when dealing with theft

and diversion of biopharmaceutical products. The sooner

the carrier/supplier informs the client of a shipping

problem the sooner the situation can be resolved. The

immediacy with which this is done can be enhanced by

the established relationship.

Globalization of the Supply Chain

BioPharm: How has globalization of the industry affected

the security of the biopharmaceutical supply chain?

Schniepp (Allergy Laboratories): The globalization

of the industry has complicated the supply chain. The

materials and APIs that used to be sourced domestically

are now sourced from foreign suppliers. The handoffs

of materials and product to get to the final user have

dramatically increased in the past 10 to 15 years. The

industry has had to understand and communicate with

different cultures in order to transport their products

safely across the globe. In a way, this globalization

has forced companies to think about the safety of their

products in a new and completely different way. Now that

this has happened the industry can expect to see a more

secure supply chain and a more efficient importation

process that guarantees safe and effective medicines to

the patients.

Bouman (Patheon): Globalization has encouraged the

development of dual–sourcing of biopharmaceuticals and

improved security of supply. Biosimilars and biobetters

are now a possibility in some markets due to globalization.

Globalization presents increased security and safety

risks to shipments, some of which require lengthy and

complex international supply routes. [Globalization has]

introduced a geographical challenge with regards to

logistics and forced the establishment of, for example,

shipping/logistics solutions to suit [those] geographies.

Information Sharing

BioPharm: How important is collaboration and

transparency in information sharing across the supply

chain? What can companies do to ensure transparency?

Bouman (Patheon): Collaboration and security are

critical in maintaining the integrity of supply chains

and ultimately the safety and efficacy of any medicinal

product. Companies have to balance transparency with

the need for safety and security of the supply chain. To

ensure transparency, companies should document and

disclose adverse events. The effectiveness of corrective

and preventative actions should also be available to

regulators.

Delivering Drugs Safely to Patients

BioPharm: What are the challenges of securing delivery

of biopharmaceuticals to patients? What steps should

companies take to secure the delivery of their products?

Schniepp (Allergy Laboratories): Companies need

to watch Internet pharmacy sales and make sure the

product being sold at a discount on these sites is, in fact,

legitimate. In addition, it is important to try and make

sure pharmacies are aware when there is a potential

for counterfeit or stolen material to enter back into trade.

Companies need to provide the lot numbers of stolen

product to pharmacies so the pharmacists can prevent

the medicine from reaching the patients.

There is no guarantee that the product has been

stored under the proper conditions which makes it

unsafe to take.

Bouman (Patheon): The main challenges are ensuring

the product quality and integrity is not adversely affected

by the distribution and storage on route to the patient.

Companies should thoroughly risk assess the entire

supply chain from factory gates to patients. Companies

should consider security and integrity risks to shipments

globally as part of their risk mitigation measures.

Distribution companies should validate the supply chain

from the factory gates all the way to the patient including

considerations for worst-case environmental conditions. ♦



Supply Chain

cess of these relationships is shared

goals, regular executive reviews,

clear communication channels,

two-way feedback, and shared

benefits. Managing supply from

a quality and security standpoint

includes an up-front definition

of requirements (i.e., audits and a

supplier quality agreement) when

selecting and approving suppliers.

Once a supplier is selected, pro-

cesses for material qualification

and approval (e.g., development,

classification, qualification, and

commercialization) are defined.

Systems for supplier selection and

approval as well as material quali-

fication and approval are moni-

tored for continuous improvement.

Supply-chain security audits may

also be performed with specially

trained auditors looking for vul-

nerabilities in the supply chain.

Technology

Technology can enable end-to-end

raw material supply-chain moni-

toring around the clock, enabling

rapid risks assessment and event

recovery. Amgen developed a plat-

form that allows for input from

the company about suppliers,

products, and part sourcing; input

from suppliers about site locations,

part origins, emergency contacts

and alternative sites and recovery;

plus other inputs such as location

risk scores, supplier financials, and

public information. This platform

gives time to recover from a sig-

nificant event affecting the supply

chain and enables the company

to put a higher quality disaster

recovery plan into place. Industry

notifications such as those from

Rx-360, which provide global alerts

on issues affecting the healthcare

supply chain, together with alerts

tailored to companies based on the

specific commodities they use, can

reduce the time it takes to assess

the impact of an event and mini-

mize resources used. In the future,

alerts on companies’ affected

manufacturing sites and raw mate-

rials will enable the industry to

more quickly assess impact and

put plans into action that address

affected resources. While it will

take time, highly specific alerts

will eventually become the norm

as more companies expect this

level of transparency.

WoRking togEtHER AS An induStRyThere are several ways the indus-

try can protect the global supply

chain. Many companies in the bio-

pharmaceutical industry are col-

laborating with Rx-360 to address

the current challenges with the

global supply chain by sharing

information, audits, and best prac-

tices, and by creating industry-

wide standards.

Some of the opportunities for

creating industry standards that

have been identified through the

Rx-360 collaboration include:

• Creating and refining unique

and foolproof material identifi-

cation processes such as tamper

evident packaging, use of water-

marks, and photo libraries to

identify packaging deviations

• Audits and documentation pro-

cedures for change control, busi-

ness continuity, spec approval,

chain of custody, quality agree-

ments, and product dossiers

• Systems and communication

including electronic audit

trails and records, advanced

shipping notifications, supply-

chain mapping, end-to-end

inventory management, testing

optimization, and monitor-

ing end-to-end variability.

Biopharmaceutical companies

and their suppliers minimize raw-

material variability by collaborat-

ing and sharing data. Working

together, the industry can better

understand the sources of impuri-

ties from raw materials and the

manufacturing process, validate

manufacturing processes with ade-

quate process capability, establish

appropriate controls by conduct-

ing raw-material characterization,

and improve raw-material specifi-

cations. Becoming more engaged

with suppliers through technical

visits, supplier relationship pro-

grams, and more effective audit

programs are also important to

minimizing raw material variabil-

ity across the industry.

The privilege of serving patients

comes with significant responsi-

bilit ies. These responsibilit ies

include ensuring patients receive

safe, quality medicines in a robust

and reliable manner. Industry play-

ers can work together on proactive

approaches that drive continuous

improvements in the raw-mate-

rials supply chain, ensuring that

patients receive trusted medicines

without compromising quality and

availability.

REfEREnCES 1. M. McLaughlin, et al., Care Pharm. 19

(9), 783-788 (2013).

2. J. Woodcock, M. Wosinska M. Clin.

Pharmacol. Ther. 93 (2), 170–176

(2013).

3. US Government Accountability Office,

Drug Shortages: Public Health Threat

Continues, Despite Efforts to Help

Ensure Product Availability: Report to

Congressional Attendees, GAO

Publication no. GAO-14-194 (February

2014), www.gao.gov/

assets/670/660785.pdf. Accessed

May 19, 2014.

4. C. Calvert, et al., Rx-360: An

International Pharmaceutical Supply

Chain Consortium. (2014) Rx-360

Upstream Supply Chain Security [White

paper], www.rx-360.org/LinkClick.

aspx?fileticket=e9wUVaoC9-

A%3D&tabid=209, accessed May 22,

2014.

5. FDA, Drug Safety and Availability.

Postmarket Drug Safety Information for

Patients and Providers: Generic

Enoxaparin Questions and Answers,

www.fda.gov/Drugs/DrugSafety/

6. FDA, Drug Supply Chain Security Act

(DSCSA): Title II of the Drug Quality and

Security Act of 2013, www.fda.gov/

Drugs/DrugSafety/

DrugIntegrityandSupplyChainSecurity/

DrugSupplyChainSecurityAct/,

accessed May 14, 2014. ♦

Continued from page 24


Product & Service InnovationsAdvertorial

Solutions for biopharmaceutical laboratoriesFor biopharmaceutical organizations challenged to

deploy high-resolution analytics across the biotherapeu-

tics development process, Waters has developed a full

suite of purposefully designed LC, MS, and bioinfor-

matics technologies that are ready to support your most

routine analysis and your most complex characterization

challenges.

A heritage of innovation that results in technologies with meaningful impactThe year 2014 marks a landmark year for Waters’ com-

mitment to biopharmaceutical laboratories, with 10

years dedicated to developing technologies for large

molecule analysis. Waters now offers a comprehensive

portfolio of solutions to support protein biotherapeutics

development:

• Reliableandreproduciblebioseparationsby

HPLC and UPLC

• Robustcomparabilityandanalyticscapabilities

for biosimilars

• ContinuouslyadvancingHDXMStechnology

and software to support higher-order-structure

studies

• Theabilitytosupportcharacterizationofanti-

body drug conjugates through the unique synergy

of UPLC®, QTof MS, and bioinformatics solu-

tions.

Built on a keen understandingof customer needsWaters is able to develop an understanding of the chal-

lenges of biopharmaceutical laboratories by building

and sustaining relationships with leaders in the field,

both in industry and academia. This is our brand prom-

ise—enduring partnership to enable success.

Driven by purposeful innovationsThis year Waters is also celebrating the 10th anniver-

sary of ACQUITY UPLC® Technology. UPLC has

provided breakthroughs in resolution, sensitivity, and

analytical speed–benefits that were quick to find suc-

cessful application in biopharmaceutical analyses.

One of the most important systems we devel-

oped for the biopharmaceutical labs is the quaternary

ACQUITY UPLC H-Class and ACQUITY UPLC

H-Class Bio Systems, which feature our automated

solvent management tool, AutoBlend Plus™, to enable

efficient and automated method development using pH

and ionic strength gradients. Today these are funda-

mental tools used around the world to manage biosepa-

rations analyses encompassing amino acid analysis,

charge variants, aggregation, peptide mapping, glycans,

and on to characteriza-

tionofRNAiimpurities.

Waters continues to

increase the capabilities

of high-resolution MS

while enabling acces-

sibility for routine use.

Our MS technologies

span from the high-

definition of ion mobil-

ity separations with

ourSYNAPT® G2-Si

HDMS® Systems, to

universal fragmentation

data provided by the

MSE data-independent

acquisition method-

ology, to our ever-

advancing Tof and QTof

instruments,nowavailablewiththenewXevo®G2-XS

QTof System.

These capabilities unite in Waters’

BiopharmaceuticalPlatformSolutionwithUNIFI®,

which brings together UPLC/MS characterization

technology with bioinformatics that improves research-

ers’ ability to acquire and process complex LC and MS

data. The system unites workflows so that results can

readily be shared from discovery to development to

GxP quality control laboratories.

Pushing the boundaries of what’s possible—and unleashing science to make it a realityFor companies performing biopharmaceutical charac-

terization, Waters provides the breakthrough separa-

tions and mass spectrometry technologies, column

chemistries, analytical standards and reagents, and soft-

ware—and, most importantly, the in-depth applications

expertise—you need to achieve success with biothera-

peutics.

Waters Corporation

Waters Corporation34 Maple St.

Milford, MA, USA 01757

Phone: 508.478.2000; 800.252.4752

Fax: 508.872.1990

www.waters.com/biopharm

Waters Biopharmaceutical

Platform Solution with

UNIFI, featuring the new

Xevo G2-XS QTof




LA

GU

NA

DE

SIG

N/S

cie

nce P

hoto

Lib

rary

/Gett

y Im

ag

es

The characterization of proteins

involves identification of their

complex chemical and physi-

cal structures and requires the

use of a range of analytical techniques.

Size exclusion chromatography (SEC)

is generally used as a non-denaturing

method that provides information on

the apparent molecular weight, the pres-

ence of aggregates or higher molecular

weight (MW) species, and the forma-

tion of degradation products, such as

protein clips, and impurities. Today, SEC

is predominantly used to measure aggre-

gation, because the determination of

protein molecular weight by calibrat-

ing the retention times against those

of known molecular standards is not

effective unless the proteins under study

have similar conformations and column

interactions as those of the standards.

The combination of SEC with down-

stream light scattering analysis and the

development of columns that can be

used for ultra high-pressure liquid chro-

matography (UHPLC)-based SEC are

overcoming many of the limitations of

SEC and enabling more detailed protein

characterization.

SEC and aggrEgationSEC is most commonly used to char-

acterize proteins by resolving mono-

mers and aggregates and quantifying

them to determine how much of the

sample is aggregated, according to

Mark Pothecary, product manager of

Malvern Instruments’ Viscotek line.

“Understanding the aggregate content

is important because aggregates not

analyzing Proteins Using SEC, MaLS, and UHPLC

Cynthia A. Challener

Light scatter-ing analysis

combined with more rapid

size exclusion chromatogra-phy improves protein char-acterization.

Cynthia A. Challener is a contributing

editor to BioPharm International.

Protein Characterization



only consume monomers and thus

reduce the efficiency of the drug,

they also are believed to cause

immune responses. Thus, even at

low levels, their presence can lead

to antibody production against

the drug, resulting in more rapid

clearance and lower efficacy, and

at higher levels, anaphylaxis,” he

explains.

In addition, Pothecary says that

characterization of oligomers,

which are ordered assemblies of

multiple proteins, is important

because oligomerization controls

protein activity. Measurement of

molecular weight gives an indica-

tion of the oligomeric state.

SEC aLonE gEnEraLLy not rECoMMEndEdBecause SEC is an isocratic method,

peak capacity can be an issue,

according to Stephan M. Koza,

principal applications chemist with

Waters Corporation. “Column

length can be increased to increase

capacity, but a balance is often

found between column housing,

pressure tolerance, and efficient run

times,” he notes. Robert Birdsall, a

senior scientist with Waters, adds

that the limited dynamic range of

SEC often requires the use of col-

umns that span zones of molecu-

lar weight ranges. “While this issue

is not difficult to overcome, gen-

erally a range of SEC columns is

required for screening samples, and

when working on the extremes of

the column (total exclusion for very

big proteins vs. total inclusion for

very small), resolution is affected

much more significantly,” Birdsall

observes.

The range of columns and buf-

fers available for use in SEC, how-

ever, means that there are always

improvements to be made in

method development, according

to Pothecary. “Alternative col-

umns, different buffers, pH, or salt

concentrations and in some cases

even an organic modifier can all

improve performance. Better sep-

aration always results in a better

characterization,” he asserts.

Koza and Birdsall also note that

SEC is rather insensitive to small

changes in apparent MW, and

non-specific interactions with the

stationary phase can be encoun-

tered depending on the column

chemistry, which can cause biased

results. “In the latter case,” says

Koza, “tailing or asymmetry in the

chromatographic peaks may be a

tell-tale sign, and this problem can

often be addressed by increasing

ionic strength.” Regardless, they

both recommend that orthogonal

methods be used to confirm any

parameter of interest.

Band broadening between detec-

tors also contributes to loss of reso-

lution and subsequent sensitivity,

according to Pothecary. While bet-

ter connections between the tub-

ing and shorter distances between

cells can improve this situation,

the best solution in this case is

integration of all the detectors into

a single unit. “Integration reduces

the distances between the detector

cells and minimizes temperature

variations experienced by the sam-

ple, which improves the separation

performance, and thus detection

and characterization,” he states.

In addition to resolution, SEC

analysis times are also an issue.

“At 20 minutes to an hour for a

measurement, it is a relatively slow

technique,” says Pothecary.

WHEn SEC aLonE iS SUitabLEIn certain purification or for-

mulation tasks, it may suffice

to determine only the fraction

of aggregated protein relative to

the unagg regated monomer,

rather than the true molecular

weights. “In this case,” says Daniel

Some, director of marketing and

a principal scientist with Wyatt

Technology Corporation, “if the

monomeric species is resolved

from the aggregates and well-

behaved in the mobile phase, SEC

alone can quantify this fraction.”

WHy doWnStrEaM anaLySiSMost proteins are generally not

globular, well-behaved, stable, and

hydrophilic like available stan-

dards. They also often do not con-

sist of discreet populations, such

as monomers and low oligomers or

fragments. “Real proteins may be

partially or completely disordered,

contain significant hydrophobic

residues that interact with column

packing material in a non-ideal

way, or perhaps be continuously

heterogeneous as a result of exten-

sive glycosylation or PEGylation

with extended conformations

vastly different from those of well-

folded globular proteins,” states

Some. He adds that because SEC

separates macromolecules by size, it

provides an avenue for downstream

characterization by other detectors

that do not depend on elution time.

LigHt SCattEring a frUitfUL aPProaCHDownstream characterization by

means of multi-angle light scatter-

ing (MALS) provides first-princi-

ples determination of molar mass

through the combined measure-

ment of light scattering intensity

and sample concentration, accord-

ing to Some. In addition, the range

of molar mass measured by a good

MALS instrument far exceeds that

of soluble proteins. Therefore,

absolute characterization of the

distribution of molar masses, at

least those that are resolved by

SEC chromatography, is possible.

In addition to measuring the abso-

lute molecular weight with light

scattering analysis, it is possible

to distinguish between monodis-

perse (i.e., single population) and

polydisperse (i.e., poorly separated

mixed populations) peaks, giving

even greater insight into the exact

composition of the sample, accord-

ing to Pothecary.




Some also notes that for proteins

conjugated to a modifier such as

glucose, polyethylene glycol (PEG),

or surfactant micelles for which no

standard SEC reference molecules

exist, the combination of MALS

with two concentration detectors—

usually ultraviolet (UV) and refrac-

tive index (RI)—can be used to

determine the molar mass of each

constituent to assess the oligomeric

state and the overall molar mass.

“Light scattering analysis with a

combined UV and RI detector can

provide information on whether

the modification occurred and to

what extent (i.e., how many PEG

molecules are attached). The com-

positional information can be

deconvolved to indicate the per-

centage of protein and PEG, which

when combined with the absolute

molecular weight measurement,

provides the mass of the complex

and its composition, which in turn

can be used to determine the num-

ber of PEG molecules and the pro-

tein oligomeric state,” he explains.

The characterization of mem-

brane proteins is also done in the

same vein, according to Pothecary.

“Membrane proteins make up some-

thing like 60% of all drug targets,

but they have proven difficult to

purify and crystallize. Today,

however, the same compositional

analysis can be done to a purified

membrane protein to find out how

much detergent it is associated with

it and to see if there is any free deter-

gent in the sample, both of which

affect crystallization,” he says.

“In addition,” states Some, “cer-

tain protein oligomers exist in

dynamic equilibrium with mono-

mers or other subunits (‘reversible

self-association’) as a function of

protein concentration. Since MALS

determines the weight-average

molar mass at each elution volume,

changes in this equilibrium across

the chromatographic peak observed

as the concentration increases and

declines clearly indicate the pres-

ence of this phenomenon and can

even be used to estimate the equi-

librium dissociation constant (Kd).”

If a dynamic light scattering

(DLS) detector module is incorpo-

rated into the MALS detector, the

fluctuation spectrum of light scat-

tered by proteins based on their

Brownian motion can be used to

determine the diffusion coefficients

of the separated components, which

can then be related to their effec-

tive sizes. “Comparison of molar

mass and size is a good indicator of

conformation, such as whether the

protein is well-folded, denatured, or

partially disordered,” Some says.

grEatEr tHroUgHPUt WitH SMaLLEr PartiCLE SizESSeveral evolutionary advances in

SEC have had a positive impact in

recent years. Smaller flow cells and

improved cell design, for example,

have made it possible to connect

more detectors together without

the negative consequences of sig-

nificant peak broadening and

tailing. “As a result, a single run

can generate more and more data,

which makes the entire process

more efficient,” says Pothecary.

UHPLC, on the other hand, offers

a step-change in measurement time,

speed, and resolution, but is still

a new technology with respect to

SEC, according to Pothecary, and

its promises still need to be fully

realized. In particular, he states that

the amplification of peak broaden-

ing between detectors is due to the

extremely narrow peaks that come

from UHPLC. Over the past few

years, however, smaller particle sizes

have led to greater sample-through-

put capabilities for SEC, according

to Koza. “Improvements in high-

performance liquid chromatography

(HPLC)/UHPLC design with respect

to system dispersion and sensitivity

and advances in particle technol-

ogy will further improve chromato-

graphic performance in the future,”

he notes.

Some agrees that UHPLC-based

SEC has begun emerging in the past

few years as the next step in SEC

technology for proteins, offering

faster separation with better resolu-

tion and much reduced consump-

tion of sample and mobile phase.

He notes, though, that until 2014,

MALS detectors did not keep pace

by decreasing the dispersion to

match the narrower eluting peaks.

The µDAWN MALS detector intro-

duced in March 2014 by Wyatt

Technology, along with the Optilab

UT-rEX RI detector introduced in

2013, is designed for UHPLC and

maintains the ultra-low dispersion

required for UHPLC with no loss in

sensitivity, according to Some. “In

combination with UHPLC UV and

IR detectors and an upgraded DLS

module, the µDAWN extends all

of the capabilities of MALS to the

realm of UHPLC,” he remarks.

fUtUrE CoMbinationSSEC also has the potential to be

combined with other downstream

measurements to further enhance

protein characterization. The mea-

surement of intrinsic viscosity (IV),

for example, gives information on

protein density and, therefore, struc-

ture. “Non-globular proteins with

either elongated or open structures

can be readily identified using IV,

which then makes size calculation

possible. Theoretically, combining

measurements of size from DLS and

IV can give even more information

on shape,” says Pothecary. Some

adds that tagging proteins with fluo-

rescent dyes offers the potential for

better resolution of protein-protein

complexes. “A third-party inline flu-

orescence detector may be combined

with Wyatt’s MALS and RI instru-

ments and software to determine

unequivocally the molar masses

of such complexes. This ability to

combine different detectors is one

of the benefits of a modular system

as opposed to a fully integrated sys-

tem,” he says. ◆



Sample 1: NTA-E3. His-tagged protein

puriÀed with NTA resin

Sample 2: R-E3. His-tagged protein

puriÀed with Roche cOmplete His-Tag

PuriÀcation Resin

Technical Service 800 262 4911

Customer Service 800 262 1640

For life science research only.

Not for use in diagnostic procedures.

COMPLETE is a trademark of Roche.

All other product names and trademarks are the property of their respective owners.

© 2014 Roche 581-60300-0614

Sample ID

Cd ppm

Co ppm

Cr ppm

Mo ppm

Ni ppm

Pb ppm

Zn ppm

Li ppm

As ppm

Se ppm

Ba ppm

1. NTA-E3 <0.05 <0.04 <0.01 <0.05 32.65 <0.3 0.38 <0.007 <0.4 <0.4 <0.003

2. R-E3 <0.05 <0.04 <0.01 <0.05 <0.04 <0.3 0.060 <0.007 <0.4 <0.4 <0.003

Elemental analysis indicates that eluate color (photo above) corre-

lates with presence of nickel. Identical histidine-tagged proteins were

purified using cOmplete His-Tag Purification Resin (R-E3) or an NTA resin

(NTA-E3) followed by elemental analysis of the eluates. Results show 800x

less nickel in protein purified using cOmplete His-Tag Purification Resin

(clear eluate) compared to that purified using NTA resin (colored eluate).

Photos and eluate analysis provided by Dr. Fritz Schomburg of Lytic Solutions, LLC.

Think your histidine-tagged protein is pure?

Clearly not.

3URWHFW�\RXU�SURWHLQ�IURP�WR[LF�QLFNHO�ZLWK�F2PSOHWH�+LV�7DJ�3XULÀFDWLRQ�5HVLQ�

Reduce nickel contamination as much as 800x and protect your protein from oxidation and aggregation

by purifying your protein with cOmplete His-Tag PuriÀcation Resin from Roche.

Roche Diagnostics Corporation

9115 Hague Road

Indianapolis, Indiana 46256

Test it in your lab Visit go.roche.com/cOmplete to request a

free 1 ml resin sample or for an instant 10% off your

next purchase of cOmplete His-Tag Purification Resin.



Sto

cktr

ek

Imag

es/

Gett

y Im

ag

es

A critical quality attribute (CQA)

has been defined as “a physi-

cal, chemical, biological, or

microbiological property or

characteristic that should be within an

appropriate limit, range, or distribution

to ensure the desired product quality”

(1). Biotech therapeutics, particularly

complex products such as monoclonal

antibodies (mAbs), can have numer-

ous quality attributes that can poten-

tially impact safety and/or efficacy of

the product (2). Identifying CQAs for a

biotech therapeutic is the first and argu-

ably the most difficult step in imple-

mentation of quality by design (QbD)

for development and production of bio-

pharmaceuticals (3, 4).

Even if a firm chooses not to pursue

intensive studies to map out complete

design spaces for their manufactur-

ing process, and instead opts for what

the Internat ional Conference on

Harmonization (ICH) Guideline Q11

refers to as a “traditional approach,”

the ability to differentiate between

what is and is not important for a mol-

ecule can drive sound decision-mak-

ing in process development, which can

lead to improved efficiency, cost sav-

ings, and more consistent product qual-

ity (5). And for those sponsors who

do embrace a more comprehensive,

“enhanced approach” to development,

a solid understanding of product qual-

ity attributes serves as the touchstone

upon which process design and inte-

grated control strategies are built.

Structural characterization is used

to assess the CQAs of biopharmaceuti-

Defining Critical Quality Attributes for Monoclonal Antibody Therapeutic Products

Anurag S. Rathore, Andrew Weiskopf, and

Andrew J. Reason

An approach for establishing the CQAs of a

mAb product by evaluating

impact and uncertainty during risk

assessment.

Anurag S. Rathore* is a professor at

the Department of Chemical Engineering,

Indian Institute of Technology, Hauz Khas,

New Delhi, 110016, India, asrathore@

biotechcmz.com; Andrew Weiskopf is

director, Technical Development, Biogen

Idec, 14 Cambridge Center, Cambridge,

MA 02142; and Andrew J. Reason is UK

business manager, Life Science Services,

Group Manager SGS M-Scan Europe.

*To whom all correspondance

should be addressed.

Monoclonal Antibodies

Anurag S. Rathore



AL

L F

IGU

RE

S A

RE

CO

UR

TE

SY

OF

TH

E A

UT

HO

RS

cal products. The structural data

must be supported by functional

data to establish a structure-func-

tion relationship. In turn, these

data can then be used to define

the structural components’ impact

on the activity of the product.

Furthermore, the characteriza-

tion data obtained are essential for

product development and regula-

tory acceptance. Characterization

of multiple product batches is

essential to demonstrate to the

regulatory body that the manufac-

turer has control of the manufac-

turing process. This is achieved by

analyzing a number of batches of

product and comparing the data.

Significant differences between

batches need to be investigated

and their impact on the function

of the product assessed. This com-

parison in the QbD paradigm also

centers around the CQAs.

T he E u rop e a n Me d ic i ne s

Agency ’s g u idel ine cover ing

“Production and Quality Control

of Monoc lona l A nt ibod ie s”

requests that “the mAb should

be characterized thoroughly” (6).

“This characterization should

include the determination of

physicochemical and immuno-

chemical properties, biological

activity, purity, impurities, and

quantity of the mAb, in line with

ICH Q6B guideline” (7). The EMA

mAb guideline also draws atten-

tion to a number of structural fea-

tures including N- and C-termini

(in particular pyroglutamic acid at

the N-terminus and lysine at the

C-terminus of the heavy chain),

free sulfhydryl and disulphide

bridge structure, glycosylation (in

particular the degree of mannosyl-

ation, galactosylation, fucosylation,

and sialylation), and other post-

translational modifications (e.g.,

deamidation, oxidation, isomerisa-

tion, fragmentation, and glycation).

In this 30th art icle of the

“Elements of Biopharmaceutical

Production” series, the authors

focus on proposing an approach

towards establishing CQAs for a

mAb therapeutic product.

ProDUCT rISK ASSESSMENTSIdentification of CQAs is often per-

formed through a series of product

risk assessments conducted over

the program lifecycle, the first of

which should be performed early

in development to bring clarity to

the goals of the Phase I process (4).

Although the criticality of some

attributes at this stage may still be

somewhat based on speculation,

these “potential CQAs” (pCQAs)

serve as both a baseline for devel-

opment to proceed and a gap anal-

ysis to identify which attributes

would benefit from further in-

vitro or in-vivo studies to ascertain

their true impact on efficacy and

safety. As the molecule progresses

through development and more

is learned about the relationship

between product attributes and

their impact (or non-impact) on

potency, pharmacokinetics (PK), or


Figure 1: The total ion current (TIC) chromatogram obtained from on-line

reverse phase–high-performance liquid chromatography with electrospray

mass spectrometry (RP–HPLC/ES–MS) analysis of a monoclonal antibody.

100

80

60

40

20

0

80

60

40

20

0

%B24.85mAU

5.0 10.0 15.0 20.0 25.0 30.0 35.0 min

Figure 2: Transformed electrospray mass spectrum prepared from

m/z data acquired during elution of the main component observed during

on-line liquid chromatography–mass spectrometry (LC–MS) analysis of a

monoclonal antibody.

100

0147800 148000 149000

mass148200

Mab +1 x G0F

+1 x G1F

Mab +1 x G1F

+1 x G2F

Mab +2 x G1F

Mab +2 x G0F

148400 148600 148800

%



safety, these pCQAs can be further

refined and accordingly designated

as CQAs as the product approaches

the licensure application.

Because assigning criticality

to an attribute hinges upon the

question of risk posed to prod-

uct safety and efficacy, a well-

rounded product risk-assessment

team should include representa-

tives with expertise in PK, toxicol-

ogy, in-vivo biology, and clinical

management. A risk-ranking and

filtering approach developed on

the firm’s experiences and regula-

tory feedback may be used. Many

such tools have been presented

in the literature, and a firm can

pick a tool of their choice as long

as the basis is rational and it has

been justified that the tools are

used consistently (8, 9). The risk-

assessment team first compiles a

list of all the quality attributes

of the product and systemati-

cally evaluates each attribute with

regards to two factors: impact and

uncertainty.

For impact, the team deter-

mines the severity of the conse-

quences that would be associated

with failure to control the attri-

bute. The team considers the

effects of the attribute not only

on potency with respect to the

intended mechanism of action,

but also PK, pharmacodynam-

ics (PD), immunogenicity, off-

target effects, and direct impact

to safety. The data used in the

impact assessment may come from

structure-activity relationship

(SAR) studies, nonclinical stud-

ies, clinical exposure history, and

toxicology reports (4). For plat-

form molecules, or new prod-

ucts with structural homology to

established classes (e.g., Fc fusion

proteins, pegylated proteins), the

team can leverage information

from related proteins. Conversely,

the more novel the protein is, the

less opportunity there may be to

apply knowledge across products.

A f ter assigning an impact

score, the team then evaluates

the quantity and relevance of the

body of data used in its assess-

ment and assigns an uncertainty

score to the attribute. The team

considers its degree of reliance

on in-vitro vs. in-vivo data, the

availability of molecule-specific

data pertaining to potency and

PK, the relevance of data lever-

aged from related molecules, and


Figure 3: Transformed electrospray mass spectrum prepared from

m/z data acquired during elution of the light chain during on-line liquid

chromatography–mass spectrometry (LC–MS) analysis of a reduced


100

023000 23100 23200 23300 23400 23500 23600 23700 23800 23900

mass

%

Light chain

Figure 4: Transformed electrospray mass spectrum prepared from m/z

data acquired during elution of the heavy chain during on-line liquid



100

050000 50200 50400 50600 50800 51000 51200 51400

mass

%

Heavy chain + G0F

Heavy chain + G1F

Heavy chain + G2F




Company DescriptionTosoh Bioscience LLC is a major supplier of

chromatography products worldwide, particularly

to the pharmaceutical, biotechnology, and

chemical industries. The company is a division of

Tosoh Corporation, a global chemical company

with headquarters and manufacturing facilities in

Japan. TSKgel® and TOYOPEARL® products are

used for the analysis, isolation, and purification of

proteins, peptides, synthetic polymers, DNA, oli-

gonucleotides, antibiotics and other small molecular

weight compounds. Continuing with a tradition of

excellence that began with the introduction of one

of the first SEC columns in 1976, we expanded

our product portfolio in 2008 to include a dedicated

system for GPC analysis, the EcoSEC GPC

System.

Facilities:• TosohCorporation(BioscienceDivision)serves

Japan

• TosohBioscienceLLCservesNorthandSouth

America

• TosohBioscienceGmbHservesEurope,Middle

East, and Africa

• TosohBioscienceShanghaiCo.,Ltd.servesChina

• TosohAsiaPTE(Singapore)servesAsia-Pacific

and India

Services• Onsitepackingassistanceforprocessscale

columns

• Custom-sizeprepackedTSKgelcolumns

• Redundantmanufacturinglinesforprocessmedia

products

Major Product Innovations• TOYOPEARLGigaCap®highcapacity/high

resolution low elution volume ion exchange resins

for protein purifications:

o TOYOPEARL GigaCap S-650S

o TOYOPEARL GigaCap Q-650S

o TOYOPEARLGigaCapCM-650S

• TSKgel-5PWtypehighresolutionresins:

o TSKgelSuperQ-5PW(20)foroligonucleotide

purification

o TSKgelSP-5PW(20)forsmallerproteinand

peptide purification

o TSKgelSP-3PW(30)forinsulinpurification

• TOYOPEARLQ-650CARalkalineresistantresin

• TOYOPEARLButyl-600,Phenyl-600,and

PPG-600 resins for mAb purification

• TOYOPEARLHexyl-650CresinforFlow

Through polishing applications

• TOYOPEARLAF-rProteinA-650Falkaline

resistant resin for mAb purifications

Markets ServedThe Tosoh Bioscience Companies serve the global

marketsfor:

• E. Coli and mammalian cell expressed biologics

suchasmonoclonalantibodies,cytokines,growth

factors, insulin, blood factors, plasma, and other

large and small proteins and peptides

• Othermarketsservedincludeoligonucleotides,

DNA, RNA, and pegylated proteins.

• TosohBioscienceoffersacomprehensivelineof

TSKgelpre-packedHPLCcolumnsforeachof

themajorchromatographymodes(SEC,IEC,

RPC,NPC,HILIC,HIC,AFC),andToyoScreen

process development columns for laboratory use.

• TheEcoSECGPCSystemisacompletesystem

for the analysis of polymers by GPC. The unit is

ideal for semi-micro columns due to its low dead

volume and as a result saves time, money, and

valuable sample.

Tosoh Bioscience LLC

Tosoh Bioscience LLC

3604 Horizon Drive, Suite 100

King of Prussia, PA 19406

Phone: 484.805.1219


www.tosohbioscience.com




the range of clinical exposure.

Process additives undergo a simi-

lar assessment, which focuses on

the sufficiency of toxicology data

and the additives’ history of use.

In general, the assessment of prod-

uct quality attributes for novel

proteins will have a higher degree

of uncertainty than platform mol-

ecules in early development. For

these products, one should strongly

consider conducting the initial

product risk-assessment exercise

early in the development cycle to

align the organization on a com-

monly-recognized target product

profile. Otherwise, cell culture,

pur if icat ion, and drug prod-

uct development may put undue

importance on meeting certain cri-

teria that are ultimately not critical,

resulting in suboptimal processes

that make unnecessary trade-offs

between attributes.

Once the impact and uncer-

tainty scores have been assigned,

the product of these two values

constitutes the risk priority num-

ber (RPN) for the attribute (9).

Although the scoring system may

define a numerical threshold for

which attributes would receive a

CQA or pCQA designation, the

degree of confidence in assigning

the impact and uncertainty scores

must be kept in mind to avoid

over-interpretation of the analysis.

Instead, the authors have found

that viewing a product’s quality

attributes from a more holistic

view, using the scores to generally

characterize their degree of criti-

cality with labels such as “high,” or

“moderate-to-low,” is preferable (4).

This is also consistent with guid-

ance from regulators, who encour-

age firms to view attributes as

lying along a “continuum of criti-

cality,” in which attributes war-

rant different degrees of control

depending on how critical they

are and how readily they can be

controlled through the process. It

should be highlighted that while

an attribute can be “less critical”,

it does not mean that a control

strategy is silent with regards to

its control; every attribute requires

a control strategy commensurate

with its degree of risk.

It is also important to note that

within the context of a product

risk assessment, it is generally a

good practice to exclude process

Figure 5: Transformed electrospray mass spectrum prepared from m/z

data acquired during elution of the heavy chain during on-line liquid


de-N-glycosylated monoclonal antibody.

Figure 6: Preparation of peptides for liquid chromatography–mass

spectrometry (LC–MS) peptide mapping analysis.

100

048600 49000 49100 49200 49300 49400

mass48700 48800 48900

%

+ 128Da+ Lysine at C-terminus

+ 162Da+ Glycation

Intact Ab

AlkylatedLC’s and HC’s

RCM TrypticPeptides

Reduce/Carboxymethylate

S S

SCM

SCM SCM

CMS

CMS CMS

CMSSCM

SCM

SCM

SCM

CMS

CMS

CMS

CMSSCM

SS S

S

S S

ProteaseDigest (Trypsin)

RP-HPLC separation

MS and MS/MS ID



capability considerations and the

extent to which they can mitigate

the risk. The fact that a highly crit-

ical attribute is easily controlled

through the process, even to the

point of not requiring routine test-

ing, should be captured separately

in process risk assessments and in

the overall control strategy design

and justifications. By evaluating

attribute criticality solely on the

basis of impact and uncertainty,

the product risk assessment only

needs to be revised when new

information is discovered regard-

ing the biology or toxicity of the

attributes themselves, and not

every time a process change is

made (8).

In general, the pCQAs identified

in the initial product risk assess-

ment fall into two categories:

• pCQAs that are known or are

highly likely to directly impact

safety or efficacy will ultimately

become CQAs. Attributes such as

residual host-cell proteins, endo-

toxin, protein aggregates, and

biological potency, which may

initially be assigned as pCQAs

during Phase I development, are

highly critical in such a funda-

mental way that no amount of

additional experimental study

will alter their assignment as

CQAs later in development.

• pCQAswhoseimpactonefficacy

is unknown or uncertain will

likely be the main focus of CQA

determination studies. These

are attributes whose criticality

can vary on a molecule-by-mol-

ecule or class-by-class basis, and

therefore, can benefit most from

further experimental studies to

accurately define their impact

to product performance. These

attributes typically include post-

translational modifications and

stability-indicating chemical

changes to the molecule, such as

glycosylation, charge isoforms,

phosphorylation, oxidation, and

deamidation.


Figure 7: On-line liquid chromatography–mass spectrometry (LC–MS)

analysis of a reduced/alkylated monoclonal antibody following digestion

with trypsin.

Figure 8: Structure-activity relationship study of complementarity determining region

(CDR) methionine oxidation for a monoclonal antibody. (A) Site-specifc oxidation

susceptibility with increasing concentrations of hydrogen peroxide reveals a CDR

methionine residue (red circles) that is most sensitive to modifcation, as determined by

liquid chromatography–mass spectrometry (LC–MS) peptide mapping. (B) CDR binding

activity assay, showing that oxidized preparations were equipotent to control.

100.0%

80.0%

60.0%

40.0%

20.0%

0.0%

100

50

0

0 0.001 0.01 0.1 1 10

(nM)

Control

78% ox

15% ox

0.00% 0.01% 0.02% 0.03% 0.04% 0.05% 0.06%

Perc

ent

Oxid

ati

on




MASS SPECTroMETry for MoLECULAr wEIGHT MEASUrEMENT AND PEPTIDE MAPPINGIntact molecular weight measure-

ment and peptide mapping are

routinely used to assess and com-

pare the protein backbone of the

light and heavy chains of mAbs

(10, 11) and can be valuable tools

in determining product CQAs.

Intact molecular weight analysis

using high end quadrupole-time-

of-flight (Q-TOF) mass spectrom-

eters is able to produce mass

accuracy within a few Daltons for

intact mAbs. This information,

coupled with analyses following

reduction and de-N-glycosylation,

allows an initial assessment of the

intactness of the product and a

number of the post translational

modifications present on the mol-

ecule. Figure 1 shows the total

ion current (TIC) chromatogram

obtained from on-line reverse-

phase, high-performance liquid

chromatrography with electrospray

mass spectrometry (RP-HPLC/ES–

MS) analysis of a mAb.

A t ransformed electrospray

mass spectrum created from m/z

data acquired during elution of

the peak observed at 24.85 min-

utes is shown in Figure 2. These

data combined with the data

obtained from analysis of the

mAb following reduction, and

the heavy chain component fol-

lowing de-N-glycosylation (trans-

formed mass spectra shown in

Figures 3–5), a l low the intact-

ness of the mAb to be assessed.

The data also provide an over-

view of the N-linked glycosyl-

ation, allow an assessment of the

level of C-terminal Lysine (at the

C-terminus of the heavy chain)

and also suggest, for this particu-

lar product, that a portion of the

heavy chain exists in glycated

form. These analyses provide a

significant amount of informa-

tion from rapid and relatively

st ra ight forward exper iments.

The data obtained from analysis

of the CQAs of further batches

or reference materials in paral-

lel can be used to provide an

assessment of comparability in

terms of batch to batch or indeed

biosimilar to reference medicinal

product.

Peptide mapping is normally

used to confirm these assign-

ments and also al low further

assessment of the protein back-

bone, particularly for post trans-

lational modifications. Figure 6

shows the basic process compris-

ing reduction/alkylation, diges-

tion, and enzymatic release of

peptides (and glycopeptide) from

a mAb for analysis.

The products of digestion are

usually analysed by on-line LC–

MS. The TIC data obtained from

peptide mapping of two batches

of mAb are shown in Figure 7

and allow a visual comparability

assessment to be made.

Low energy (for peptide molec-

ular weight) and high energy

(for sequence assessment) mass

spectrometric detection of the

peptides during elution allow a

further two dimensions of analy-

sis. The data produced also allow

Figure 9: Studying the effects of Fc glycan galactosylation on binding activity of a monoclonal antibody. Potency testing

across a wide range of agalactosyl glycan content fnds no correlation between levels of G0F glycan and complementarity

determining region (CDR) binding activity (A), but a modest decrease in FcγRIIIa binding activity was observed with increased

agalactosyl levels (B).

120

100

80

60

40

20

0

180%

160%

140%

120%

100%

80%

60%

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

A)

% C

DR

Bin

din

g A

ctiv

ity

% F

cγR

Illa

Bin

din

g A

ctiv

ity

% G0F % G0F



Company DescriptionBio-Rad Laboratories is a leading provider of innovative

tools to the life science and clinical diagnostics markets,

where the company’s products are used for scientific

discovery, drug development, and biopharmaceutical

production. Bio-Rad’s Life Science Group has long

served the bioprocessing industry by supplying advanced

purification and process technologies. Bio-Rad provides

a full line of scalable—from pilot to production—process

chromatography resins and hardware solutions.

Markets ServedThe Bio-Rad Laboratories Life Sciences Group is

ISO 9001:2009 registered and focuses on meeting the

needs of global biopharmaceutical companies and contract

manufacturing organizations.

Products and ServicesBio-Rad products are used in the purification processes of

many FDA and EMEA approved biological therapeutics.

Bio-Rad products are designed to deliver the scalability,

lot-to-lot reproducibility and security of supply needed in

today’s demanding commercial downstream processes.

• Nuvia™ a family of chromatography resin–next

generation ion exchange and mixed-mode products

built on a proven rigid polymeric base matrix. The resin

offers superior flow properties and low nonspecific

binding while delivering high capacity and unique

selectivity.

• UNOsphere™ S & Q resins. Based on a single-step

polymerizationprocess,UNOsphereresinsdelivers

high binding capacities at high flow rates and low

backpressures.

• CHT™ ceramic hydroxyapatite. A chemically pure form

of hydroxyapatite sintered at high temperatures to yield

amechanicallyrobustsupport.CHTretainstheunique

separation properties of crystalline hydroxyapatite, but

can be used reproducibly for many cycles at high flow

rates and in process-scale columns.

• CFT™ceramicfluoroapatite.CFThassimilar

propertiestoCHTandallowsforpurificationsatvalues

aslowaspH5.6.

• UNOsphere™SUPrA,anaffinitychromatographyresin

(rProteinA)builtonarigidpolyacrylamidematrix,

designed for fast-flow and high recovery of monoclonal

antibodies.

• Macro-Prep®resins.Polymericmethacrylatesupports

available with strong and weak ion exchange and

hydrophobic interaction functionalities. These rigid

macroporous

hydrophilic

supports provide

excellent capacity,

resolution, and

throughput.

•Chelex® resins.

Chelatingresins

that bind

polyvalent

cations with

high selectivity,

remove metal

ions from samples

and buffers.

•AG® resins.

Extensively

processed to

remove both

organic and inorganic impurities, AG resins are used for

the separation of low molecular weight molecules such

as inorganic ions, organic acids, and carbohydrates.

• InPlace™andEasyPack™ process chromatography

columns. Both column styles have variable height

adapters for axial compression and/or flow packing,

sanitary design and inflatable seals, and are

customizable up to 2 m in diameter. Bio-Rad columns

are driven by Bio-Rad process skids, available in a range

of sizes from pilot to production-scale.

• ProcessChromatographyHardwareeBookisaresource

of product and technical information available at

bio-rad.com/processhardwarebook.

Technical Services:

The Bio-Rad Laboratories Life Sciences Group’s

technical support offerings include technical telephone

and on-line support, regulatory support files, and

process-scale applications development services.

Bio-Rad Laboratories

Bio-Rad Laboratories

2000 Alfred Nobel Drive

Hercules, CA 94547

Phone: 510-741-1000

Toll free: 1-800-424-6723

www.bio-rad.com/process




a comparability assessment of the

N- and C-termini of each chain

(in particular presence and rela-

tive levels of pyroglutamic acid

at the N-terminus and lysine

at the C-terminus of the heavy

chain), free sulfhydryl and disul-

phide bridge structure (from a

comparison of reduced and non-

reduced digests), glycosylation (in

particular the degree of manno-

sylation, galactosylation, fucosyl-

ation, and sialylation), and other

post-translational modifications

(e.g., deamidation, oxidation,

isomerizat ion, f ragmentation,

and glycation).

GAINING ProDUCT KNowLEDGE THroUGH SAr AND PK STUDIESFor platform-driven molecules,

such as mAbs, a pre-established

set of pCQAs can often be applied

across programs, but care must

be taken to ensure that they are

relevant to each new molecule

under development. For exam-

ple, as part of early-stage prod-

uct characterization, a new mAb

was tested to determine whether

its susceptibility to methionine

oxidation was typical to that of

other platform mAbs. Figure 8A

illustrates the levels of site-spe-

cific methionine oxidation mea-

sured by LC–MS peptide map in

the presence of increasing con-

centrations of an oxidizing agent.

This study found that although

the two conserved methionine

residues in the Fc domain were

prone to oxidation, the most sus-

ceptible methionine residue was

located within the complemen-

tarity determining region (CDR).

This finding prompted additional

follow-up to determine the crit-

icality of oxidation at the CDR

site. Oxidized preparations of the

mAb were prepared, characterized

to ensure suitability of use (i.e., lack

of extensive aggregation or fragmen-

tation), and were then submitted for

potency testing by binding assay.

As shown in Figure 8B, preparations

of the mAb containing up to 78%

oxidized methionine at the CDR

site were found to be equipotent to

unstressed control material, pro-

viding assurance that this product

quality attribute was not a critical

determinant of product activity.

When SAR studies are con-

ducted with legacy programs, the

longer history of product devel-

opment can be turned to one’s

advantage, especially if multiple

cycles of process development

can provide a valuable source of

materials for study. For example,

terminal ga lactosylat ion was

identified as a pCQA for a mAb,

largely due to a high degree of

uncertainty regarding its impact

on ef f icacy. Because the lev-

els of biantennary had changed


Figure 10: Affinity extraction and liquid chromatography–mass

spectrometry (LC–MS) peptide map glycoprofiling to monitor site-specific

dependent clearance of an Fc fusion protein. Over 22 days, the glycan

population at the Fc site held steady (A), while a site on the receptor

domain “site A” exhibited slight preferential clearance of the asialylated

biantennary glycan, G2F (B).

60

50

40

30

20

10

0

0 5 10 15 20 25

G2F

G1F

G0F

G2F

A2G2

A2G3F

A1G2F

A2G2F

A3G3F

% o

f to

tal g

lyca

n po

pula

tion

60

50

40

30

20

10

0

% o

f to

tal g

lyca

n po

pula

tion

Days

0 5 10 15 20 25Days

A)

B)

Fc

Site A




over the course of develop -

ment, archived materials could

be incorporated into SAR studies

to investigate CDR binding and

FcγRIIIa binding activities with

the drug substance lots actually

used in Phase 1 studies. With aga-

lactosyl (G0F) glycan levels from

36–75% adequately covered by

clinical materials, only a hypo-

galactosylated preparation of the

mAb (via galactosidase diges-

tion) was needed to help supple-

ment the study. Figures 9A and 9B

summarize the results of these

studies. It was found that CDR

binding activity was unaffected

by galactosylation of the Fc gly-

can, while FcγRIIIa binding activity

decreased modestly with increased

G0F content, consistent with litera-

ture reports. On the basis of these

data, as well as the extensive clini-

cal history that was established and

the wealth of relevant literature, Fc

glycan galactosylation was deemed

to be a moderately critical quality

attribute for this molecule.

Assessing the impact of an

attribute on PK can be challeng-

ing if the attribute of interest is

inherently microheterogeneous,

such as glycosylation. But in some

cases, powerful analytical tools

such as mass spectrometry, can

be employed to deconvolute the

results of PK studies conducted

with heterogeneous source materi-

als. To study the effects of glycan

structure on the clearance of an Fc

receptor fusion protein, an affinity

extraction method was developed

that could specifically recover the

drug from cynomolgus monkey

serum samples collected at vari-

ous timepoints. Quantitative mass

spectrometry was then used to

determine whether site-specific

glycan profiles changed between

timepoints, which would suggest

preferential clearance of certain

glycoforms. Figures 10A and 10B

illustrate the results from this

study, which found that the criti-

cality of glycan structure was

highly site-dependent. The com-

position of glycans at the Fc site

(see Figure 10A) was essentially

unchanged over 22 days, with

percentages of G0F, G1F, and G2F

(biantennary glycans with 0, 1, or

2 galactoses) holding steady for the

duration of the study. By contrast,

Figure 10B shows that the rela-

tive population of sialylated bian-

tennary glycans on the receptor

domain, such as A2G2F, increased

slightly at the expense of the

asialylated glycan G2F over time.

This example underscores the

importance of considering critical-

ity for some attributes on a site-by-

site basis; a given glycan (G2F) can

be non-critical at the Fc, but mod-

erately critical on the receptor.

SUMMAryProduct r i sk assessment can

be a valuable tool to not only

help direct the course of process

development and control strat-

egy design, but also to identify

oppor tunit ies to ga in bet ter

understanding of what is truly

important about the molecule

itsel f. Designed exper iments,

using wel l- character ized test

articles and advanced analyti-

cal methods, can help resolve

uncertainties surrounding attri-

bute cr it ical ity. Ult imately, a

clear picture of attribute criti-

cality, followed by mapping of

their linkages to process param-

eters, can enable well-justified,

science-based control strategies

that put the right controls at the

points where they can be most

ef fect ive in ensuring product

efficacy and patient safety.

ACKNowLEDGMENTSThe authors would like to thank

Li Zang, R ichard Strong, and

Xiaoping Hronowski for their

contributions to the SAR and PK

studies cited in this publication.

rEfErENCES 1. ICH, ICH Harmonized Tripartite

Guideline Q8: Pharmaceutical

Development, Step 4 version (August

2009).

2. A. S. Rathore, Trends Biotechnol. 27

(12) 698-705 (2009).

3. A. S. Rathore and H. Winkle, Nature

Biotechnol. 27 (1) 26-34 (2009).

4. A. S. Rathore, Trends Biotechnol. 27

(9) 546-553 (2009).

5. ICH, ICH Harmonized Tripartite

Guideline Q11: Development and

Manufacture of Drug Substances

(Chemical Entities and

Biotechnological/Biological Entities),

Step 3 version (September 2011).

6. EMA, Guideline on Development,

Production, Characterization and

Specifications for Monoclonal

Antibodies and Related Products,

EMEA/CHMP/BWP/157653/2007

(December 2008).

7. ICH, ICH Topic Q6B Specifications:

Test Procedures and Acceptance

Criteria for Biotechnological/Biological

Products, Step 5 version (September

1999).

8. R.J. Seely and J. Haury, “Applications

of Failure Modes and Effects Analysis

to Biotechnology Manufacturing

Processes” in Process Validation in

Manufacturing of Biopharmaceuticals,

A.S. Rathore and G. Sofer, Eds.)

Taylor & Francis (2005) pp 13-30.

9. CMC Biotech Working Group, A-Mab:

A Case Study in Bioprocess

Development. October 2009, www.

casss.org/associations/9165/files/

A-Mab_Case_Study_Version_2-1.pdf,

accessed June 5, 2014.

10. S. Kozlowski, “Implementation

Activities for QbD: FDA Office of

Biotechnology Products,”

presentation at 2010 WCBP CMC

Strategy Forum (Bethesda, MD,

2010).

11. L. Zang, X. L. Hronowski, Y.

Lyubarskaya, A. Buko, H. Madden, W.

Meier, R. Mhatre, “LC–ESI/MS and

MALDI-MS for Monitoring of

Glycoform-Related Clearance of a

Complex Glycoprotein in Cynomolgus

Monkeys,” presentation at the 58th

ASMS Conference on Mass

Spectrometry (Salt Lake City, UT,

2010). ◆


MAb Manufacturing:Where are we headed,

cost or capabilities?

www.biopharminternational.com/MAb

For questions, contact Sara Barschdorf at [email protected]

Sponsored by

Presented by

ON-DEMAND WEBCAST

EVENT OVErVIEW:

Investing money to reduce costs is a good business practice.

Investing money to increase value and expand capabilities is bet-

ter. In monoclonal antibody (MAb) production, investments in

improved capabilities through smartly integrated process designs

can turn each dollar spent on capability improvements into 5 or 20

revenue dollars...or more.

View this one hour webcast and learn how you can improve your

capabilities:

n Upstream: high MAb titers, while reducing time for cell culture

operations

n Downstream: capacity of capture and polishing

chromatography steps

n Integration: combine technologies into a highly fexible facility,

with small footprint and minimized fxed cost

register today for this FrEE WEBCAST.

Presenter:

Günter Jagschies

Strategic Customer Relations

GE Healthcare Life Sciences



SpotlightSpotlight

Biochemistry Analyzers Improve Accuracy

Xylem’s YSI brand 2900 Series biochemistry analyzers accurately and rapidly monitor and control fermentations and cell cultures. YSI biochemistry analyzers offer both offline and online analysis of samples for companies that manufacture vaccines, small molecules, alcoholic beverages, chemicals, and biofuels.The YSI 2900 Series includes the 2900, the 2950, and the 2900M biochemistry analyzers.

YSI biochemistry analyzers are able to measure, monitor, and control processes accurately and quickly (under 1 minute) due to their biosensor technology. According to the company, this leads to higher production and increased profit with less labor time.

Xylemwww.YSILifeSciences.com

Quantitative Mycoplasma DNA Offers Quality Control

ATCC has expanded its solutions for mycoplasma quality control to include quantitative mycoplasma genomic DNA prepared as Certified Reference Materials. These preparations support its range of quality control products, which include the Universal Mycoplasma Detection Kit and a collection of 10 titered mycoplasma reference strains. ATCC Certified Reference Materials are calibrated to one or more specified properties, making them useful in challenge assays, verifying or comparing test methods, and benchmarking assay performance during assay validation or implementation. Quantitative mycoplasma DNA Certified Reference Materials were isolated from strains most frequently associated with cell culture contamination, and were quantified for genome copy number using digital PCR-based technology.

ATCC www.atcc.org

Microbioreactors Increase Productivity

Applikon Biotechnology’s micro-Matrix technology platform for the handling and growth of large numbers of microbial strains, clone libraries, mutant banks, and cells is easy-to-use and cost-effective. The system offers 24 independent bioreactors in a microtiter plate footprint. pH and dissolved oxygen can be controlled in each individual bioreactor via gas and liquid addition. Temperature is controlled individually in each bioreactor by the integrated cooling and heating system. The micro-Matrix offers a scale down of small-scale bioreactors. The bioreactor’s square well cassette design is based upon SBS-format microtiter plates, which integrate into lab automation robots. According to the company, the PC-based interface offers an intuitive interaction for advanced process control in each of the 24 bioreactors.

Applikon Biotechnologywww.micro-matrix.com

Company Page Company Page

BIO RAD LABORATORIES Cover Tip, 41

CATALENT PHARMA SOLUTIONS 52

EMD MILLIPORE 11

EUROFINS LANCASTER LABORATORIES 46, 47

GE HEALTHCARE LIFE SCIENCES 44, 51

PARENTERAL DRUG ASSOCIATION 21

ROCHE DIAGNOSTICS GMBH 33

THERMO FISHER SCIENTIFIC 7, 25

TOSOH BIOSCIENCE 2, 37

VETTER PHARMA-FERTIGUNG GMBH 14, 15

WATERS CORP 5, 29

WTG-10TH ANNUAL BIOLOGICAL PRO 49

Ad Index

Cell Culture


Product & Service Innovations Advertorial


Company DescriptionEurofins Lancaster Laboratories is a global leader in

bio/pharmaceutical laboratory services providing inno-

vative and timely scientific solutions to streamline the

drug development process.

With five service models to offer, our clients can

choose the most efficient and cost-effective service

solution for their project. We also provide 24-hour

data access via our innovative and secure online tool at

LabAccess.comSM.

Services/InnovationsBiochemistry

• Spectrophotometry(CD,Bradford,A280,BCA)

• Electrophoresis(CE,SDS-PAGE,2Dgels,west-

ernblots,IEF)

• Chromatography(AAA,peptidemapping,glycan

profiling,SEC,CEX,RP-HPLCandUPLC)

• Massspectrometry(Iontrap,LC/MS/MS,

ESI-TOF,MALDI-TOF,Q-TOF,TOF-TOF,

Orbitrap)

Molecular & Cell Biology

• Cell-basedpotencyassays(cellproliferation,

cAMP,reportergene,cellsurfacereceptorbind-

ing, apoptosis, alkaline phosphotase induction,

lentiviraltransduction)

• ELISA(HCP,ProteinA,sandwichELISA,com-

petitiveELISA)

• qPCR(rDNA,Viruses)

• Geneticstability

Virology

• Viralclearancestudies(infectivityassays,qPCR

assays)

• Viralsafetytesting(in-vitro,retrovirus,reverse

transcriptaseassays)

Microbiology

• Sterilityandmycoplasmatesting

• Endotoxin

• Process/facilityvalidation

cGMP Cell Bank Manufacturing and Cell Line

Characterization

• cGMPmanufacturingofmasterandworkingcell

banks

• Fullcell-linecharacterizationservicesfortesting

master,workingandend-of-productioncellbanks

FacilitiesA part of Eurofins biopharma product testing group—

thelargestnetworkofharmonizedbio/pharmaceutical

GMPproducttestinglaboratoriesworldwide—Eurofins

Lancaster Laboratories has a global capacity of more

than500,000squarefeetwithinourlocationsintheUS

andEurope.AllofourfacilitiesoffercGMP-compliant

laboratory services and operate under the same strict

qualitycontrolprogram.UtilizingthesameLIMS

systemandcentralizedbilling,workingwithanyofour

global facilities is a seamless operation.

Major Services • Methoddevelopment,optimization,cGMPquali-

fication and validation

• Drugsubstanceandproductcharacterization

• Fullstabilityandreleaseprogramsforclinicaland

marketed products

• Rawmaterialandexcipienttesting(USP/NF,EP,

JP)

• Microbiologyincludingmycoplasma,sterility,

endotoxin,andparticulatematter

• EUreleasetesting

• R&DandcGMPcellbankmanufacturing,testing

and storage

• Viralandmolecularbiologytesting

• Process/facilitiesvalidation–viralclearance,resid-

ualimpuritytesting,extractables&leachables,

watertesting,environmentalmonitoring,disin-

fectant efficacy, on-site sample collection

• Consulting/protocolwriting.

Markets ServedWeprovidefullCMCtestingservicestosupportmore

than800virtualandlargebio/pharmaceuticalcompa-

niesandCMOs.

Eurofins Lancaster Laboratories, Inc.

Eurofins Lancaster Laboratories, Inc.2425 New Holland Pike

Lancaster, PA 17601

Phone: 717.656.2300

www.EurofnsLancasterLabs.com

Number of employees: > 1500

Year founded: 1961


www.EurofinsLancasterLabs.com

Winner of the 2013 CRO Leadership Award for quality,

regulatory, reliability, productivity and innovation.

Leading experts in:

Chemistry

Biochemistry

Microbiology

Molecular &Cell Biology

Virology

Global Services:

Method Development/Optimization

Validation/Qualification/Transfer

Product Release Testing

Stability Storage & Testing

Raw Materials Testing

Impurities & Residuals Testing

Characterization

Cell Banking

Cell Line Characterization

Viral Clearance

Bioassays

Professional Scientific StaffingSM

Perfect timing.

Every time.

The art of mastering cell bank production requires

expertise, innovation and exquisite attention to detail

where every minute counts. With more than 50 years

of combined experience, our passionate, and often

nocturnal, scientists obsess 24/7 to ensure your cell

banks become masterpieces. To that, we offer you:

• Direct access to your scientist for any question, any time.

• Constant oversight and monitoring of your cell banks.

• Continual troubleshooting and status updates during

expansion.

For the most accomplished service in the industry,

trust our cell bank experts to be on your watch.

Cell banking

done right.



New Technology Showcase

Pa

ge h

ea

de

r im

ag

e: A

rth

ur

S. A

ub

ry/G

ett

y I

ma

ge

s

New Thermo ScieNTific SoLAµ PLATeSIs sample failure and re-analysis affecting

your workflow? Achieve consistent

sample extractions using low sample

volumes. Our award winning fritless

SPE technology removes variability and optimizes your high throughput

laboratory workflow. Thermo Scientific™ SOLAμ™ plates are designed for

bioanalytical and clinical research analysts who consistently require cleaner,

highly reproducible and robust sample extraction at very low sample volumes.

Thermo Scientific, tel. 800.332.331, www.thermoscientific.com/sola-spe

ToYoPeArL Nh2-750f from ToSoh BioScieNceTOYOPEARL NH2-750F, a salt tolerant anion

exchange resin, is capable of aggregate

removal in both flow-through and binding

and elution modes. This new resin is ideal for

process scale applications from the capture

of proteins from biological feedstock without

dilution to the intermediate or final purification of monoclonal antibodies (mAbs)

where aggregates and other impurities are removed. Tosoh Bioscience,

tel. 484.805.1265, www.separations.us.tosohbioscience.com

AggregATe removAL USiNg high reSoLUTioN cATioN exchANge chromATogrAPhY mediA Nuvia™ HR-S media is a new cation

exchanger (CEX) designed for high

resolution of closely related product impurities such as aggregates. It delivers

excellent resolution with a final aggregate content of <0.3% and a high recovery

of >80% from a heterogeneous feed containing monoclonal antibody aggregates

and monomer. Furthermore, aggregate content and recovery in the eluate were

shown to be a function of the target conductivity measured at the

end of collection. Bio-Rad Laboratories, bio-rad.com/info/hrs

LABorATorY ServiceS As a member of Eurofins’ BioPharma

Product Testing Group—the

largest network of harmonized bio/

pharmaceutical GMP product testing

laboratories worldwide—Eurofins

Lancaster Laboratories supports all functional areas of bio/pharmaceutical

manufacturing, including method development, microbiology, process validation,

and quality control throughout all stages of the drug development process.

Eurofins Lancaster Labs, tel. 717.656.2300,

www.EurofinsLancasterLabs.com

iNTegrATed Lc/mS PLATformThe Waters Biopharmaceutical Platform

Solution with UNIFI brings together UPLC/

MS characterization technology with

the UNIFI Scientific Information System

for intact protein mass analysis, peptide

mapping, glycan analysis workflows,

and bioseparations. The platform now supports a mix of Q-Tof MS and

optical detectors within a networked workgroup. For peptide and protein

bioanalysis, configurations are available with tandem quad MS.

Waters, tel. 508.478.2000, www.waters.com/biopharm

BioProceSS ANALYZerRoche Custom Biotech offers a

bioprocess analyzer designed to

monitor fermentation procedures.

The instrument incorporates cobas

photometric technology, which is

intended to offer high precision,

linearity, a broad dynamic range, and sensitivity. The autodilution

feature reduces the need for follow-up measurements.

Roche Custom Biotech, tel. 800.428.5433,

www.custombiotech.roche.com

cATALeNT LAUNcheS New AdvASePT™ TechNoLogYADVASEPT Technology is an advanced aseptic

filling solution for biologics, parenteral,

respiratory, and other products. ADVASEPT

features a glass-free primary packaging

container that reduces and even eliminates

some of the concerns associated with

traditional glass vials. ADVASEPT reduces foreign particulates and decreases

protein surface interaction while reducing breakage and container weight.

Catalent, tel. 877.587.1835, www.catalent.com

SiNgLe-USe BioreAcTorSEMD Millipore’s Mobius CellReady 200-L

bioreactor integrates several features

that are intended to provide ease of use,

reliability, and operational flexibility.

The unit contains a working volume of

40–200 L, which allows it to function as

both a seed and production vessel, and its standard design is optimized for

the cultivation of mammalian cells in suspension.

EMD Millipore, tel. 800.548.7853, www.millipore.com


Now in its 9th year the Global Pharma Manufacturing Summit promises to arm you with

information and strategies that will prepare you for the challenges facing the pharma industry.

Book your place now and enjoy:

• Industry Leading Speakers & Content – hear from our expert speaker faculty representing some of the leading companies in pharma manufacturing

• Cutting-Edge Workshops & Think Tanks – a mix of case studies, interactive discussions and engaging roundtables

• Unparalleled Networking Opportunities – over 8 hours of structured and informal networking

• Three Specialized Streams of Content – select a stream that suits your business challenges, choose between Manufacturing, Quality & Compliance or Outsourcing and Supply Chain

• Picturesque Boston – take in the sites of this beautiful city

Are you prepared for the next decade of pharmaceutical manufacturing?

6Q�ƒPF�QWV�OQTG�RNGCUG�XKUKV�gpmsummit.com

or email [email protected] or call 416 214 1144

Produced by



Final Word

Optimizing Human PerformanceHuman error reporting and investigations should

be deep and lead to effective, lasting solutions.

Human performance is both a major

challenge and a massive opportunity for

the biopharmaceutical industry. Human

error causes batch failures, product recalls, and

other product quality and patient safety issues;

leads to accidents; and can potentially under-

mine regulator and investor confidence in both

the boardroom and the business. Considering

that, on average, a deviation can take 40 person

hours simply to investigate and report, the ben-

efits of reducing human errors are easy to see.

Unfortunately, the typical response to human

errors—root cause analysis followed by cor-

rective actions based on tired and worn-out

themes, such as “Read and understand the

SOP”—rarely succeeds in preventing re-occur-

rences, or in affecting lasting reform. How,

then, can excellence in human performance be

achieved?

Even the use of complex automation and

detailed policies, procedures, and processes

can’t change the fact that biopharmaceutical

organizations are run by humans, and, like it or

not, humans make errors. The nature of biopro-

cessing requires a substantial degree of human

intervention in the execution of day-to-day

operations. Not surprisingly, GMP investiga-

tions regularly uncover incidences of human

errors. For some organizations, the reported

incidence of human error is unacceptably

high. Perhaps more damning is when the trend

remains largely unchanged over the years, sug-

gesting that, for some, it’s just become the norm

and not something that is largely preventable.

This trend has heightened the concerns of

regulatory agencies, which are pushing for a

more formal approach to human error preven-

tion. Industry organizations are increasingly

being tasked to “dig deeper” to discover the

true causes of human errors. Notice the plu-

ral—rarely is there a single root cause and the

pursuit of that alone can often blind an inves-

tigation and lead to suboptimal corrective or

preventative actions.

In a three-part series, the BioPhorum

Operations Group presents leaders and manag-

ers at all levels in bioprocessing a road map to

human performance excellence, the hallmark

of a high reliability organization. Achieving

excellence in human performance is a proven,

eminently achievable system of cultivating and

sustaining exceptional levels of performance.

By learning from experts in the field and adapt-

ing best practices from industries renowned

for human performance prowess, biopharma-

ceutical organizations can position themselves

for excellence in human performance and the

industry as a whole.

In the first article in the series, Optimizing

Human Performance: Part One, the author

explains how companies can prevent human

error by envisioning excellence by changing

the company’s perspective and transitioning

to an organization where the true root causes

of human errors are addressed and prevented.

This transition is achieved by understanding

human performance, realizing that human

error is a result of a systemic problem, and by

using open reporting.

V i s i t B i o P h a r m I nt e r n a t i o n a l . c o m /

HumanError to read the complete series. ◆

Achieving excellence in human

performance is an achiev-

able system of cultivating

and sustaining exceptional

levels of performance.

ONLINE EXCLUSIVE!Visit BioPharmInternational.com/

HumanError to read the full article.

Gerry McAuley is a business consultant and facilitator to the Human Performance Group

at the BioPhorum Operations Group.

Le

on

tura

/iS

tock V

ecto

rs/G

ett

y I

ma

ge

s


GE and GE monogram are trademarks of General Electric Company.HyClone is a trademark of General Electric Company or one of its subsidiaries.© 2014 General Electric Company – All right reserved. First published in May 2014.GE Healthcare Bio-Sciences AB, Björkgatan 30, 751 84 Uppsala, Sweden

05/2014

www.gelifesciences.com/hyclone

HyClone™ cell culture media, sera, and process liquids are now part of GE Healthcare

HyClone cell culture products and services help you improve your processes, cut costs, and increase yields.In your quest to optimize cell culture conditions, we are a partner like no other.

GE works


Every molecule has a challenge.

We have a smart biologics solution.

Call: + 1 888 SOLUTION (765-8846)


Visit: www.catalent.com/biologics

smart biologics. integrated solutions. better treatments.

ʺ 2

014

Cata

len

t P

harm

a S

olu

tio

ns.

All

rig

hts

rese

rved

.

CA

P is

a r

egis

tere

d t

radem

ark

of C

evec

Pharm

ace

utica

ls G

mbH

DEVELOPMENT DELIVERY SUPPLY

biologics

SPEED TO CLINICAccelerated development with one partner. Optimized cell line expression with GPEx‰ technology. Integrated analytical, fill/finish and clinical supply.

S

MORE PRODUCTS TO CLINICState-of-the-art clinical biomanufacturing facility.Innovative solutions for difficult-to-express proteins.Increased flexibility through single-use systems.

M

ADVANCED TECHNOLOGIESSMARTag™ technology for more efficacious ADCs. GPEx‰ and CAP‰ cell lines for biologics and biosimilar development. OptiGel Bio™ and ZydisBio™ technologies, plus glass-free injectable innovation with Advasept™ technology.

A

RIGHT THE FIRST TIMEHigher yields, stability and expression rates.More successful regulatory submissions.Reliable on-time delivery.

R

TRIED & TESTEDProven results with 400+ antibodies, 60+ recombinant proteins and a robust portfolio for biosimilar development. Established regulatory pathway with 25+ clinical trials across 6 continents.

T

As your strategic partner for

biologic development success, we

have the technology platforms and

integrated services to create smart,

tailored solutions that enable you

to get more products and better

treatments to clinic, faster.


volume 27 number 7 biopharmfiles.pharmtech.com/alfresco_images/pharma/2018/09/11/1c07e3fd … ·...

Documents