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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
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ES456314_BP0714_CVTP2_FP.pgs 06.23.2014 17:36 ADV blackyellowmagentacyan
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
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
BioPharmThe Science & Business of Biopharmaceuticals
EDITORIALEditorial Director Rita Peters [email protected]
Managing Editor Susan Haigney [email protected]
Scientific Editor Adeline Siew, PhD [email protected]
Community Editor Melanie Sena [email protected]
Art Director Dan Ward [email protected]
Contributing Editors Jill Wechsler, Jim Miller, Eric Langer, Anurag Rathore, Jerold Martin, Simon Chalk, and Cynthia A. Challener, PhD Correspondents Hellen Berger (Latin & South America, [email protected]), Jane Wan (Asia, [email protected]), Sean Milmo (Europe, [email protected]) ADVERTISING
Publisher Mike Tracey [email protected]
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
BioPharmThe Science & Business of Biopharmaceuticals
INTERNATIONAL
www.biopharminternational.com
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
ES458359_BP0714_004.pgs 06.25.2014 01:44 ADV blackyellowmagentacyan
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
6 BioPharm International www.biopharminternational.com July 2014
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.
ES458365_BP0714_006.pgs 06.25.2014 01:45 ADV blackyellowmagentacyan
© 2014 Thermo Fisher Scientifc Inc. All rights reserved.
All other trademarks are the property of Thermo Fisher Scientifc
and its subsidiaries.
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ES458092_BP0714_007_FP.pgs 06.24.2014 23:21 ADV blackyellowmagentacyan
Glo
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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
8 BioPharm International www.biopharminternational.com July 2014
Global News
ES458332_BP0714_008.pgs 06.25.2014 01:42 ADV blackyellowmagentacyan
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
ES458315_BP0714_009.pgs 06.25.2014 01:40 ADV blackyellowmagentacyan
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
10 BioPharm International www.biopharminternational.com July 2014
Global News
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ES458103_BP0714_A11_FP.pgs 06.24.2014 23:22 ADV blackyellowmagentacyan
12 BioPharm International www.biopharminternational.com July 2014
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,
Read Jill’s blogs at
PharmTech.com/wechsler.
Fda is working with
supply-chain parties to
tackle its multiple assign-
ments under dScSa.
ES458360_BP0714_012.pgs 06.25.2014 01:44 ADV blackyellowmagentacyan
July 2014 www.biopharminternational.com BioPharm International 13
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 ♦
ES458366_BP0714_013.pgs 06.25.2014 01:45 ADV blackyellowmagentacyan
Product & Service Innovations Advertorial
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Once products reach Phase III, we provide seamless
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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
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opment process.
International production facilitiesVetter’s manufacturing facilities include:
• Europe: Three commercial aseptic filling facilities
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14 BioPharm International www.biopharminternational.com July 2014
ES458313_BP0714_014.pgs 06.25.2014 01:40 ADV blackyellowmagentacyan
It takes a unique blend of expertise
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ES458109_BP0714_015_FP.pgs 06.24.2014 23:22 ADV blackyellowmagentacyan
16 BioPharm International www.biopharminternational.com July 2014
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,
www.pharmsource.com
ES458344_BP0714_016.pgs 06.25.2014 01:43 ADV blackyellowmagentacyan
July 2014 www.biopharminternational.com BioPharm International 17
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.
ES458348_BP0714_017.pgs 06.25.2014 01:43 ADV blackyellowmagentacyan
18 BioPharm International www.biopharminternational.com July 2014
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,
ES458346_BP0714_018.pgs 06.25.2014 01:43 ADV blackyellowmagentacyan
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
ES458345_BP0714_019.pgs 06.25.2014 01:43 ADV blackyellowmagentacyan
20 BioPharm International www.biopharminternational.com July 2014
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.
ES458347_BP0714_020.pgs 06.25.2014 01:43 ADV blackyellowmagentacyan
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.
ES458088_BP0714_021_FP.pgs 06.24.2014 23:21 ADV blackyellowmagentacyan
22 BioPharm International www.biopharminternational.com July 2014
-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
ES458324_BP0714_022.pgs 06.25.2014 01:41 ADV blackyellowmagentacyan
July 2014 www.biopharminternational.com BioPharm International 23
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
ES458329_BP0714_023.pgs 06.25.2014 01:42 ADV blackyellowmagentacyan
24 BioPharm International www.biopharminternational.com July 2014
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
ES459468_BP0714_024.pgs 06.25.2014 22:05 ADV blackyellowmagentacyan
Time (min)
0 0.5 1.0 1.5 2.0 2.5 3.0
10
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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
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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
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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.
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prior to injection
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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
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To download the full application note
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ES458091_BP0714_025_FP.pgs 06.24.2014 23:21 ADV blackyellowmagentacyan
26 BioPharm International www.biopharminternational.com July 2014
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
ES458327_BP0714_026.pgs 06.25.2014 01:42 ADV blackyellowmagentacyan
July 2014 www.biopharminternational.com BioPharm International 27
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. ♦
ES459467_BP0714_027.pgs 06.25.2014 22:05 ADV blackyellowmagentacyan
28 BioPharm International www.biopharminternational.com July 2014
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
ES458316_BP0714_028.pgs 06.25.2014 01:41 ADV blackyellowmagentacyan
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-
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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
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• Reliableandreproduciblebioseparationsby
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• Robustcomparabilityandanalyticscapabilities
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Built on a keen understandingof customer needsWaters is able to develop an understanding of the chal-
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and sustaining relationships with leaders in the field,
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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
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One of the most important systems we devel-
oped for the biopharmaceutical labs is the quaternary
ACQUITY UPLC H-Class and ACQUITY UPLC
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charge variants, aggregation, peptide mapping, glycans,
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tionofRNAiimpurities.
Waters continues to
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Our MS technologies
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These capabilities unite in Waters’
BiopharmaceuticalPlatformSolutionwithUNIFI®,
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ers’ ability to acquire and process complex LC and MS
data. The system unites workflows so that results can
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GxP quality control laboratories.
Pushing the boundaries of what’s possible—and unleashing science to make it a realityFor companies performing biopharmaceutical charac-
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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
July 2014 www.biopharminternational.com BioPharm International 29
ES458314_BP0714_029.pgs 06.25.2014 01:40 ADV blackyellowmagentacyan
30 BioPharm International www.biopharminternational.com July 2014
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
ES458378_BP0714_030.pgs 06.25.2014 01:45 ADV blackyellowmagentacyan
July 2014 www.biopharminternational.com BioPharm International 31
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.
Protein Characterization
ES458377_BP0714_031.pgs 06.25.2014 01:45 ADV blackyellowmagentacyan
32 BioPharm International www.biopharminternational.com July 2014
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. ◆
Protein Characterization
ES458376_BP0714_032.pgs 06.25.2014 01:45 ADV blackyellowmagentacyan
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.
ES458107_BP0714_033_FP.pgs 06.24.2014 23:22 ADV blackyellowmagentacyan
34 BioPharm International www.biopharminternational.com July 2014
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
ES458662_BP0714_034.pgs 06.25.2014 03:10 ADV blackyellowmagentacyan
July 2014 www.biopharminternational.com BioPharm International 35
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
Monoclonal Antibodies
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
%
ES458661_BP0714_035.pgs 06.25.2014 03:10 ADV blackyellowmagentacyan
36 BioPharm International www.biopharminternational.com July 2014
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
Monoclonal Antibodies
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
monoclonal antibody.
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
chromatography–mass spectrometry (LC–MS) analysis of a reduced
monoclonal antibody.
100
050000 50200 50400 50600 50800 51000 51200 51400
mass
%
Heavy chain + G0F
Heavy chain + G1F
Heavy chain + G2F
ES458665_BP0714_036.pgs 06.25.2014 03:10 ADV blackyellowmagentacyan
Product & Service InnovationsAdvertorial
July 2014 www.biopharminternational.com BioPharm International 37
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
Email: [email protected]
www.tosohbioscience.com
ES458363_BP0714_037.pgs 06.25.2014 01:44 ADV blackyellowmagentacyan
38 BioPharm International www.biopharminternational.com July 2014
Monoclonal Antibodies
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
chromatography–mass spectrometry (LC–MS) analysis of a reduced
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
ES458663_BP0714_038.pgs 06.25.2014 03:10 ADV blackyellowmagentacyan
July 2014 www.biopharminternational.com BioPharm International 39
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.
Monoclonal Antibodies
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
ES458667_BP0714_039.pgs 06.25.2014 03:10 ADV blackyellowmagentacyan
40 BioPharm International www.biopharminternational.com July 2014
Monoclonal Antibodies
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
ES458668_BP0714_040.pgs 06.25.2014 03:11 ADV blackyellowmagentacyan
Product & Service InnovationsAdvertorial
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
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• Macro-Prep®resins.Polymericmethacrylatesupports
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•Chelex® resins.
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•AG® resins.
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• InPlace™andEasyPack™ process chromatography
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Phone: 510-741-1000
Toll free: 1-800-424-6723
www.bio-rad.com/process
July 2014 www.biopharminternational.com BioPharm International 41
ES458330_BP0714_041.pgs 06.25.2014 01:42 ADV blackyellowmagentacyan
42 BioPharm International www.biopharminternational.com July 2014
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
Monoclonal Antibodies
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
ES458666_BP0714_042.pgs 06.25.2014 03:10 ADV blackyellowmagentacyan
July 2014 www.biopharminternational.com BioPharm International 43
Monoclonal Antibodies
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). ◆
ES458664_BP0714_043.pgs 06.25.2014 03:10 ADV blackyellowmagentacyan
MAb Manufacturing:Where are we headed,
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July 2014 www.biopharminternational.com BioPharm International 45
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.
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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.
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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.
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Product & Service Innovations Advertorial
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Company DescriptionEurofins Lancaster Laboratories is a global leader in
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With five service models to offer, our clients can
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• Cell-basedpotencyassays(cellproliferation,
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cGMP Cell Bank Manufacturing and Cell Line
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FacilitiesA part of Eurofins biopharma product testing group—
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Eurofins Lancaster Laboratories, Inc.
Eurofins Lancaster Laboratories, Inc.2425 New Holland Pike
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Phone: 717.656.2300
www.EurofnsLancasterLabs.com
Number of employees: > 1500
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www.EurofinsLancasterLabs.com
Winner of the 2013 CRO Leadership Award for quality,
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48 BioPharm International www.biopharminternational.com July 2014
New Technology Showcase
Pa
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New Thermo ScieNTific SoLAµ PLATeSIs sample failure and re-analysis affecting
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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
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AggregATe removAL USiNg high reSoLUTioN cATioN exchANge chromATogrAPhY mediA Nuvia™ HR-S media is a new cation
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excellent resolution with a final aggregate content of <0.3% and a high recovery
of >80% from a heterogeneous feed containing monoclonal antibody aggregates
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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
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Eurofins Lancaster Labs, tel. 717.656.2300,
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iNTegrATed Lc/mS PLATformThe Waters Biopharmaceutical Platform
Solution with UNIFI brings together UPLC/
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BioProceSS ANALYZerRoche Custom Biotech offers a
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The instrument incorporates cobas
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cATALeNT LAUNcheS New AdvASePT™ TechNoLogYADVASEPT Technology is an advanced aseptic
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SiNgLe-USe BioreAcTorSEMD Millipore’s Mobius CellReady 200-L
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EMD Millipore, tel. 800.548.7853, www.millipore.com
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Now in its 9th year the Global Pharma Manufacturing Summit promises to arm you with
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50 BioPharm International www.biopharminternational.com July 2014
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
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tock V
ecto
rs/G
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