BioPharm

Volume 32 Number 12

INTERNATIONAL
BioPharm International

December 2019 The Science & Business of Biopharmaceuticals

www.biopharminternational.com
DECEMBER 2019

BUILDING A
BIOPHARMA COMPANY
UPSTREAM PROCESSING
Cell and Gene Therapies I Viral Vectors I Combination Products

STARTING MATERIALS FOR

CELL AND GENE THERAPIES

DOWNSTREAM
PROCESSING
VIRAL CONTROL FOR
VIRAL VECTORS

MANUFACTURING
ANTIBODY PURIFICATION
PROCESS DEVELOPMENT

QUALITY/REGULATIONS
QUALITY ISSUES SLOW
NEW THERAPY ADVANCES
Volume 32
Number 12

BP1219_Cover.indd 1 12/6/19 10:10 AM

 ©2019 America’s Biopharmaceutical Companies. innovation.org
Macrophage defending the body

Cancer started this fight.

It’s about time we finished it.

CAR-T Cell Therapy, originally designed to defeat Leukemia,

is now also on the verge of defeating Multiple Myeloma.
That’s the true beauty of innovation:
one breakthrough can lead to thousands more.
Welcome to the future of medicine. For all of us.

AdLayout.indd 2 12/6/19 2:22 PM

 BioPharm
I N T E R N AT I O N A L

The Science & Business of Biopharmaceuticals

ADVERTISING EDITORIAL
Publisher Mike Tracey MTracey@mmhgroup.com Editorial Director Rita Peters RPeters@mmhgroup.com
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EDITORIAL ADVISORY BOARD
BioPharm International’s Editorial Advisory Board comprises distinguished
AUDIENCE DEVELOPMENT specialists involved in the biologic manufacture of therapeutic drugs,
diagnostics, and vaccines. Members serve as a sounding board for the
Audience Development Christine Shappell cshappell@mmhgroup.com
editors and advise them on biotechnology trends, identify potential
authors, and review manuscripts submitted for publication.

K. A. Ajit-Simh Hanns-Christian Mahler

MJH LIFE SCIENCESTM President, Shiba Associates
Chairman and Founder Mike Hennessy, Sr Madhavan Buddha
Vice Chairman Jack Lepping Freelance Consultant
President and CEO Mike Hennessy, Jr Rory Budihandojo
Chief Strategy Officer & President, Agency Services George Glatcz Director, Quality and EHS Audit
Boehringer-Ingelheim
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Lonza AG
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Table of Contents

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.

COVER STORY
12 Building a Biopharma Company
The innovative spirit of biotech startups is a driving force behind the development
of new therapeutic products, but building a successful biopharmaceutical
company from the ground up has its risks and challenges.
Cover Design by Maria Reyes
Images: daphnusia/Stock.Adobe.com

FEATURES COLUMNS AND DEPARTMENTS

FROM THE EDITOR

Nearly four decades after the
QUALITY/REGULATIONS MANUFACTURING first diagnosis, the fight to
Quality Issues Offset Antibody Purification Process treat HIV/AIDs continues.
Biomedical Advances Development and Manufacturing Rita Peters������������������������������������������������5
Jill Wechsler Yanhuai (Richard) Ding,
Problems in assuring reliable drug quality Margaret Marino, and Hemant Kumar AD INDEX�����������������������������������������������37
and supply dampens progress in bringing Downstream process development and
lifesaving therapies to market. . ��������������� 8 manufacturing play a crucial role to ASK THE EXPERT
ensure safety, quality, identity, purity, Investigating deviations or failures
and efficacy.����������������������������������������� 24 of combination products needs
to accommodate both the drug
and device components.
Susan J. Schniepp ���������������������������������38
DOWNSTREAM PROCESSING
Prevent, Detect, and Remove:
Viral Control for Viral Vectors UPSTREAM PROCESSING
Cynthia A. Challener The Evolving Role of Starting
Ensuring that viral vectors are free of Materials in Cell and Gene Therapy
viral contaminants requires a focus on Brad Taylor and Dominic Clarke
prevention and control. ����������������������� 16 Accelerated approval pathways and
growing demand for cell and gene
therapies are putting pressure on providers
of cellular starting materials, and they must
ensure a steady supply. ������������������������� 30

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

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4 BioPharm International  December 2019  www.biopharminternational.com

From the Editor
Rita Peters is the
editorial director of
BioPharm International.
Nearly four
decades after the
first diagnosis,
the fight to treat
HIV/AIDs continues.
www.biopharminternational.com
Fighting the Good Fight
H
ealth organizations, medical professionals, caregivers, and patients mark
World AIDs Day—Dec. 1, 2019—to increase awareness of this decades-
long public health concern. While current statistics demonstrate that
progress has been made in the diagnosis, prevention, and treatment of human
immunodeficiency virus (HIV)-related illnesses, the toll the virus has taken on
the world population—an estimated 32 million deaths—is still profound.
The World Health Organization (WHO) estimates that, at the end of 2018, 37.8
million people globally were living with HIV. Of those infected, 79% had been
diagnosed, 62% received treatment, and 53% had achieved suppression of the HIV
virus (1). The research and development efforts of the bio/pharmaceutical scien-
tists were instrumental in this progress to combat the virus.
The first AIDS cases were diagnosed in the United States in 1981. In 1987, FDA
approved the first therapy against the disease, azidothymidine, a nucleoside
reverse transcriptase inhibitor originally developed to treat cancer. Drug-resistant
variations of the virus necessitated the development of other antiretroviral drug
classes including fixed-dose combination drugs. In 2018, the first biologic treat-
ment, ibalizumab, was approved (2).
Research continues today on antiretrovirals to treat HIV, prophylaxis drugs for
HIV-negative people at risk for HIV, and vaccines to prevent HIV or provide a cure
for those living with HIV. FDA lists 34 investigational drugs for HIV/AIDS and
related infections (3).
While diagnostic tools and therapies have helped make HIV a chronic condi-
tion—not a death sentence—for many infected patients, there are gaps in treat-
ments. In a statement to mark World AIDs day, the National Institutes of Health
(NIH) reported that approximately 38,000 people in the US were diagnosed with
HIV in 2018; and while the rate of HIV incidence has declined significantly from a
peak in the 1990s, progress on further reducing that rate has stalled (4).
Ending the HIV Epidemic: A Plan for America is a US Department of Health and
Human Services initiative to reduce the incidence of HIV domestically by 75% in
five years, and by 90% by 2030. Under this initiative, NIH plans to fund HIV pre-
vention, diagnosis, treatment, and care efforts and will expand partnerships with
agencies, community organizations, health departments, and other organizations
to determine the best implementation of research advances.
NIH also noted the efforts will ensure that underserved communities benefit
from these strategies and other challenges faced by those vulnerable to HIV—
including housing and food insecurity; lack of healthcare access; and discrimina-
tion—are addressed (4).
On a global scale, WHO reports that in 2018, 62% of adults and 54% of chil-
dren living with HIV in low- and middle-income countries were receiving lifelong
antiretroviral therapy; however, there were 1.7 million new infections in 2018 and
770,000 people died from HIV-related causes (1).
NIH and the Bill & Melinda Gates Foundation recently announced investments
of $100 million over four years to develop affordable, gene-based cures for sickle
cell disease and HIV (5), an example of the ongoing efforts to help those afflicted—
and eradicate additional infections—that deserves year-round attention.
References
1. WHO, HIV/AIDs, www.who.int, accessed Nov. 25, 2019.
2. NIH, Antiretroviral Drug Discovery and Development, www.niaid.nih.gov.
3. NIH, AIDsInfo, aidsinfo.nih.gov, accessed Nov. 25, 2019.
4. NIH, “NIH Statement on World AIDS Day 2019,” Press Release, Nov 25, 2019.
5. NIH, “NIH Launches New Collaboration to Develop Gene-Based Cures for Sickle Cell
Disease and HIV on Global Scale,” Press Release, Oct. 23, 2019. ◆
December 2019  BioPharm International  5
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6   ADVERTORIAL
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 Regulatory Beat
Quality Issues Offset Biomedical Advances
Problems in assuring reliable drug quality and supply
dampens progress in bringing lifesaving therapies to market.
P
harmaceutical companies developed, and
FDA approved, dozens of new drugs and
biotech therapies in 2019, as new dis-
coveries in genomics and drug development
continue to bear fruit. Even if 2019 approval
numbers don’t set new records, the list includes
notable breakthroughs, including Novartis’ con-
troversial gene therapy Zolgensma; Vertex’s
triple combo for cystic fibrosis; and new treat-
ments for cancer, migraine, light-sensitivity,
Parkinson’s disease, pneumonia, rheumatoid
arthritis, tuberculosis, and urinary tract infec-
tions. The steady rise in applications for inves-
tigational therapies has made it difficult for the
Center for Biologics Evaluation and Research
(CBER) to keep pace, while the Center for Drug
Evaluation and Research (CDER) continued to
reorganize its Office of New Drugs (OND) to
better assess and process a growing volume of
submissions requiring special attention.
At the same time, high price tags on trans-
formative therapies heightened challenges for
prescription drug reimbursement and payment
strategies. Health plans, payers, and policy mak-
ers continue to debate multiple proposals for
reforming drug coverage and pricing, ranging
from wider importing of less costly products
from abroad, federal government
price negotiations, and specific limits
on annual price increases and patient
out-of-pocket costs. There’s much talk
of “value-based pricing,” but legal
and technical difficulties limit this
approach. The resulting uncertain-
ties make it difficult for manufactur-
ers to plan research programs, devise
pricing and marketing strategies, and
commit to upgrades in production
operations.
Jill Wechsler
MANUFACTURING GAINS ATTENTION
is BioPharm International’s
Washington editor, A main cause of delay in bringing
jillwechsler7@gmail.com. cutting-edge therapies to market in
BioPharm International  www.biopharminternational.com  December 2019
8  
recent months has been difficulties in ensuring
that production systems can ensure product
safety and quality. The transition from pilot-
scale to commercial manufacturing of gene and
cellular therapies can be challenging and costly,
observed CBER Director Peter Marks at the PDA/
FDA Joint Regulatory Conference in September
2019. He emphasized the need for high-quality
manufacturing of these new products, noting
that treatments made from living cells or tissues
often are not easily characterized, are suscep-
tible to microbial contamination, and involve
complex manufacturing materials and processes.
CBER published several guidances on testing
and producing new cellular and gene thera-
pies and has promoted additional assistance for
manufacturers of advanced technologies, Marks
added. But limited gene therapy manufacturing
capacity will continue to be a major problem
as multiple new products gain market approval,
particularly those for treating chronic condi-
tions in larger patient populations.
Such hurdles have prompted leading man-
ufacturers such as Pfizer and Sanofi to make
major investments in new biotech manufac-
turing sites. In addition, firms of all sizes look
to work with contract manufacturing organi-
zations with capacity for quality biotech pro-
duction. To address these needs, as well as the
difficulties of smaller developers of treatments
for rare conditions, Marks backs the creation of
a public-private consortium that can produce
quality materials for preclinical and clinical
studies more reliably and at lower cost.
VisionsofAmerica/Joe Sohm/Getty Images
WIDESPREAD SHORTAGES
While manufacturing issues delayed access to
new breakthrough therapies, such problems
also continued to disrupt production of many
common, low-cost medicines that are impor-
tant for treating many serious health condi-
tions. In response to concerns from Congress
Contin. on page 35
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BioPharm International  December 2019

10   ADVERTORIAL
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 Cover Story: Building a Biopharma Company

Building a Biopharma Company

The innovative spirit of biotech startups is a driving force behind the
development of new therapeutic products, but building a successful
biopharmaceutical company from the ground up has its risks and challenges.
FELIZA MIRASOL

B
iotech/biopharma startup companies are experiencing
generally favorable funding environment for innovative
drug development ideas thanks in part to the regulatory
approval success of new drug products in recent years. In 2018,
63% of new molecular entities (NME) approved by FDA were
initially developed by smaller bio/pharma companies, according
to Switzerland-based venture capital firm HBM Partners (1).
Today, it is these smaller, innovative companies that account for
the majority of the early development of new therapeutics.
Biotech startups are good environments for innovation and
early drug development work for three key reasons. For one,
startups have relatively low capital needs and overhead costs
while they address key technical challenges. Second, founders
typically have the luxury and the drive to constantly assess
risks, which is crucial for any startup, and can make a thor-
ough study of the best markets that their technology can best
than larger pharmaceutical companies. The cost for developing
a new drug and bringing it to market has been estimated at
upwards of $2 billion, according to industry experts (3), and
major pharmaceutical companies do not generally want to take
on the burden of early innovation and failures.
Instead, major pharma companies are looking at startup bio-
tech firms—either by spinning out their own or collaborating
with startups with interesting technology—to take on the work
of early innovative drug development. This way, Big Pharma can
minimize risks at the early stages of development and, if success-
ful, have a pipeline of potential new, innovative drug products.
This approach bodes well for biotech startups because, as part of
an overall strategy to revive R&D and break stagnation, major
pharma companies are actively seeking out startups and are
investing in them (4).
daphnusia/Stock.Adobe.com

serve. Third, founders of startups have incentives in terms of
real-world impact and financial return, so they are often most
motivated to see their technology/innovation succeed and will
push for that (2).
Because smaller companies are more flexible and agile, they
can move faster and push projects forward more aggressively
ATTITUDES HAVE CHANGED
Funding for biotech startups is favorable these days, not just
from large pharma, but investment firms as well. Today, com-
pared to two decades ago when the biotech bubble burst, ven-
ture capital (VC) firms show more willingness to return to the
biotech space (5). A common model used today for starting up

12 BioPharm International December 2019 www.biopharminternational.com

BP1219_012-014_CoverStory_BuildingBiopharma_Mirasol .indd 12 12/6/19 9:18 AM


a biotech company is one where the VC
creates the company by putting together
a hand-picked executive team to develop
an idea. The VC houses the team in its
own offices and invests a substantial
amount of money into the venture, which
allows the VC to take a controlling own-
ership stake from the start.
However, a VC-created startup is not
the only model for getting a new bio-
tech firm up and running. In addition
to the larger investment houses, smaller
firms have now also come into play and
are looking to make small investments
in promising new initiatives. Typically, a
large VC does not waste time making
small investments, which in the past was
a challenge for biotech startups. Often, a
startup had to work hard for major fund-
ing and could not begin work unless an
influx of cash in the millions-of-dollars
range was received from a VC.
Nowadays, the cost of starting up a
new company has dropped significantly,
supported by changes in infrastructure
led by “a combination of open source
software, modern web frameworks, SaaS
[software as a service] developer tools,
cloud hosting, and better distribution
channels” (6). Instead, a biotech startup
can run on a small infusion of cash suf-
ficient to get it to the next funding point,
such as validating the molecule through
modeling processes or demonstrating
efficacy in animal studies. This approach
has opened up opportunity for smaller
investment firms to fund early biotech
companies. For example, for as little as
$100,000—compared to a traditional
startup investment of $10 million—bio-
tech founders can work to prove that
their innovative concept works; whereas
in the past, they couldn’t move forward
unless a large VC provided funding (6).
TAKE IT FROM EXPERIENCE
Establishing a startup in biotechnology
or biopharmaceutical drug development
requires thought and strategy, as much as
an adventurous spirit. Failure can hinge
on many reasons, including a flawed
financial strategy, inexperienced man-
agement, poor or lackluster science, bad
www.biopharminternational.com
BP1219_012-014_CoverStory_BuildingBiopharma_Mirasol .indd 13
Cover Story: Building a Biopharma Company
timing, and/or not taking enough calcu-
lated risks (7).
Industry experts recommend that
entrepreneurs clearly identify the unmet
market need that its technology can
address. Founders must clearly state the
problem that the startup can solve to the
foundation of the company’s value to the
marketplace.
“It is important to solve a problem you
are passionate about, but there must be
a large enough market for this technol-
ogy; in other words, make sure that there
are enough people who care about this
problem enough to pay for your solu-
tion. Going after a small or niche market
is acceptable, too, but your sources of
capital will be fewer, and you will need
to clearly articulate how your company
can even recover its costs. When look-
ing for your market, ‘don’t be a hammer
in search of a nail’; that is, be objective
when identifying a need instead of try-
ing to make your special interest into a
market that might never exist,” wrote
Adriana Tajonar from the California
Institute for Quantitative Biosciences
in a perspective piece published in
Molecular Biology of the Cell (2).
STARTUP INSIGHT
Executives in the startup trenches have
a first-hand look at the challenges of
building a biopharma company. For
example, when building a biotech/bio-
pharma company from the ground up,
key goals that founders should pursue
include getting to cash-flow positive
as quickly as possible to limit dilution;
attracting motivated, entrepreneurial
and experienced team members; cre-
ating shareholder value; and applying
a business model that enables contin-
uous growth, but is simple to execute,
according to Lindsay A. Rosenwald,
MD, chairman, president, and CEO of
Fortress Biotech, Inc.
Fortress Biotech, a rapidly growing
New York-based biopharmaceutical
company specializing in the identifi-
cation, in-licensing, development, and
marketing of FDA-approved phar-
maceuticals and high-potential clin-
December 2019
ical-stage assets, has more than 25
programs in clinical and preclinical
development with product candidates
spanning six therapeutic areas, including
oncology, rare diseases, and gene therapy.
The company has established partner-
ships with academic research institutions
and biopharmaceutical companies.
Evelina Vajeso, CEO of Ilya Pharma,
an Uppsala, Sweden-based clinical-stage
biopharmaceutical company, says build-
ing up data step by step, reducing risks,
and planning out the development strat-
egy for a drug candidate are also import-
ant.
Ilya Pharma targets unmet clinical
needs such as the treatment of post-sur-
gical wounds in special populations,
problematic diabetic wounds, and indica-
tions in the gastrointestinal tract, such as
inflammatory bowel disease. The com-
pany’s lead candidate, ILP100, EudraCT
No. 2019000680-24, is currently in its
first in-human trial, and a Phase II pro-
gram is planned to start in 2020 under
investigational new drug status.
Rosenwald recommends using busi-
ness development as R&D (don’t try to
invent anything); putting parameters
around the types of product candidates
to acquire (e.g., clinical-stage product
candidates that have excellent human
data, unmet medical need, and a clear
path to market); and building relation-
ships with the best research organiza-
tions.
Success also hinges on keeping in line
with certain best practices, such as main-
taining excellent relationships with key
opinion leaders (KOLs) and listening
to advice from quality consultants and
advisors. “KOLs (particularly those well-
versed in the field of medicine that a
startup’s product candidate is meant to
serve) will help you avoid poor choices
when it comes to drug development.
Another best practice is to work with
world-class consultants and advisors to
make sure your development programs
are formulated with the highest chances
for clinical success. And last but not least,
hire experienced and motivated employ-
ees to facilitate efficient and successful
BioPharm International 13
12/6/19 9:18 AM
 Cover Story: Building a Biopharma Company

execution of your programs,” advises
Rosenwald.
Vajeso also points out that, even
though many may say something will
not work, experience has taught her
otherwise. For her, a good practice to
follow is surrounding oneself with peo-
ple who have an open mindset and are
eager to learn and develop.
Ilya’s lead candidate, ILP100, is in
the cell- and gene-therapy space, and
Vajseo says she is surprised at how fast
the project is growing. “We are currently
running a first-in-human study but
really mostly working with the Phase
II programs for new trials to start next
year. In developing a new and innova-
tive compound, it is crucial to work with
the best senior experts with an open
mind and who have seen multiple com-
plex compounds before. Do not waste
time with generic advice,” Vajeso says.
Experts also advise avoiding major
pitfalls early on, such as taking on too
much risk at the start. “My advice is to
create a durable business model, grow
slowly, forge partnerships, and spread
the risk,” Rosenwald cautions. “Another
pitfall to steer clear of is sticking with
losing product candidates for too long.
Cut them early!”
In Fortress Biotech’s case, the com-
pany had to overcome a challenge
related to its drug candidate for amy-
loidosis. Rosenwald explains that the
company had to deal with market
confusion over Fortress Biotech’s drug
candidate and a competitor’s product
that was further along in clinical tri-
als. Though Fortress Biotech believed
its candidate demonstrated superior-
ity over the competitor’s product, the
confusion over the two drugs made
it difficult for the company to raise
the necessary development capital.
“We recognized that we had to pivot
and were fortunately able to forge a
partnership with a large pharmaceu-
tical company in a $500-million
deal to develop the drug candidate,”
Rosenwald explains.
THE COMPANY CULTURE
Quality is an integral aspect in drug
development, not just quality of the
product, but quality of the environ-
ment, processes, and company mindset.
In Vajeso’s opinion, enforcing quality
is about “always keeping the science
and data in mind.” Beyond that, having
good people with key expertise goes a
long way in implementing the necessary
quality aspects in drug development.
For Rosenwald, enforcing quality
into the core of a company depends on
having a dedicated management team,
and having external advisors who are
experienced in the areas you are work-
ing in to help grow, support, and main-
tain a culture of quality.
REFERENCES
1. U. Geilinger and C. Leo, HBM New
Drug Approval Report (HBM Partners,
Zug, Switzerland, January 2019).
2. A. Tajonar, “How to Start a
Biotech Company,” Mol Biol
Cell. 25 (21) 3280–3283 (2014).]
3. J.A. DiMasia, et al., Journal of Health
Economics 47, 20–33 (2016).
4. JLL, “Big Pharma Poised for Disruption
in 2019 While Mid-Tier Companies
Double Down on Innovation,”
Press Release, Jan. 17, 2019.
5. B. Booth, “The Creation of Biotech
Startups: Evolution Not Revolution,”
LifeSciVC.com, Aug. 15, 2019, lifescivc.
com/2019/08/the-creation-of-biotech-
startups-evolution-not-revolution/.
6. J. Friedman, “How Biotech Startup
Funding Will Change in the Next
10 Years,” YCombinator.com,
YCombinator.com Aug.
5, 2019, blog.ycombinator.com/
how-biotech-startup-funding-will-
change-in-the-next-10-years/.
7. R. Fernandez, “Top 5 Reasons Why
Biotech Startups Fail,” Labiotech.edu,
Nov. 27, 2018, www.labiotech.eu/tops/
biotech-startups-failure-advice/. ◆

Biotech Startup Resources: A Snapshot

Complementing the funding environment for biotech startups,
new resources aimed at supporting the financial, research,
and technical needs of fledgling biopharma companies have
been announced recently.
In November 2019, a consortium of biopharma-related
organizations established the Center for Advanced Biological
Innovation and Manufacturing, a $50-million center in the
Boston, MA, area to foster innovations in cell and gene
therapy, advance biologic innovation and manufacturing,
and accelerate developments in promising biologic-based
technologies. Representatives from Harvard University,
Massachusetts Institute of Technology (MIT), Fujifilm Diosynth
Biotechnologies, GE Healthcare Life Sciences, and Alexandria
Real Estate Equities will serve on the center’s board of
directors. Other contributing members include Boston-area
medical centers, MilliporeSigma, and the Commonwealth of
Massachusetts. The center will provide preferred access to
a new manufacturing facility, shared innovation space, and a
platform for workforce development and training.
In October 2019, Japan-based Astellas Pharma announced
a $12.5-million investment into two innovation incubators
operated by LabCentral in Cambridge, MA, which will feature
core lab space for process development studies and a non-
GMP pilot plant.

14 BioPharm International December 2019 www.biopharminternational.com

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technologies who can also help you maximize efficiencies. By joining forces with you, we provide
a powerful cutting-edge service covering contract development and manufacturing services
for mAbs and viral vectors, product characterization, biosafety testing and toxicology testing
services. So partner with us and let nothing stand in the way of reaching your vital goals.

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 Downstream Processing
Prevent, Detect, and Remove:
Viral Control for Viral Vectors
Ensuring that viral vectors are free of viral contaminants
requires a focus on prevention and control.
CYNTHIA A. CHALLENER
V
iral vectors must be free of viral contaminants, both
adventitious agents introduced via raw materials and
those generated during processing. Because conven-
tional viral clearance treatments would degrade or destroy
many viral vectors, assessment of the potential risk for con-
tamination and the implementation of prevention and con-
trol strategies are essential. Detection can be an issue, too.
Multiple analytical methods must be used, many of which
have performance limitations, adding to the challenge.
VARIOUS REGULATORY REQUIREMENTS
Regulatory authorities require testing to be performed at
every stage of the manufacturing process. Cell substrate
banks, viral seed banks, raw materials of animal origin, bulk
harvests, and the batches of the final manufactured clinical
product all have to be tested, according to Francesca Vitelli,
head of process development, for viral vectors at Lonza.
Both adventitious viral agents and replication-competent
viruses are a concern, adds Tony Hitchcock, technical direc-
tor with Cobra Biologics.
16 BioPharm International December 2019
BP1219_016-019_Downstream_ViralClearance_Challener.indd 16
While there are no regulations solely dedicated to the viral
safety of viral vector products, several guidance documents from
various agencies provide relevant information on ensuring the
viral safety of biological products. There are also guidance docu-
ments specifically for cell and gene therapies, according to Karen
Tiano, spokesperson for MilliporeSigma, and some do mention
that testing for adventitious viruses is expected. Select guidelines
for viral contamination testing are listed in Table I.
RANGE OF POTENTIAL CONTAMINANTS
Many viral contaminants may be present in viral vector prod-
ucts. The risk for specific contaminants is dependent on the raw
materials and the process, according to Lorraine Borland, prod-
uct manager for regenerative medicine–cell and gene therapy in
norman blue/Stock.Adobe.com
the cell line, media, and testing solutions business of Sartorius
Stedim Biotech.
CYNTHIA A . CHALLENER, PhD, is a contributing editor to
BioPharm International.
www.biopharminternational.com
12/6/19 9:19 AM
 Downstream Processing

Table I. Select international guidelines for viral contamination testing. ICH is International Council for Harmonization.

Source Title
Q5A (R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines
ICH Guideline
of Human or Animal Origin (September 1999)
FDA Guidance Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy
for Industry Investigational New Drug Applications (INDs) (April 2008)
FDA Guidance Characterization and Qualification of Cell Substrates and Other Biological Materials Used
for Industry in the Production of Viral Vaccines for Infectious Disease Indications, Guidance for Industry (February 2010)
European
EP 5.2.3 Cell Substrates for the Production of Vaccines for Human Use
Pharmacopoeia
European
EP 2.6.16 Test for Extraneous Agents in Viral Vaccines for Human Use
Pharmacopoeia
EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4,
European Commission Good Manufacturing Practice, Guidelines on Good Manufacturing Practice Specific
to Advanced Therapy Medicinal Products (Effective May 2018)
FDA Draft Guidance Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy
for Industry Investigational New Drug Applications (INDs) (July 2018)
FDA Draft Guidance Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus
for Industry During Product Manufacture and Patient Follow-up (July 2018)

“The highest risk pathways for intro-
duction of adventitious viruses are typi-
cally raw materials used in the upstream
portion of the manufacturing process,”
asserts Morven McAlister, senior director
of regulatory and validation consultancy
at Pall Biotech. “Raw materials such as
cell-culture media and trypsin typically
cannot be autoclaved and so represent the
highest risk of entry of these viruses. This
risk is heightened with the use of serum.
The cell line is also a potential source of
adventitious viruses. To reduce the risk
associated with the cell line, it must be
very well characterized and both the mas-
ter and working cell banks thoroughly
tested,” she adds.
“The manufacturing process, if not
carried out in a closed system, may also
have multiple aseptic process steps where
breaks in the process or transfer of the
intermediate material may increase con-
tamination risk,” Borland notes. For
instance, Hitchcock notes that pro-
ducer cells and viral seed stocks can also
become contaminated when used. The
generation of replication-competent viral
vectors during the manufacturing process
is also a key concern.
For raw materials, McAlister adds that
contaminants can be placed into two cat-
egories: adventitious viruses that enter the
viral preparation inadvertently through
raw materials or poorly characterized cell
lines and helper viruses such as baculo-
virus, adenovirus, or herpes simplex virus,
which are deliberately used to stimulate
expression of the virus of interest (gener-
ally adeno-associated virus [AAV] pro-
duced via transient routes).
Efforts to control for the presence
of viral contaminants have focused on
testing for retroviral contamination and
species-specific viruses when animal-de-
rived raw materials are used, according
to Vitelli. Examples include bovine or
porcine adventitious agents and spe-
cies-specific viruses such as rhabdovirus,
polyomavirus SV40, and arboviruses for
other animal and insect cells.
“Where bovine serum or porcine tryp-
sin has been used in the process, there
is a risk of introducing bovine and por-
cine viruses such as bovine polyomavi-
rus and bovine and porcine circovirus,”
notes Borland. “Minute virus of mice and
vesivirus are viruses that have emerged
in recent years as contaminants of bio-
reactors, and screening for both is now
included as standard for rodent cell lines.”
Detection is more complicated with
viral vectors compared to antibodies,
according to McAlister, because human
cell lines are generally used for their man-
ufacture. A typical panel for a human cell
line could include herpes simplex virus,
HIV-1, hepatitis A virus, porcine par-
vovirus, and possibly encephalomyocar-
ditis virus. “When working with human
cell lines—for example HEK293 cells—
besides standard viral safety issues, spe-
cial precautions should be taken because
this cell line is susceptible to infection
by human viruses,” she observes. Other
human viruses that may need to be tested
for include cytomegalovirus, human
T-lymphotropic virus, Epstein-Barr virus,
hepatitis B virus, human papillomavirus,
and hepatitis C virus.
It is easier to identify residual helper
viruses such as baculovirus, adenovirus,
and herpes simplex virus because they
have been deliberately introduced and
are also usually present at much higher
concentration, according to McAlister.
Due to that fact, however, the challenge
becomes removal rather than detection,
she comments.
MORE SOURCES TO CONSIDER
In addition to raw material and pro-
cess risks, the facility, equipment,
utilities, and people involved in the
manufacturing the process are all
potential sources of viral contamina-
tion, according to Borland.

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 Downstream Processing
“The facility itself may be a point of
entry for rodents, providing a pathway
for viral and bacterial contamination to
transfer to the process stream. If using
stainless-steel bioreactors, the cleaning
and sterilization regimes must be vali-
dated to ensure no cross-contamination
of product. Such a risk is driving the
movement to sterile, single-use systems.
Water systems and non-sterile gas sys-
tems must also be taken into consider-
ation,” Borland says. In multi-product
facilities, there can also be opportunities
for cross contamination by adventitious
agents, according to Hitchcock.
Operators, Borland asserts, may pres-
ent the biggest risk to the process. “Viral
manufacturing processes require aseptic
manipulation within cleanrooms to con-
trolled standards. People provide perfect
reservoirs of bacteria, mycoplasma, and
viruses, and therefore, the controls around
people working on the processes must be
to the highest standards,” she explains.
MANY CHALLENGES
One of the biggest challenges to assur-
ing that viral vectors contain no viral
contaminants is the fact that traditional
viral clearance steps such as filtration and
treatment with heat or strong acids can-
not be used with many viral vectors such
as enveloped viruses (e.g., lentiviruses),
because they are too fragile and cannot
withstand these processes. AAV is one
exception; it is a relatively robust virus
and so typically tolerates standard virus
hold strategies to eliminate unknown
adventitious agents in the preparation,
according to McAlister.
Neutralization of viral vector prod-
ucts without impacting the viral con-
taminants is also difficult, Hitchcock
says. As a result, detection of unknown
viral contaminants present at low levels
is highly challenging.
The range of potential viral contami-
nants and numerous sources, meanwhile,
creates the need for a holistic approach
to viral contaminant detection using a
combination of methodologies including
both general and specific assays, observes
18 BioPharm International December 2019
BP1219_016-019_Downstream_ViralClearance_Challener.indd 18
Vitelli. Examples are adventitious agent
tests, usually non-specific tests capable of
detecting a broad range of viruses; spe-
cies-specific assays designed to detect the
presence of identified potential contam-
inants (e.g., specific bovine or porcine
viruses in serum or trypsin, respectively,
or murine viruses in mouse cells); and
tests for retroviruses.
The limitations of the testing meth-
ods provide a huge challenge to the
industry, Borland agrees. “Traditional
in-vitro and in-vivo methods are broadly
specific and will detect viruses that infect
a range of cell types but may not detect
viruses that do not cause cytopathic
effects (CPE). Molecular methods such
as real-time polymerase chain reaction
(PCR) are more specific and have the
ability to target those viruses that do not
cause CPE in cell culture; however, they
are limited by the fact they are specific.
Methods such as [transmission electron
microscopy] TEM, which is used to
detect retroviruses, are limited by their
sensitivity,” she explains.
There are few tools available for accu-
rate, efficient, and reliably precise assays
to determine the activity of residual
viruses, agrees Vitelli. “Generally, the limit
of detection for these assays tends to be
low, and more sensitive methods such as
PCR-based assays can sometime result
in false positives. In addition, risks are
posed by potentially unknown viral con-
taminants that may be undetectable using
current analytical tools,” she states.
Borland notes that next-generation
sequencing has been applied for general
viral detection in biologics; technology
advances and validation of this technique
may bring it into routine testing use.
Another concern for McAlister is the
time required to test for the absence of
viruses. “Current methods are laborious
and may require more time to perform
than the actual product is stable for. This
issue is one of the biggest drivers for the
development and acceptance of rapid
alternative microbiology methods to
allow testing within the shortest time-
frame possible,” she comments.
Once adequate testing is established,
Vitelli notes that another substantial chal-
lenge is obtaining enough purified viral
material for use in formal viral clearance
studies, which is costly and time-con-
suming to generate. “These tests also typ-
ically require purified material that must
be redirected from other potential uses
that are critical to the product develop-
ment cycle and timeline,” she observes.
Tiano adds that there is only a finite
amount of sample available for testing,
which creates challenges, particularly
when material is required for cytotoxicity
pre-studies and viral interference test-
ing in addition to virus spiking stud-
ies. “Reduction of the sample size for
pre-studies is being made possible, how-
ever, with the development of sensitive
molecular assays useful for testing cells,
virus stocks, and raw materials used in the
production of viral vectors,” she notes.
PREVENTION, DETECTION,
AND MAYBE REMOVAL
The traditional approach to assuring
that no viral contaminants are present
in biologic products involves preven-
tion, detection, and removal. Prevention
involves ensuring that only high-quality,
pure, contaminant-free raw materials
are purchased from reliable suppliers,
detection involves verification of the
absence of contaminants in raw mate-
rials and process intermediates, and
removal involves steps to remove or
inactivate any potential viral contami-
nants that may be present.
Because the latter step cannot be per-
formed for many viral vector products,
a risk-based approach must be taken,
according to Borland. “Performing a
detailed and relevant risk assessment is
key to ensuring that an appropriate and
comprehensive virus control strategy is
employed,” adds McAlister. She also
notes that because few viral vector pro-
cesses have been performed at large scale,
knowing how to do this risk assessment
can be a challenge. “The good news is,”
she observes, “that many years of expe-
rience have been developed in closely
www.biopharminternational.com
12/6/19 9:19 AM

related processes such as monoclonal
antibodies and vaccines, and this experi-
ence can be leveraged for these processes.”
In addition, Hitchcock believes the
best strategies clearly rely on understand-
ing the vector design; selection of the
appropriate producer cell line and man-
ufacturing process, including the use of
closed manufacturing systems, especially
with regards to the production of replica-
tion-competent vectors; implementation
of a stringent quality system and man-
agement of suppliers to ensure that the
required control measures are in place to
minimize the risks of adventitious viral
contamination and for multi-product
areas/facilities, adoption of procedures for
prevention of cross-contamination and
that demonstration of the removal of pre-
viously manufactured product from the
cleanroom facility and shared equipment.
“The over-arching requirement,” states
Vitelli, “centers on good facility design,
process design, material control, and
strict compliance with good manufac-
turing practices to ensure safety and suc-
cess. Fundamental facility controls are
typically established during the facility
design phase, such as the segregation of
personnel, material and waste flows, and
selection of cleanable materials of con-
struction, and are propagated by validated
facility management practices to include
robust environmental monitoring, prod-
uct changeover, and visual inspection.”
Following the general viral safety strat-
egy that incorporates prevention through
safe sourcing, detection, and removal has
resulted in safe biological products for
many years, says Tiano. “Cell and gene
therapies is an exciting and rapidly devel-
oping area. Although the therapies may
be new, using this strategy for guaran-
teeing viral safety will help ensure that
these new therapies are as safe as more
traditional biological therapies.”
LIMITED OPTIONS
There are limited options for viral clear-
ance other than extensive testing of mate-
rials going into the process. Many of the
same strategies used to inactivate/remove
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Downstream Processing
contaminating viruses can impact the Since the chromatography steps purify
quality/potency of the final viral gene the vector product, viral clearance is only
therapy product. Manufacturers can look achieved when there is a difference in
to adopting viral removal steps into their partitioning between the vector and
raw material entry points, Borland sug- potential viral contaminants,” she explains.
gests. She points to next-generation virus Lonza’s R&D group is evaluating
filters that have been developed to offer a chemical additives and exploring differ-
cost-efficient strategy for media filtration, ent lysis reagents that have viral inactiva-
but notes that this technology is not yet tion capabilities without risking impact
adopted throughout the entire industry. on the quality of the viral vector product.
Techniques such as nanofiltration,
ultraviolet-treatment, gamma irradia- SCALE-UP ISSUES
tion, and high temperature, short-time As next-generation processes move
treatment can also be used to ensure that toward commercialization, there has
no viruses are present in starting materi- been a general shift away from adher-
als, according to McAlister. She stresses, ent cell-culture processes in open, man-
though, that it is important to ensure ual-intensive, flatware systems that are
during process development that sub- difficult to scale to automated, suspension
jecting raw materials to these techniques cell-culture processes in closed bioreac-
does not affect their performance. tors that are more efficient and readily
Viral clearance technologies that are scalable. This shift is also enabling the
used in the manufacturing process for use of sterile, disposable systems, which
viral vectors that can withstand them is in turn enabling improved risk-mitiga-
are engineered into the manufacturing tion strategies, according to Borland.
process and are most commonly heat Hitchcock notes that as viral vector
inactivation and the use of viral retentive manufacturing processes are scaled, the
filtration, according to Vitelli. In some likelihood of the generation of replication
cases, such as for AAV products, affinity competent viruses increases, which poses
chromatography and exposure to acidic challenges for purification.
pH conditions (< pH3) may be employed. Improving overall process yield will
For removal of helper virus, McAlister be an issue, in fact. McAlister points to
notes that nanofiltration works well downstream processing yields, typically
because there is a large difference in around 30%, for AAV as an example.
diameter between the virus of interest “Nanofiltration, if not done properly, can
and the contaminating virus. She notes, further reduce this yield. Appropriate
however, that direct-flow filtration is not filterability trials must be performed to
well adapted for the removal of viruses ensure that a scalable scheme for virus
at high concentration. “It is generally control is designed,” she observes. Vitelli
recommended, therefore, that an initial adds that as the per-dose demand for
virus removal step that can remove sig- viruses increases, notably AAV, vendors of
nificant amounts of the helper virus, such viral-retentive filters should continue to
as membrane chromatography, be per- work closely with product developers and
formed first.” contract development and manufacturing
Some chromatography steps that are organizations to provide scaling recom-
used in the purification of non-envel- mendations and new product sizing.
oped viral vectors may contribute to viral For viral vectors that can withstand
clearance for the vector as well, accord- heat inactivation, these steps may also
ing to Tiano. “These steps may include pose unique challenges with respect to
an affinity resin or an anion exchange scale up due to the need to adequately
resin, which are optimized to purify the control both the temperature and dura-
viral vector product and coincidentally tion of exposure in the liquid state,
may remove potential viral contaminants. according Vitelli. ◆
December 2019 BioPharm International 19
12/6/19 9:19 AM
 Keep Pace with the Latest
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Industry Trends with PDA

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The Parenteral Drug Association (PDA) is the leading global provider
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 Rising Demands for Viral Vector
Analytics: The Most Common
A Q&A Analyses Requested
Analytical technology that reveals the impact of process
on critical quality attributes.
V
ironova has been offering
Jonathan Royce nanoparticle characterization and
Instruments Business Unit Director viral clearance testing services
Vironova AB
from its GMP-compliant laboratory in
Stockholm to biopharmaceutical clients for
more than a decade. Recently, however,
Vironova launched the innovative low-
voltage MiniTEMTM transmission electron
microscopy (TEM) system, which enables
automated image analysis close to the
process so that developers can quickly
review information about critical quality
attributes in house.
In this interview, BioPharm International sat
down with Jonathan Royce, instruments
business unit director at Vironova, to
discuss the increasing demand for
viral vector analytics and to learn how
automated TEM-based image analysis can
provide objective data that reveal process
impact on viral particle quality.
BioPharm: What analytics solutions
does Vironova provide to support the
development of viral particle-based
pharmaceuticals?
Royce: Vironova provides analytical
services and systems that scientists can
use to evaluate the morphology, integrity,
and purity of the viral vectors they are
producing to insert the gene of interest
into a patient. Our analyses are based on
TEM, which allow for the generation of both
visual and quantitative results.
In product development, these analyses
might be used to make decisions about
things like manufacturing techniques,
storage conditions, long-term product
stability studies, and different types
SPONSORED BY
AdLayout.indd 22
of formulations that might affect long-
term product stability, for instance. In
manufacturing, TEM can be used to
generate quality control (QC) data during
batch release. It might be used in an
interim QC step to make stop/go decisions
on a process. It can also provide insights
necessary to investigate deviations that
may occur in manufacturing.
BioPharm: As the cell and gene
therapy market has exploded over the
last couple of years, have you noticed
any trends in client requests and the
kind of analyses developers ask for?
Royce: Yes, we have seen several trends.
In fact, Vironova’s history mirrors the
development of drug-delivery systems and
virus-based technology.
We started by supporting several drug
manufacturers that were developing
liposome-based drug-delivery systems.
That was followed by periods where viral-
based vaccines for pandemic flu were a
strong focus. Then in recent years, there has
been a real explosion in AAV gene therapy.
Most recently, in 2019, we have seen a big
spike in requests for lentivirus analyses.
Those trends are not unexpected when
you look at the clinical pipeline; the early-
phase products that were based on AAV
are starting to move into later stages, and
now a wave of lentivirus-based products
is coming. It is quite analogous to what is
happening in clinical development.
Similarly, clients are requesting specific
analyses that follow the clinical development
of the various therapeutic types. For
example, AAV manufacturers in the early
12/6/19 2:22 PM

phase of development are interested in looking at factors
like particle integrity because their main focus is ensuring
their vectors contain the gene of interest. At the same time,
we are seeing more developers entering late-phase clinical
manufacturing, and these clients are more interested in
analyses related to purity. Once clients approach large-scale
and commercial manufacturing, the focus shifts to ensuring
the downstream process is producing a pure product.
BioPharm: You recently performed a market survey
about the needs and challenges in analytics in the
development and manufacturing of viral-based
pharmaceuticals. What was your reason for doing
this study?
Royce: We thought that it was important to gather some
direct feedback from the developers of analytical techniques
to understand the challenges and needs of analytical
development laboratories in the biopharmaceutical
space. The analytical field for viral vectors is still relatively
undefined, so it is important that developers of analytical
tools stay closely connected to development laboratories
so that we can stay a step ahead of their needs.
For instance, early insights into the needs of lentivirus
developers inspired us to create some artificial intelligence-
based analysis methods that enable the quantification of
polymorphic viral vectors, and which is nearly impossible
to do using traditional analysis techniques. So, we use
the insights gained from tools like surveys to ensure our
technology is ready for when users need to implement it.
BioPharm: Did the survey findings match your
experience of the trends you see in client requests?
Royce: Broadly speaking, yes. For example, as I mentioned
previously, we are seeing more interest in lentivirus
analyses, which the survey indicated is of growing interest
in the market. We also see increased interest in purity
analysis, which was confirmed by the survey to be a
primary analysis of interest.
Another interesting observation from the survey was that,
so far, not been much focus has been on ensuring that
the analytical methods used for viral vectors are GMP
compliant. A lot of this work is being done in the R&D
laboratories, which is something that we at Vironova feel
will be a very important requirement moving forward. Here
too, we’re trying to stay a step ahead to ensure that our
software, for example, will be GMP compliant in the way
it handles data. When these analyses are ready to move
from the R&D lab into the QC lab, our technology will be
ready to make that move, as well.
BioPharm: In what way is the Vironova technology
such a powerful solution for viral particle analysis
in pharmaceutical development?
Royce: When it comes to gene- and cell-therapy vectors,
no other alternatives provide both visual and quantitative
information. Several complementary technologies such as
dynamic light scattering, ultracentrifugation, and surface
AdLayout.indd 23
RISING DEMANDS FOR VIRAL VECTOR ANALYTICS:
plasmon resonance are on the market, however. These
technologies, together with TEM, make up a package
of orthogonal methods that is really powerful in fully
characterizing a gene-therapy product.
TEM has a unique position in this package in that one can
extract multiple analyses from a single sample prep. Only
a few microliters of sample are needed from which you can
get quantitative results on purity and integrity, for instance.
It provides direct visual confirmation of sample quality.
People say a picture’s worth a thousand words, and that’s
true even in the analytical lab. We’ve seen, for example,
that the individuals who sign off on the release of a batch
truly appreciate the extra security of a visual inspection.
BioPharm: What are your plans for developing the
Vironova technology further? And what innovations
can we expect from Vironova in the coming years?
Royce: We’re going to continue to stay a step ahead of
market needs and develop solutions that enable cell- and
gene-therapy manufacturers. Expect to see continued
developments in vector technology, for example, and we
need to be close to those developments to ensure we
have analytical solutions that match what’s coming into
the clinical pipeline.
We also believe that automation will be key to improving
the reliability of results, and therefore we’re working really
hard to harness the power of informatics, electronics, and
even fluid mechanics to minimize sources of error and
streamline the entire analytical workflow.
We believe there’s enormous potential to use machine
learning to streamline analytical development, and we’re
working hard to bring the full force of AI into the analytical
lab and enable users to train machines using their own
proprietary data. So in one sense, we’re looking to
democratize the technology of AI, while on the other hand,
trying to ensure that every user can use their methods to
differentiate themselves in the market.
And finally, we want to achieve these goals in a way that
enables validation in GMP environments. This is critical—
it’s absolutely going to be a requirement in the future for
anyone trying to bring an analytical method into the QC
lab that data is managed in a way that’s compliant with 21
CFR Part 11, and that the interaction with the software is
controlled in a way so that users have one level of access
while administrators have another level.
We understand this very well at Vironova. We are not only
developing analytical tools; we’re also providing analytical
services for pharma and biotech companies, and we use
our software in our own workflows. Our lab in Stockholm
has recently filed an application with the Swedish Medical
Products Agency to become the world’s first GMP-certified
freestanding QC laboratory for TEM analyses. We believe
that the software we’re using in those analyses fulfills the
requirements of Part 11 today and we’re committed to
continuing to maintain compliance moving forward.
12/6/19 2:22 PM
 Manufacturing
Antibody Purification Process
Development and Manufacturing
Downstream process development and manufacturing play a crucial
role to ensure safety, quality, identity, purity, and efficacy.
YANHUAI (RICHARD) DING, MARGARET MARINO, AND HEMANT KUMAR
A
biotech company’s journey to develop a protein-based
therapeutic drug from discovery, process development,
manufacturing, and clinical trials to commercial-
ization is long and complex. Multiple activities are involved,
and many challenges are encountered when complying with
chemistry, manufacturing, and control (CMC) requirements.
Downstream process development and manufacturing play a
crucial role to ensure the protein drug’s safety, quality, identity,
purity, and efficacy (SQIPE) meet regulatory requirements for
clinical trials and commercialization.
In this article, the authors analyze the challenges and seek
effective solutions for CMC compliance (Figure 1), specif-
ically focusing on protein complexity, raw material quality,
upstream process (e.g., media source and titer), downstream
process development (e.g., process capacity, efficiency, scal-
ability, and control), manufacturing complexity, and product
SQIPE.
PROTEIN DRUG COMPLEXITY
Antibodies are complicated biologic molecules in their
nature, including size (e.g., 150 kDa IgG–900 kDa IgM),
24 BioPharm International December 2019
BP1219_024-029_Quality_Purification_AnaptysBio.indd 24
heterogeneity (e.g., glycosylation, deamidation, oxidation),
structure (e.g., monomer, dimer, trimer, hexamer), charge
(e.g., pI of 5.0–9.0), hydrophobicity, and genetic source (e.g.,
rodent, human). Due to their intrinsic complexity, smart
design for protein purification is necessary.
RAW MATERIALS
Raw material screening and selection is the first thing to
be considered for purification. It is best practice to select a
high grade of raw materials (e.g., chemicals) when process
development is initiated. For chemicals, multi-compendial
grade is the first option. Single compendial grade—such as
United States Pharmacopeia–National Formulary (USP–NF),
European Pharmacopoeia (Ph.Eur.), or Japanese Pharmacopeia
(JP)—is acceptable if multi-compendial grade is not avail-
Kateryna_Kon/Stock.Adobe.com
YANHUAI (RICHARD) DING, PHD, is director, downstream process
development and manufac turing; PEGGY MARINO, PHD, is
vice-president, program management; and HEMANT KUMAR,
PHD, is senior vice-president, head of process development and
manufacturing, all at AnaptysBio.
www.biopharminternational.com
12/6/19 9:20 AM
 Manufacturing

Figure 1. CMC considerations for protein purification process development (PD) and manufacturing. mAbs is monoclonal
antibodies; CMC is chemistry, manufacturing, and controls; CAPA is corrective action and preventive action; DS is drug substance;
DP is drug product; IEX is ion exchange chromatography; HIC is hydrophobic interaction chromatography; SEC is size exclusion
chromatography; TFF is tangential flow filtration; USP is United States Pharmacopeia; EP is European Pharmacopoeia; JP is
Japanese Pharmacopoeia; BP is British Pharmacopoeia; ACS is American Chemical Society; NF is National Formulary.

Raw Materials:
• Resin: ProA, IEX, HIC, SEC, memetic ligand
• Molecule: mAbs, Fc-fusion proteins,
• Chemical: Tris, sodium acctate, sodium
biosimilars, vaccine, viral vector, cell
phosphate
therapy
• Water: deionized water, WFI
• Biochemical & Biophysical property:
• Filter: depth filter, viral filter, 0.22 μm filter
Size, pl, post-translation modification
• Medbrane: TFF membrane, Sartobind Q
• Host: Mammalian, microbial, insect,
membrane
human
Biological Raw Material, • Chemical Grade: Multicompendial, USP, EP, JP,
Complexity Grade BP, ACS, NF

Quality, PD,
• QA: ensure quality requirement met Regulatory Equipment, • PD: Process development (study design,
(e.g., documentation) affairs Manufacturing protocol, report, viral clearance study, tech
• Operation, CMC compliance, deviation transfer, scale-up)
investigation, CAPA • Equipment: bioprocess skid, pump, tank, floor
• QC: Testing and releasing for DS/DP and scale, pH/conductivity meters, Solo VPE
manufacturing support • Facility: ISO 7/5, Physical and air recirculation
• RA: ensure PD/MFG/clinical trail and filling
segregation, terminal HEPA filtration, positive
activities met regulatory requirement
pressure cascade system
(e.g., ICH 5A, 5E, 7, 8 , 9, 10, 11)

able. Finally, some chemicals may
not be available in compendial grade.
These need to be considered on a
case-by-case basis regarding the purity,
application, and option for substitution
by a compendial-grade chemical.
Using a high grade of raw materi-
als can minimize negative impact to
product SQIPE and avoids poten-
tial timeline delays and reduces cost
from process development, technol-
ogy transfer, and manufacturing, to
regulatory filing. The raw materials
used are for upstream process (e.g.,
cell lines, media components, addi-
tives), downstream process develop-
ALL FIGURES COURTESY OF THE AUTHORS.
bacteria, fungi, mycoplasma, and endo-
toxin), and storage during manufac-
turing. Due diligence of vendors for
critical raw material supply chain from
primary and secondary vendors for
late-stage and commercial production
is highly recommended.
CLARIFICATION
Harvest via clarification connects
upstream and downstream processing.
It is often conducted by centrifuga-
tion, depth filtration, microfiltration, or
alternative tangential flow.
Depth filtration, a disposable tech-
nology, is routinely used for cell-cul-
ture (e.g., activated carbon, cellulose,
glass fiber), charged or non-charged
(e.g., positively charged ligand), capac-
ity, and pore size (e.g., 2–20 µm). A
properly designed depth filtration step
could result in high viral clearance
(>4 log10 reduction) (1) and impu-
rity removal (e.g., host cell proteins
[HCP]).
Disk-stacked centrifugation is
designed for a large bioreactor harvest
(e.g., ≥10,000L). A reliable scale-up
and/or scale-down model between
scales from bench, pilot, to manufac-
turing is essential for large-scale har-
vest and troubleshooting by small scale.

ment (e.g., chromatography resins,
chemicals, buffers, membranes, filters,
column housings, tubing, bags, tanks,
water), formulation (e.g., excipients,
buffers), and fill/finish (e.g., vial, pre-
filled syringe). It is important to mon-
itor and control raw material critical
attributes, grades, impurities (e.g., trace
elements, leachables, extractables), lot-
to-lot variations, safety (e.g., viruses,
ture harvest (bioreactor ≤ 2000 L). It
removes cells, cell debris, and other
impurities by size and/or charge. A
number of depth filters are available
on market (e.g., Millipore, 3M, Pall,
and Sartorius). Although depth filters
share similar mechanisms for particle
and impurity removal, each filter has
its unique properties in grade (e.g., low
extractable and endotoxin), media fea-
A mature model can be established
based on cell-culture conditions (e.g.,
cell line, cell viable density, cell viability,
titer, and media osmolality), centrif-
ugation system design, feed flowrate,
bowl speed, sigma factor, discharge
rate, and centrate quality (e.g., tur-
bidity and/or lactate dehydrogenase
activity). An automated centrifuge
with a disposable flow-path marketed

www.biopharminternational.com December 2019 BioPharm International 25

BP1219_024-029_Quality_Purification_AnaptysBio.indd 25 12/6/19 9:20 AM

 Manufacturing

Figure 2. Critical considerations for downstream process development and manufacturing.

Scalability &
Facility Design
Development Proof
Assessment
Clonality &
COGs CHO CL
Productivity &
Stability
Analytical &
Process Manufacturability
Assessment Assessment
(Ph1 to Ph2b)

Resin & Biochemical

Manufacturability
Assessment Column Stability (PTMs)
(For Accelerated Performance & Potency
Process Development)
Process
Performance,
CQAs &
Impurities

CMC ✓ Evaluating technical viability of a drug candidate at the industrial scale

Focus
✓ Functions as a bridge between discovery and process development stage

for cell therapy (Sartorius) eliminates CAPTURE STEP RETROVIRUS INACTIVATION

cross-contamination, minimizes cell
lysis, and enhances process efficiency,
quality, and control.
MAB PURIFICATION-BY-DESIGN
The purification process for a mono-
clonal antibody (mAb) typically con-
tains clarification, purification of
capture, intermediate and polishing
chromatography, viral clearance, final
formulation, and bulk drug substance
(BDS) filtration steps. The best down-
stream process should possess high
capacity, efficiency, controllability, scal-
ability, flexibility, cost-effectiveness,
and biosafety (Figure 2).
A platform protein approach for
mAb purification offers advantages
(Figure 3) and can save time and
resources, as well as expenses related to
raw material screening, process param-
eter selection, process development,
documentation preparation (e.g., using
template strategy), technology transfer,
scale-up, product characterization, for-
mulation development, and regulatory
filing. A platform approach also can
anticipate process yield, product purity,
and quality.
A mAb-purification capture step
often uses Protein A resin, a 42-kDa
sur face protein or iginall y iden-
tified f rom Staphylococcus aureus
(2). Protein A resins are made of
either native or engineered pro-
tein cross-linked to different
matr ix (e.g., Eshmuno A f rom
Millipore, PraestoAP from Purolite,
and MabS elect S uRe f rom GE
Healthcare). This protein has a high
binding affinity to mAb or Fc-fusion
protein by hydrophobic interaction
with Fc domain. To select a Protein
A resin, one needs to consider the
resin-binding c apacit y, specific-
ity, stability, cleanability, sensitivity
to caustic (e.g., sodium hydroxide)
solutions, ligand detecting kit avail-
ability, flow capability, good man-
ufacturing practice (GMP) supply,
and resin cost. For a thorough review
of the progress seen in Protein A
chromatographic media, see Bolton
and Mehta (3). The current major
drawback from Protein A resin is its
high cost (approximately $14,000/L
for MabSelect SuRe).
Low pH retrovirus inactivation is usu-
ally conducted at low pH (3.3–3.6)
for ≥60 minutes hold time if the mAb
is stable at the test pH. Low pH ret-
rovirus inactivation is a robust viral
clearance step, which can reach >4
Log10 reduction value (LRV). It was
reported >5 LRV under pH 3.9-4.1
(4). A previous study showed >5 LRV
at pH 3.8 held for 60 min (unpub-
lished data). It is known that pH, hold
time, buffer matrix, acid (e.g., ace-
tate, citrate, glycine), and temperature
(15–30 °C) have impact on retrovirus
inactivation kinetics (4). The lower pH,
higher temperature, and longer hold
time maximize the retrovirus inacti-
vation, but this must be tempered by
the sensitivity of the antibody. Current
industrial practice is toward a modular
approach based on the understanding
and historical data from mAb, buf-
fer type, salt concentration, acid type,
and operating range for pH, tempera-
ture, and hold time. If mAb is unsta-
ble for low pH retrovirus inactivation
treatment, detergent inactivation (e.g.,
polysorbate 80) or UV-C inactivation

26 BioPharm International December 2019 www.biopharminternational.com

BP1219_024-029_Quality_Purification_AnaptysBio.indd 26 12/6/19 9:20 AM


Figure 3. Platform protein approach used for monoclonal antibody (mAb) purification process.
Current Platforms Using ProA for mAb Purification
Three-column Platforms
Harvest
ProA
Low pH VI
Depth Filtration
CEX
AEX
Small Virus Retentive Filtration
UF/DF
Formulation & Final Fill
system (UVivatec, Sartorius) can be an
alternative.
INTERMEDIATE PH
(5.1-5.5) HOLD
This step can result in a significant
impurity removal (>150-fold HCP
reduction) due to impurity precipita-
tion and/or adsorption by a charged
depth filter. This may allow a two-col-
umn process. The intermediate depth
filtration process design parameters
include pH range, hold time, mixing,
temperature, HCP testing method, and
depth filter type.
CATION-EXCHANGE
CHROMATOGRAPHY
(CEX) STEP
In most cases, CEX step is conducted
after the intermediate pH hold and
depth filtration step, which provide for
the needed pH and conductivity adjust-
ment prior CEX loading. CEX is per-
formed in a bind-and-elute mode, which
removes both process- and product-re-
lated impurities (e.g., HCP, rProtein
A, aggregates, and acidic species). The
www.biopharminternational.com
BP1219_024-029_Quality_Purification_AnaptysBio.indd 27
Two-column Platforms (GEH)
Harvest
ProA (MSS/MSS LX)
Low pH VI
Depth Filtration
Multi-modal (MM)
Small Virus Retentive Filtration
UF/DF
Formulation & Final Fill
drawbacks from this step are from its
efficiency (e.g., resin diffusion) and viral
clearance capability (<3 LRV for parvovi-
rus reduction). However, it is still possi-
ble to have >4 LRV retrovirus reduction
when proper resin and operating condi-
tion are designed and developed.
ANION-EXCHANGE
CHROMATOGRAPHY
(AEX) STEP
In either resin or membrane for-
mat, AEX is often carried out after
the CEX step to further remove pro-
cess-related impurities (e.g., HCP,
DNA, endotoxin) and viruses. The
AEX step is an effective step to remove
both retro- and parvoviruses. The
CEX and AEX column order can be
switched to overcome issues related
to equipment, process, or facility. For
example, if the CEX eluate salt con-
centration were too high, it would
need a significant dilution to decrease
conductivity prior AEX load and this
could encounter limitation of equip-
ment (e.g., tank size) or facility fit (e.g.,
suite size). Under these circumstances,
December 2019
Manufacturing
Two-column/membrance Platforms
Harvest
ProA
Low pH VI
Depth Filtration
AEX membrane
Small Virus Retentive Filtration
UF/DF
Formulation & Final Fill
AEX could be considered as second
column step (unpublished data).
AEX-membrane chromatogra-
phy (e.g., Sartobind Q) has unique
advantages in process efficiency, buf-
fer consumption, disposability, and
is ready-to-use. Its shortcomings are
mainly from its low-binding capac-
ity and cost (e.g., at large scale-up).
Therefore, it is ideal to put it after
CEX column, which will minimize
impurity breakthrough and enhance
viral c learance c apacit y. Natr ix
Separations’ 3-D hydrogel membrane
columns (e.g., NatriFlo HD-Q) over-
come the limitations f rom conven-
tional membrane chromatography (5).
SMALL VIRAL
RETENTIVE FILTRATION
Small viral retentive filtration is a
robust viral clearance step (>6 LRV for
parvovirus). A number of commercial
viral filters are available (e.g., Sartorius,
Merck Millipore, Pall, Asahi-Kasei).
The viral filter selection depends on
filter pore size (e.g., 15–35 nm), filter
design (e.g., dead-ended, hollow-fi-
BioPharm International 27
12/6/19 9:20 AM
 Manufacturing

Figure 4. Proposed continuous monoclonal antibody downstream processing higher than inlet of membrane) is rec-
and manufacturing based on science and engineering. ATF is alternative ommended.
tangential flow; PCC is periodic counter current chromatography; STIC is salt Bioburden and endotoxin are strictly
tolerant interaction chromatography. controlled to the lowest level during
DSP and manufacturing to minimize
Harvest ATF/SPTFF (or direct capture after ATF)
Centrifugation/DF (multi-DF approach recommend)
safety risks to the patient. Bioburden
and endotoxin excursions occasion-
Equipment: BioSMB, PCC, or LEWA for continuous capture
ally have been reported f rom poor
Capture/0.2 Suggestion: familiar with the equipment, software, engineer, column environmental monitoring and con-
µm filtration quality optimizing eluate pH between 3.5-3.8 to eliminate low pH titration
step having sufficient chase after elution to avoid dead volume trol, insufficient equipment cleaning
and maintenance (e.g., suite, biosafety

Stage I
Suggestion: directly align with Capture step without pH titration to cabinet), and lack of standardized
Low pH VI
3.5-3.8 for VI use inline titration (Cadence VI system) to adjust pH 5.1-5.5
for HCP reduction
in-process 0.22-µm filtration per unit
Equipment: inline pH/conductivity/temperature probe, mixer, automatic
control valves and pump, UV monitor, SE-HPLC
operation. Personal hygiene and gown-
ing are other possible causes.

Depth Filtration/0.2
µm filtration
Suggestion: Select a proper depth filter to remove HCP (expect <200 folds)
apply multicolumn strategy for DF set-up for continuous approach
CHALLENGES AND
SOLUTIONS FOR FUTURE
MAB MANUFACTURING
CEX: directly load without pH and conductivity adjustment using salt
tolerant CEX resin. Use AEX or HIC after CEX to further remove impurities
Multiple major challenges for biologic
Polishing I and VC drug development and manufacturing
Capto adhere: need load pH adjustment but the 3rd column can be
eliminated. have been reported from early- to late-
stage of clinical trials. Manufacturing
AEX: use inline pH titration and/or use Cadence inline diafiltration (ILDF) changes that are implemented in late-
Stage II

Polishing II
by Pall or inline de-salting by Millipore for conductivity adjustment use
salt tolerant membrane chromatography (e.g., Sartobind STIC) by reusing
stage development include upstream
HIC: directly load CEX eluate onto HIC column (pH 5.5) with bind/elute processes (e.g., cell line and media
mode for aggregate removal if CEX provides > 4LRV for Retrovirus clearance
change to improve titer, implemen-
tation of centrifugation for late-stage
Small Virus Suggestion: high capacity of VF (>10,000 g/m2 Planova BioEX)
multi-filter approach for continuous process
harvest), downstream processes (e.g.,
Retentive Filtration
resin and/or column order change to
improve capacity, efficiency, and viral
Suggestion: Single-pass tangential flow filtration (SPTFF) by Pall
clearance capacity), technology transfer,
UF/DF
and Millipore scale-up (e.g., equipment), facility fit
(e.g., disposable, stainless steel), formu-
lation change at late stage, and DS/DP
ber), capacity (e.g., L/m2, g/m2), and ULTRAFILTRATION specification setting.
cost. Process conditions (e.g., product AND DIAFILTRATION When harvest material with very
purity, pH, conductivity, buffer matrix) Ultrafiltration and diafiltration is high titer (>10g/L) is generated from
and recovery must also be consid- employed for mAb formulation the upstream process, the downstream
ered. Different viral filters have dif- by protein concentration and buf- processing can become the bottleneck
ferent load capacity (e.g., >10,000 g/ fer exchange into final formulation due to its intrinsic limitation in process
m2 from Planova 20N BioEX) with- buffer. Different types (e.g., A, C, capacity, efficiency, and cost from res-
out significant flux decay (unpublished D) of membranes (e.g., regenerated in-based purification technology.
data). High capacity can reduce raw cellulose or polyethersulfone) are Large-scale manufacturing
material cost significantly. To improve available for screening and selection (>10,000L stainless steel bioreactor)
both viral clearance capability and based on recover y, product qual- becomes less flexible due to its larger
process-related impurity removal (e.g., ity, and process efficiency. For bulk footprint of equipment, tank size, filter
HCP, DNA), the authors expect ven- drug substance with high concentra- housing, cleaning-in-place, steaming-
dors to develop innovative viral filters tion (>100 g/L) and viscosity (>10 in-place, change-over, system valida-
with dual functions of size exclusion centipoise), C or D type of mem- tion, and maintenance.
and charge in the future. brane with special system set-up and In-line and on-line analytical
design (e.g., retentate solution level methods are still not fully available to

28 BioPharm International December 2019 www.biopharminternational.com

BP1219_024-029_Quality_Purification_AnaptysBio.indd 28 12/6/19 9:20 AM


monitor product quality (e.g., charge
variance, glycan), stability (e.g., aggre-
gates, fragments), purity (e.g., monomer
%), activity (e.g., enzyme-linked immu-
nosorbent assay binding), and impurity
(e.g., rHCP, rDNA, rProtein A).
Manufacturing site and scale changes
cause unforeseen scale-up issues includ-
ing cell culture grown profile, harvest
quality, centrifugation efficiency, elution
volume increase by additional buffer
chase through pipe, filter clogging due
to slightly material differences between
lab and manufacturing.
Documentation is one of the crucial
activities for the drug manufacturing
lifecycle. It is important to capture cor-
rect information from process parame-
ters, parts, in-process sampling, storage
condition, retains, testing methods, and
drug release specifications.
PROMISING APPROACHES
TO HANDLE CHALLENGES
For higher titer harvest, continuous
Protein A capture is the most promis-
ing option using new resins with high
binding capacity, affinity, stable ligand,
and low cost ((Figure 4). This tech-
Figure 4).
nology has been successfully conducted
at lab, pilot, and manufacturing scale
(e.g., Pall’s Cadence BioSMB, GEH’s
periodic countercurrent chromatog-
raphy, LEWA EcoPrime, Novasep
BioSC, Semba Octave). It significantly
reduces process time, resin cost, col-
umn size, and buffer amount. A nano-
fiber-based Protein A resin from GEH
could make a revolutionary change to
enhance process efficiency, flexibility,
and robustness (6).
A non-Protein A process is an alter-
native to reduce resin cost and poten-
tial Protein A immunogenicity in some
patients. A process that included CEX,
multimodal, and AEX (e.g. Sartobind
STIC) has demonstrated desirable
recovery, purity, and impurity from
mAb purification (7). Other technol-
ogies such as crystallization may be
another alternative to replace Protein
A (8, 9). Crystallization has been used
www.biopharminternational.com
BP1219_024-029_Quality_Purification_AnaptysBio.indd 29
for enzyme and insulin purification for
decades (10).
The low pH retrovirus inactivation
step can be integrated into the Protein
A step by controlling elution buffer
pH and volume without pH titration.
As described previously, it is feasible to
have >4 LRV for retroviral inactivation
when pH is controlled between 3.4–
3.7 and hold time for 60–90 minutes.
Alternatively, a single-use virus inacti-
vation system (e.g., Cadence VI system)
can be adopted as a robust tool for the
continuous intermediate pH hold (e.g.,
pH 5.3 for further HCP removal) and
subsequent step load conditioning.
To connect the second column (e.g.,
CEX) with the third one (e.g., AEX),
in-line buffer dilution and pH titra-
tion system can achieve the desire load
pH and conductivity for the third col-
umn load. A flow-through (overloaded)
mode CEX showed higher capability
and impurity removal (11). This allows
both second and third columns in flow-
through mode (e.g., AEX). Biogen has
demonstrated a flow-through mode
platform for both AEX and HIC (12).
The platform eliminates intermediates
pH/conductivity adjustment between
two columns and reduces process time,
cost, and hardware (e.g., tank).
In conclusion, mAb purification
from process development to large-
scale manufacturing is evolving rap-
idly. To overcome bottlenecks from
the upstream process, lower efficiency,
capacity, and discontinuous processing
nature from downstream processing,
the continuous downstream process
strategy is currently one of the most
promising options. This approach
relies on new type of Protein A resin,
which should have higher binding
capacity and resistance to CIP. The
intermediate polishing steps should
possess high capacity and through-
put. To transform the laboratory-scale
continuous process into large-scale
manufacturing, a biopharmaceutical
company has to smartly design a “new
era” mAb purification process based on
December 2019
Manufacturing
molecule complexity, manufacturing
complexity, online product purity and
quality monitoring, control, biosafety
assurance, CMC compliance, and reg-
ulatory requirements.
It is exciting for downstream scien-
tists to explore novel disruptive tech-
nologies such as crystallization to
replace Protein A step by direct capture
mAb from high titer harvest to make
a revolutionary move for future mAb
purification process development and
manufacturing.
ACKNOWLEDGMENT
The authors sincerely thank Dr.
Michael Ultee for his review and
invaluable inputs.
REFERENCES
1. J X Zhou, “Orthogonal virus
clearance applications in
monoclonal antibody production,”
in Process Scale Purification of
Antibodies
Antibodies, 169-184, (2009).
2. T. Löfkvist T and J. Sjöquist, Acta
Pathologica Microbiologica
Scandinavica
Scandinavica. 56 (3) 295–304, (1962).
3. G.R. Bolton and K.K.I Mehta, Biotechnol
Prog. 32: 1193–1202, (2016).
4. R. Wright and M. Heitzmann,
Proceedings of the 2009 Viral
Clearance Symposium, Developments
in Biologics. 133: 25-43, 2009.
5. R. Jacquemart and J. Stout, BioProcess
International, 14(1) (January 2017).
6. F. Southey, “GE to Open Fibre-Based
Chromatography in UK,” BioPharma-
reporter.com, Nov. 27, 2018.
7. N. Kateja et al., J Chromatogr
A. 1579:60-72, (Dec. 7, 2018).
8. R. Braatz, “Future-Proof
Operations-A Proactive Approach
to Current DSP Challenges and
Bottlenecks,” CBI Bioprocess
Series, Disruptive Downstream
Technologies, June 21–22, 2018.
9. Y.H. Ding, “Harvest Clarification,
Flocculation and the Potential of
Protein Precipitation in Continuous
Technologies,” CBI Bioprocess
Series, Disruptive Downstream
Technologies, June 21–22, 2018.
10. I. A. Mirsky et al., Journal of clinical
investigation 42 (12) (1963).
11. H.F. Liu, et al., J Chromatography
A. 1218(39) 6943-52 (2011).
12. R. Gronke and A. Gilbert, “The Search
For Process Intensification And
Simplification: Alternative Approach
Versus Current Platform Process For
Monoclonal Antibodies,” BioProcessing
Summit, Aug. 12-16, 2019. ◆
BioPharm International 29
12/6/19 9:20 AM
 Upstream Processing

The Evolving Role of Starting Materials

in Cell and Gene Therapy
Accelerated approval pathways and growing demand for cell
and gene therapies are putting pressure on providers of cellular
starting materials, and they must ensure a steady supply.
BRAD TAYLOR AND DOMINIC CLARKE

T
he number of product approvals for cell and gene
therapies is rising steadily. Earlier this year, FDA
issued a statement revealing that there are already
more than 800 active cell-based or directly administered
gene therapy investigational new drug applications (INDs)
currently on file, and that by 2020, they expect to be receiv-
ing more than 200 INDs per year (1). Based on this forecast,
the industry expects cell and gene therapy products to surge
in the market and remain a prominent part of the pharma-
ceutical industry for years to come (2).
FDA has developed four distinct pathways to speed the
progress of promising new therapies through clinical trials,
and if results merit, on to approval. Advanced therapies may
new approvals, 32% were authorized as first-in-class, and
58% were approved to treat rare or “orphan” diseases.
There are three cell therapy products that have been
approved thus far: Provenge (sipuleucel-T) from Dendreon
Pharmaceuticals, Kymriah (tisagenlecleucel) from Novartis,
and Yescarta (axicabtagene ciloleucel) from Kite Pharma, a
Gilead Sciences company. These are likely to be the tip of
the iceberg. Because many new cell and gene therapies are
targeting unmet medical needs, orphan diseases, or both,
they are much more likely to request (and receive) accel-
erated approval. The Alliance for Regenerative Medicine
reports that as of the end of 2018, 263 cellular therapies and
362 gene-modified cellular therapies were being evaluated in
DesignCells/Stock.Adobe.com

be eligible for one or more of these designated pathways

if they treat a serious condition, address unmet medical
needs, or obtain early clinical results that show significantly
improved outcomes compared to current therapies. In 2018,
FDA’s Center for Drug Evaluation and Research (CDER)
issued a record-breaking 59 new drug approvals (3). Of these
BRAD TAYLOR*, PhD, btaylor@hemacare.com, is global marketing
director, and DOMINIC CL ARKE, PhD, is global head of cell
therapy, both at Hemacare Corporation, 8500 Balboa Boulevard,
Suite 130, Northridge, CA 91325.
*
To whom correspondence should be addressed.

30 BioPharm International December 2019 www.biopharminternational.com

BP1219_030-035_Development_Hemacare.indd 30 12/6/19 9:41 AM

 CORPORATE CAPABILITIES    www.biopharminternational.com
Catalent
About Catalent
Catalent is the leading global provider of
advanced delivery technologies, development,
and manufacturing solutions for drugs,
biologics, gene therapies, and consumer
health products. With over 85 years serving
the industr y, Catalent has the proven
expertise, superior technologies, and flexible
solutions at the right scale to help ensure
successful product development, launch,
tech transfer, and reliable global supply.
Our fundamental philosophy is to help
clients efficiently allocate their research and
manufacturing expenditures by strategically
enga ging t hem to meet t heir unique
outsourcing needs.
Catalent has built this expertise through
helping partners of all sizes, from the smallest
innovators to the largest of biopharmaceutical
leaders, to advance thousands of molecules
through each phase of development and
on to commercial supply. By arranging our
expertise, capabilities, technologies, and
capacity, we provide services from specific,
CATALENT tailored program support or comprehensive,
14 Schoolhouse Road, integrated solutions that are fast, flexibility,
Somerset, NJ 08873 reliable, and that help our partners reduce
TELEPHONE project risk. In fact, our team of nearly
+1 888.765.8846 13,000 at 35 sites develop more than 700
EMAIL projects and help launch in excess of 200
solutions@catalent.com products every year. We produce more than
WEBSITE 72 billion doses of over 7000 products for
www.catalent.com more than 1000 customers — or 1 in 20
doses taken by patients globally. Our passion
is to help unlock the full potential of your
product.
ADVERTORIAL
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Technology Highlights
With our wide range of expert services—
including ana ly tica l, biologics,
preformulation, and formulation—we drive
faster, more efficient development timelines
and produce better products. These include:
• Paragon Gene Therapy, part of Catalent
Biologics, focuses on transformative
technologies, including adeno-associated
virus (AAV) gene therapies, next-generation
vaccines, and oncology immunotherapies.
• GPEx® Boost technology for advanced
cell expression, a nd adva nced
biopharmaceutical development, analytical,
and manufacturing.
• SMARTag® technology for antibody-drug
conjugation, affording precision design of
next-generation biologic therapies.
• OneBioSM Suite, a single solution from cell
line development through clinical supply
reduces timelines, risk, and complexity.
• OptiForm® Solution Suite to assist in rapid,
optimized dose form development.
• Bioavailability enhancement including lipid-
based systems, Pharmatek SDTM spray dry
technology, particle-size engineering, and
OptiMelt® hot melt extrusion.
• Unique delivery technologies: including
OptiShell® gelatin-free capsule technology,
the Zydis® orally disintegrating tablet
platform, and controlled release dose design,
as well as inhaled and injectable dose forms.
• Catalent R.P. Scherer Softgel is a global leader
in innovative oral and topical softgel tech-
nologies, and nearly 90% of NCEs approved
by the FDA over the last 25 years have been
developed by us.
December 2019  BioPharm International   31
 Upstream Processing
Figure I. Phase I–III clinical trials over a four-year period.
804
631
2015 2016
Ph. 1: 192 Ph. 1: 261
Ph. 2: 376 Ph. 2: 475
Ph. 3: 96 Ph. 3: 68
clinical trials (see Figure 1)) (4). The
majority of these clinical trials are for
cancer indications, with chimeric anti-
gen receptor (CAR)-T cell therapies
alone accounting for 181 Phase I–III
clinical trials (5).
While a robust pipeline is certainly
a strong indicator of future therapeu-
tic success, the rapid increase in the
number of cell-based therapies headed
toward commercialization is placing
growing demands on cell-therapy
starting material suppliers. Unlike
other biological drug products such
as therapeutic proteins, monoclonal
antibodies, or vaccines, drugs based on
living cells are by nature uniquely vul-
nerable to supply chain complications
and setbacks. Apheresis center capacity,
donor network access, sample handling
expertise, and quality control systems
all contribute to the ability to achieve
reproducible starting material quality
and efficacy.
STARTING MATERIAL
VARIABILITY
The raw materials for allogeneic cell
therapies cannot be manufactured on
demand, but instead, rely on a net-
work of volunteer donors. This cre-
32 BioPharm International December 2019
BP1219_030-035_Development_Hemacare.indd 32
1028
946
2017 2018
Ph. 1: 314 Ph. 1: 341
Ph. 2: 550 Ph. 2: 595
Ph. 3: 82 Ph. 3: 92
ates variability in cell therapy starting
material from the outset. Small donor
networks are vulnerable to issues, such
as unexpected drops in the number of
donations, uneven reliability, and inad-
equate diversity to meet the specific
needs of their clients. Sourcing cells
from a large, diverse donor network
avoids many of these complications,
but cell-therapy manufacturing and
supply companies must still deal with
the inherent variability of living cells
and tissues.
Many different factors can intro-
duce variability into the total yield of
white blood cells (WBC) and other
therapeutic cells during apheresis col-
lection. Disease, for example, impacts
cellular functional capabilities and
overall cell health. Cells collected from
patients with illness display significant
physiological differences compared to
those collected from healthy donors.
Cell subset composition, cell pheno-
type expression, and the presence of
inflammatory or stress-related factors
can all impact target cell health, func-
tion, yield, and downstream therapeu-
tic potency.
The collection of healthy donor cells
is also subject to considerable variabil-
ity, and a well-established donor center
will be aware of the many factors that
impact WBC counts (6). Data gener-
ated illustrates the variability present
in apheresis collections from normal
healthy donors (Figure 2). For exam-
ple, WBC yields vary significantly with
donor body mass index (BMI) and
advanced age. Factors such as age, gen-
der, BMI, ethnicity, current medica-
tions, and medical history have all been
documented to result in differences
in WBC profiles (7, 8). Stressful per-
sonal issues and lifestyle habits such as
smoking, drinking to excess, poor sleep
habits, and poor nutrition all impact
WBC counts. Good donor communi-
cation can give cell collection center
staff valuable knowledge about which
factors known to affect target cell col-
lection may be present, as well as the
opportunity to modify cell collection
protocols appropriately.
Apheresis and healthcare experts
should understand donor variabil-
ity issues and be trained to optimally
match the unique physiological charac-
teristics of each donor with the project
needs of the client. They also need
the training and expertise to operate
and maintain apheresis instrumenta-
tion and to decide which collection
methods best suit the donor and client.
Differences in staff training and apher-
esis equipment and supplies can also
introduce variability. Standardizing
equipment and training between the
manufacturers’ various collection sites
can alleviate starting material variabil-
ity and downstream processing risk.
SAFEGUARDING QUALITY
ALL FIGURES COURTESY OF THE AUTHORS.
Along with donor-related variability,
collection methods and post-collec-
tion sample handling also contribute
to starting material variability. It is all
but inevitable that a small percent-
age of cells will be lost to purifica-
tion or target cell modification steps,
which is why it’s best to develop a
process that is as integrated as possi-
ble. Automation and closed-loop sys-
www.biopharminternational.com
12/6/19 9:41 AM
 Upstream Processing

Figure 2. Differences in white blood cell (WBC) yield correlate to donor biometrics such as age and body mass index (BMI).
A shows that there is a significant positive correlation (95% confidence by Spearman correlation test) between donor BMI and
total WBC yield per apheresis collection unit. This correlation grows more pronounced as BMI increases from normal (cutoff
at first red line) to overweight (cutoff at 2nd red line) to obese in terms of medically defined weight categories. p=<0.0001,
two-tailed t-test. B shows that there is a significant negative correlation between donor age and total WBC yield per apheresis
collection. This correlation grows more pronounced beyond age 65 (denoted by red line, 95% confidence level by Spearman
correlation). p=<0.0001, two-tailed t-test (n=2490 cell collections). CBC is complete blood count.

BMI versus WBC (A) Age versus WBC (B)

5 5
Total CBC WBC (Yield x 10^10)

Total CBC WBC (Yield x 10^10)

4 4

3 3

2 2

1 1

0 0
0 20 40 60 80 0 20 40 60 80
BMI Age

tems can cut down on process related
cell loss.
Flawed sample handling during
cell collection and transfer to the
manufacturing facility, however, car-
ries a greater risk than minor process
losses. Contamination risk, whether
f rom outside sources or intrinsic
contamination from other cell types,
is an ongoing concern for cell ther-
apy developers because it can result
in serious medical and financial con-
sequences. Risks of this type can be
avoided through stringent oversight of
good manufacturing practices (GMP)-
compliant cleanrooms and isolator
hoods as well as through the use of
closed culturing systems and automated,
inline quality attribute monitoring.
Contamination isn’t the only risk to
starting material quality. Cells are capa-
ble of responding to their environment,
and exposing cells to physiological
stress factors can lead to apoptosis and
loss of target cell function and potency.
For years, the mesenchymal stem
cell (MSC) therapy field struggled
with intermittent loss-of-function
issues, despite promising clinical trial
results for treating a host of differ-
ent diseases. Several research groups
reported that the cells were vulner-
able to loss of viability and function
following cryopreservation and sug-
gested that it might only be possible
to use MSCs that were freshly iso-
lated (9). Because this would pres-
ent obvious logistical problems for a
commercialized therapy, some intense
investigation followed. It was eventu-
ally determined that MSCs are partic-
ularly susceptible to heat stress during
cell thawing. Post-thaw recovery of
MSCs in culture for a 24-hour period
allows these cells to fully regain their
functional potency (10).
Cell therapy source material losses
resulting from sub-optimal cell pres-
er vation and storage techniques
can result in bottlenecks that slow
the entire manufacturing process.
Biopreservation and cryopreservation
cocktails, as well as cell freezing and
thawing methods, can have an enor-
mous impact on product quality and
efficacy. Similarly, shipping and stor-
age logistics can introduce risk to
these vulnerable products in the form
of unforeseen delays or inadequate
temperature regulation, which can
affect product stability, again leading
to loss of viability and functionality.
Because cryopreservation of therapeu-
tic cells is central to their successful
commercialization, cryopreservation
and shipping logistics need to be opti-
mized as early as possible during pro-
cess development.
PLANNING FOR SUCCESS
Cell sourcing and variability are two
of the most important challenges fac-
ing the fledgling cell therapy indus-
try. Inconsistent access or inconsistent
starting material quality can leave
manufacturers shorthanded, increas-
ing the risk of batch failure or missed
production deadlines. With increased
pressure on hospitals and other apher-
esis centers to procure greater quanti-
ties of high-quality target cells, these

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BP1219_030-035_Development_Hemacare.indd 33 12/6/19 9:41 AM

 Upstream Processing
centers are scrambling to increase
yields without sacrificing quality.
While ideally all donors would be
able to donate higher blood volumes
rich in the target cell population, real-
istically, donors with these character-
istics are not always readily available.
Manufacturers need to incorporate
collection methods that help counter
issues such as low volume yields or the
presence of contaminating cell types.
Cell collection efficiency refers to
the ratio of the target cell population to
contaminating cell types present in the
apheresis product as well as the ratio
of total yield of target cells collected
to those calculated to be present in the
donor’s circulation. Because contami-
nating cell types can slow or complicate
downstream isolation protocols, yield
and purity should be balanced with the
goal of consistently delivering maxi-
mum therapeutic efficacy to the patient.
The best way to protect cellular
starting material quality is to have
strong quality management systems
in place f rom start to finish (11).
Real-time monitoring and quality
control checkpoints using validated,
physiologically relevant functional
potency assays are a necessary part of
the process. Cell collection and pro-
cessing centers need to be tightly coor-
dinated to prevent loss of efficacy due
to raw material transfer logistics.
As the industry evolves, steps are
being taken to improve access to donor
materials and ensure their consistent
quality. Cell collection centers and
their pharmaceutical manufacturing
partners need to integrate and coor-
dinate their efforts early in the devel-
opment process. Establishing and
maintaining large, diverse donor net-
works involves proactive outreach to
potential donors by experienced, highly
trained staff. Training should include
expertise in donor selection and an
understanding of the impact of demo-
graphics and lifestyle characteristics
on cell yield and purity. It should also
cover collection methods, instrumen-
34 BioPharm International December 2019
BP1219_030-035_Development_Hemacare.indd 34
tation, data collection, and biological
sample handling and storage.
DISCUSSION
Cell and gene therapy companies are
still newcomers to the medical field.
As new products start emerging onto
the scale-up and marketing stage,
manufacturing and supply companies
are actively building the expertise and
infrastructure necessary for commer-
cial success.
Issues such as starting material
sourcing and quality validation will
require the integration of a number of
different strategies. One of the most
important strategies manufacturers
need to implement is investing signif-
icant resources early on for intensive
product testing and characterization,
including characterization of apheresis
materials that are the critical founda-
tion for the product.
Discerning which quality attributes
are the most critical and developing
quality control assays that accurately
assess these attributes throughout pro-
cess development and manufacturing
are crucial to commercial success. In
some ways this is an ongoing pro-
cess; scale-up may necessitate manu-
facturing changes that impact which
quality attributes are the most critical
to track, or whether further critical
quality attribute (CQA) assays need
to be appended to the quality con-
trol systems. This is where exhaus-
tive product characterization pays off.
Understanding the optimal operating
limits of critical reagents and meth-
ods can speed process adaptation and
product re-validation.
Cell-therapy starting material sourc-
ing is a tremendous challenge, but one
that can be mitigated through a variety
of integrated efforts. Hospitals and
apheresis clinics are set up to handle
patients; they are generally not pre-
pared to accommodate increased
demand for cell therapy starting mate-
rials. While one cannot always avoid
a hospital setting for the collection
of patient donor materials, perhaps a
new paradigm is necessary to transi-
tion away from hospitals as the main
resource for healthy donor materials,
and toward apheresis suppliers whose
business model is specifically geared
toward supporting cell and gene ther-
apy development.
Some larger-scale apheresis material
collection centers are already incor-
porating the preparation of GMP-
compliant materials on site, integrating
cell collection with GMP-compliant
preliminary processing (12). This pro-
vides the benefit of regulatory com-
pliance and assured quality from the
outset, while also avoiding the need to
transport collected apheresis products
to an off-site facility for preliminary
characterization, processing, and target
cell isolation procedures.
The development and standardiza-
tion of suitable sample handling pro-
tocols based on tissue and cell type is
another critical support issue for both
cell-therapy starting materials and final
product. Automation, process integra-
tion, closed-system design, and compli-
ance with current GMP can all be used
to safeguard cell-therapy product quality.
Regulatory guidelines issued by
FDA and other regulatory agencies
are still evolving to suitably accom-
modate advanced medicinal products
such as cellular therapies. Feedback
from newly approved products has led
to an increased emphasis on commer-
cial preparedness on the part of cell
therapy companies seeking expedited
approval in order to assure patients
are protected from supply chain short-
ages (13). As the cell and gene ther-
apy industry matures, manufacturing
and supply companies are putting in
place the physical infrastructure and
expertise needed to minimize variabil-
ity and expand starting-material sourc-
ing capabilities. Standardizing quality
control systems and nomenclature,
strengthening raw material and reagent
characterization, and optimizing sam-
ple handling methods will significantly
www.biopharminternational.com
12/6/19 9:41 AM

reduce risk for the industry. Close coop-
eration between research and develop-
ment labs, regulatory agencies, apheresis
supply centers, and manufacturing facil-
ities will drive successful commercializa-
tion of these much-needed therapies.
REFERENCES
1. FDA, “Statement from FDA Commissioner
Scott Gottlieb, MD, and Peter Marks,
MD, PhD, Director of the Center for
Biologics Evaluation and Research on
New Policies to Advance Development
of Safe and Effective Cell and Gene
Therapies,” Press Release, Jan. 15, 2019.
2. A. Philippidis, Genetic Engineering and
Biotechnology News 39 (7) (2019).
REGULATORY BEAT— Contin. from
page 8
and the public, FDA issued a report
in October 2019 examining the
financial, manufacturing, and pol-
icy issues underlying short supplies
of important prescription medi-
cines in the United States. The ana-
lysts found that of 163 drugs that
first went into shortage between
2013 and 2017, 62% of supply
disruptions were associated with
manufacturing or product quality
issues; only a few had problems due
to increased demand or natural
disasters (1).
A lead proposal from FDA offi-
cials is that manufacturers able
to ensure a reliable supply of
high-quality therapies should be
able to command higher prices,
an approach designed to encour-
age companies to invest in modern
production systems able to avoid
shortages, particularly for the low-
priced, low-profit sterile injectables
that companies often decide to
abandon, rather than commit to the
long-term upgrades needed to meet
standards. To support this approach,
FDA Acting Commissioner Ned
www.biopharminternational.com
BP1219_030-035_Development_Hemacare.indd 35
3. FDA, “2018 New Drug Therapy
Approvals,” www.fda.gov/
media/120357/download, 2019.
4. L. Scull, “Cell & Gene Therapy Sector
Overview,” Presentation for the
Alliance for Regenerative Medicine,
Feb. 27, 2019, https://alliancerm.
org/wp-content/uploads/2019/02/
ARM_BCA_CT_Workshop_FINAL.pdf.
5. ARM, “Regenerative Medicine &
Oncology,” http://alliancerm.org/
wp-content/uploads/2019/06/Oncology-
Report-FINAL.pdf, June 2019.
6. B. Taylor and D. Clarke, “Why is
Healthy Donor Tissue So Important
for Cell and Gene Therapies?”
Hemacare.com, June 27, 2019.
Sharpless and CDER Director Janet
Woodcock called for a system able
to measure and rate a facility’s
“quality management maturity”
that can inform the public about
its commitment to reliable quality
production (2).
In addition, the report included
more common actions to prevent
and address ongoing shortages, such
as permitting longer expiration
dates where justified or increasing
penalties on firms that fail to pro-
vide timely and adequate noti-
fication of a likely interruption in
production. FDA also could require
manufacturers of certain drugs to
conduct periodic risk assessments
to identify vulnerabilities in supply
chains and plans to mitigate such
risks. And new international stan-
dards for harmonizing post-approval
changes in drug manufacturing and
formulation, as proposed in a new
guideline (Q12) developed by mem-
bers of the International Council for
Harmonisation (ICH), would make it
easier for manufacturers to modern-
ize or alter a production facility that
serves multiple markets.
Manufacturers should “sell qual-
ity—not just medicine,” Woodcock
December 2019
Upstream Processing
7. E. Nah., et al., Ann Lab Med.
38 (6) 503–511 (2018).
8. L. Jamshidi and A. Seif, J Res
Med Sci. 19 (2) e4955 (2017).
9. R. Chinnadurai, et al., Stem Cells
34 (9) 2429–2442 (2016).
10. B. Antebi, et al. Journal of Translational
Medicine 17, 297 (2019).
11. D. Clarke and B. Taylor,
European Biopharmaceutical
Review, pp. 24–28 (2019).
12. HemaCare, “HemaCare Details Expanded
GMP Capabilities at CAR-TCR Summit in
Boston, MA.,” Press release, Sept. 4, 2018.
13. C. Bennett, “Cell Therapy Manufacturing:
The Supply Chain Challenge,”
GenEngNews.com, Nov.16, 2018. ◆
stated in an FDA “voices” posting
(3). Even though industry strongly
opposed an earlier CDER effort to
establish a system for rating com-
panies on their ability to achieve
qu a l it y d r ug m a nu f ac t u r i n g ,
Woodcock maintained that a firm’s
ability to reliably make a product
in sufficient quantities and with
sufficient speed to “ensure that sup-
ply consistently meets demand over
sustained periods of time” should
be a strong selling point. This dis-
cussion will continue in 2020.
REFERENCES
1. FDA, Report–Drug Shortages: Root
Causes and Potential Solutions, FDA.
gov, Oct. 29, 2019, www.fda.gov/drugs/
drug-shortages/report-drug-shortages-
root-causes-and-potential-solutions>
2 N. Sharpless and J. Woodcock,
“Statement on FDA’s New Report
Regarding Root Causes and Potential
Solutions to Drug Shortages,” Oct. 29,
2019, www.fda.gov/news-events/press-
announcements/statement-fdas-new-
report-regarding-root-causes-and-
potential-solutions-drug-shortages.
3. J. Woodcock, “To Help Reduce Drug
Shortages, We Need Manufacturers to
Sell Quality—Not Just Medicine, FDA
Voices,” FDA.gov, Oct. 24, 2019, www.
fda.gov/news-events/fda-voices-
perspectives-fda-leadership-and-
experts/help-reduce-drug-shortages-we-
need-manufacturers-sell-quality-not-
just-medicine.◆
BioPharm International 35
12/6/19 9:41 AM
 CORPORATE CAPABILITIES    www.biopharminternational.com

USP
About USP Services and Capabilities
USP is an independent scientific organization USP’s qua lit y sta ndards for biologics
whose standards, programs, advocacy and range from product-specific standards for
education efforts have helped increase the well-characterized biologics like insulin
availability of quality medicines, dietary and somatropin to performance standards
supplements, and foods for billions of people applicable to therapeutic drug product classes
worldwide. In keeping with its mission to such as monoclonal antibodies to standards
support and promote public health, USP that describe procedures and methods
docu menta r y sta nd a rd s a nd physic a l for demonstrating process performance
Reference Standards are trusted in more than throughout the product lifecycle. Our
140 countries to help ensure the identity, standards for biologics fall into several broad
purity, quality, and strength of medicines. categories including:
By providing a consistent benchmark for • Protein standards
analytical testing throughout the product • Peptide standards
lifecycle, USP standards protect the integrity • Blood-related standards
of the global supply chain for biologics and • Cell and tissue standards
help ensure the quality and consistency of • Glycosaminoglycan and carbohydrates
biotherapeutics for patients around the world. standards
• Raw and ancillary material standards
Markets Served • Vaccine standards
USP standards for biologics are publicly
available and relied upon by manufacturers,
regulatory agencies, healthcare professionals,
and others to verify and demonstrate the
quality of biopharmaceutical processes
and products. Standards are developed in
collaboration with international scientific
and healthcare experts to identif y and
address the evolving and increasingly
complex needs of the biopharmaceutical
industry. Future standards will evolve with
the science of biologics and needs of patients,
hea lthcare practitioners, industr y and
regulators.

USP
12601 Twinbrook Pkwy,
Rockville, MD 20852 USA
TELEPHONE
301.881.0666
EMAIL
MCG@usp.org
WEBSITE
www.usp.org/biologics

BioPharm International  December 2019

36   ADVERTORIAL

Contin. from page 38
The best trait to have as an
investigator is inquisitiveness.
Continuing to ask questions
and avoiding assumptions
leads to better outcomes.
Once you develop an investigational history with
the pre-filled syringe, you will also want to include
a historical review in your investigation. This review
should determine if the deviation occurred with this
or other products, with the specific manufacturing
line or other manufacturing lines, and/or with one
group of operators or multiple sets of operators. The
historical review can help you prioritize the resources
and aid in your detailed system review.
In the situation you described, you can provide a
historical review for the drug component part of the
pre-filled syringe, but you will need to outreach to
the syringe supplier and your client to start develop-
ing the historical review for the device component
until you have a body of knowledge for this compo-
nent. The best way to obtain necessary information
for the investigation of the device component is to
establish a communication channel between your
company and the supplier of the syringe, with your
client’s knowledge and approval. It would be wise
to codify what information you would like to have
access to through quality agreements with both the
syringe supplier and your client.
The detailed investigation should include a review
of various systems. The systems most often reviewed
are equipment and machinery, the manufacturing
process, the raw materials used in manufacturing,
the specifications, the environment, and finally, the
operators. This is not to imply that these systems are
the only areas you should look at during the inves-
tigation but that these are the most probable areas
where you will uncover the root cause of the devia-
tion. The raw material or supplier system may need
to be updated to accommodate the syringe supplier.
Rather than rely on the client’s evaluation and audit
of the syringe supplier, it would be beneficial for your
company to perform their own audit and assessment
and establish a quality agreement. Inform your client
www.biopharminternational.com
BP1219_037-038_AsktheExpert.indd 37
Ask the Expert
that you want to develop your relationship with the
syringe supplier to assure their assistance and timely
responses for an investigation; make sure you inform
your client when you do reach out to the supplier
during an investigation. This will help facilitate both
your client’s and the syringe supplier’s involvement
and open the lines of communication should you
require either of their assistance for an investigation.
Once the aforementioned elements have been
investigated, results from the investigation must be
documented. The written narrative should clearly
explain what happened, when it happened, and who
was involved or observed what happened. The narra-
tive documents the solution and rationale for the root
cause that was determined through the investigation
process. This should also include any action being
taken by the syringe supplier should this component
be implicated in the investigation.
The key to any successful investigation is not stop-
ping too soon and assuming you have the solution
prior to completing the investigation. Ask questions
until you can think of no more questions to ask and
be sure to document the answers to your questions. If
you follow your investigation procedure, make adjust-
ments to accommodate the new component, and
thoroughly document your results, you should have
an acceptable investigation regardless of whether you
are manufacturing a traditional product or a combi-
nation product.◆
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December 2019 BioPharm International 37
12/6/19 9:41 AM
 Ask the Expert
Investigating Combination Product Failures
Investigating deviations or failures of combination products needs
to accommodate both the drug and device components, says Susan
J. Schniepp, executive vice-president of post-approval pharma
and distinguished fellow, Regulatory Compliance Associates.
Q
: I work for a contract manufacturer and
am responsible for performing investi-
gations and reporting the results to the
clients regarding their drug products. We have
recently contracted with a client to manufac-
ture a pre-filled syringe. Can you tell me what
changes I should make to my investigation pro-
cedure when investigating deviations and com-
plaints for this type of combination product?
A
: Overall, the actual investigation pro-
cess for a pre-filled syringe product
should be similar to the process already
used by you to investigate the drug products.
The purpose of performing an investigation
into a deviation is to determine why the devia-
tion happened and what impact it has on the
product quality. To determine the impact of the
deviation on the product quality, it is important
to determine the ‘root cause’ of the deviation.
The process used in industry to determine the
root cause is the investigation procedure. This
procedure, regardless of the product you are
investigating, should require the investigator
to review various quality and manufacturing
systems to determine whether they were the
cause of the deviation under investigation. Each
investigation must address the following ele-
ments: root cause, impact to the material or
product, the immediate correction taken, the
corrective action to prevent re-occurrence for
specific product/operation, and the preventive
action taken to prevent re-occurrence for all
products/operations. The complication with
combination products is that the investigation
procedure needs to accommodate both the drug
and device components of the product.
It is important to consider a few general rules
when performing an investigation regardless
of the product being investigated. Remember,
38 BioPharm International December 2019
BP1219_037-038_AsktheExpert.indd 38
Susan J. Schniepp,
executive vice-president
of post-approval pharma
and distinguished
fellow, Regulatory
Compliance Associates.
one size does not fit all. Simple errors require
simple corrections while serious deviations
require broader investigations. The complexity
of the investigation is related not only to the
seriousness of the investigation but also to the
complexity of the factors that could influence
the outcome.
In performing an
investigation, it is important
for the investigator to widen
their perspective and look for
ways to relate similar issues.
The best trait to have as an investigator is
inquisitiveness. Continuing to ask questions and
avoiding assumptions leads to better outcomes.
Using other tools, such as fishbone diagrams
and determination of most probable number
(MPN), are to be encouraged, but they do not
take the place of asking questions. In performing
an investigation, it is important for the investiga-
tor to widen their perspective and look for ways
to relate similar issues. The best way to ensure
events are not related is to try and relate them,
not the other way around. Keep in mind that
human error is rarely a true root cause. There is
usually something in the process that causes that
Fanatic Studio/Getty Images
human error. In addition, you should always
verify the facts of the investigation.
Contin. on page 37
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12/6/19 9:41 AM
 USP Biologics is using our wealth of experience
in standards development to push the future of
therapy forward for tomorrow’s innovations.

Become involved with USP Biologics

• Collaborating with you to face the challenges of
today’s biologics
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characterized standards
• Providing you with educational services and
support throughout the product lifecycle

Learn how USP Biologics

can support you at usp.org/biologics-bp2

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