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The Science & Business of Biopharmaceuticals
INTERNATIONAL
November 2017
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The Science & Business of Biopharmaceuticals
INTERNATIONAL
November 2017
Volume 30 Number 11
DELIVERING BIOLOGICS IN PREFILLED SYRINGES
EXPRESSION SYSTEMS
PLATFORM TECHNOLOGIES
IMPROVE PROTEIN
EXPRESSION
CLEANING VALIDATION
EVALUATING SURFACE
CLEANLINESS USING
A RISK-BASED APPROACH
CLINICAL TRIAL LOGISTICS
MOVING TOWARD
DIRECT-TO-PATIENT
MODELS
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INTERNATIONAL
BioPharmThe Science & Business of Biopharmaceuticals
EDITORIAL
Editorial Director Rita Peters [email protected]
Senior Editor Agnes M. Shanley [email protected]
Managing Editor Susan Haigney [email protected]
Science Editor Feliza Mirasol [email protected]
Science Editor Adeline Siew, PhD [email protected]
Manufacturing Editor Jennifer Markarian [email protected]
Associate Editor Amber Lowry [email protected]
Art Director Dan Ward [email protected]
Contributing Editors Jill Wechsler, Jim Miller, Eric Langer, Anurag Rathore, and Cynthia A. Challener, PhD
Correspondent Sean Milmo (Europe, [email protected])
ADVERTISING
Publisher Mike Tracey [email protected]
National Sales Manager Steve Hermer [email protected]
East Coast Sales Manager Scott Vail [email protected]
European Sales Manager Linda Hewitt [email protected]
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© 2017 UBM. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical including by photocopy, recording, or information storage and retrieval without permission in writing from the publisher. Authorization to photocopy items for internal/educational or personal use, or the internal /educational or personal use of specific clients is granted by UBM for libraries and other users registered with the Copyright Clearance Center, 222 Rosewood Dr. Danvers, MA 01923, 978-750-8400 fax 978-646-8700 or visit http://www.copyright.com online. For uses beyond those listed above, please direct your written request to Permission Dept. fax 440-756-5255 or email: [email protected].
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EDITORIAL ADVISORY BOARDBioPharm International’s Editorial Advisory Board comprises distinguished
specialists involved in the biologic manufacture of therapeutic drugs,
diagnostics, and vaccines. Members serve as a sounding board for the
editors and advise them on biotechnology trends, identify potential
authors, and review manuscripts submitted for publication.
K. A. Ajit-SimhPresident, Shiba Associates
Madhavan BuddhaFreelance Consultant
Rory BudihandojoDirector, Quality and EHS Audit
Boehringer-Ingelheim
Edward G. CalamaiManaging Partner
Pharmaceutical Manufacturing
and Compliance Associates, LLC
Suggy S. ChraiPresident and CEO
The Chrai Associates
Leonard J. GorenGlobal Leader, Human Identity
Division, GE Healthcare
Uwe GottschalkVice-President,
Chief Technology Officer,
Pharma/Biotech
Lonza AG
Fiona M. GreerGlobal Director,
BioPharma Services Development
SGS Life Science Services
Rajesh K. GuptaVaccinnologist and Microbiologist
Denny KraichelyAssociate Director
Johnson & Johnson
Stephan O. KrauseDirector of QA Technology
AstraZeneca Biologics
Steven S. KuwaharaPrincipal Consultant
GXP BioTechnology LLC
Eric S. LangerPresident and Managing Partner
BioPlan Associates, Inc.
Howard L. LevinePresident
BioProcess Technology Consultants
Hank LiuHead of Quality ControlSanofi Pasteur
Herb LutzPrincipal Consulting Engineer
Merck Millipore
Hanns-Christian MahlerHead Drug Product Services
Lonza AG
Jerold Martin
Independent Consultant
Hans-Peter MeyerLecturer, University of Applied Sciences
and Arts Western Switzerland,
Institute of Life Technologies.
K. John MorrowPresident, Newport Biotech
David RadspinnerGlobal Head of Sales—Bioproduction
Thermo Fisher Scientific
Tom RansohoffVice-President and Senior Consultant
BioProcess Technology Consultants
Anurag RathoreBiotech CMC Consultant
Faculty Member, Indian Institute of
Technology
Susan J. SchnieppFellow
Regulatory Compliance Associates, Inc.
Tim SchofieldSenior Fellow
MedImmune LLC
Paula ShadlePrincipal Consultant,
Shadle Consulting
Alexander F. SitoPresident,
BioValidation
Michiel E. UlteePrincipal
Ulteemit BioConsulting
Thomas J. Vanden BoomVP, Biosimilars Pharmaceutical Sciences
Pfizer
Krish VenkatManaging Partner
Anven Research
Steven WalfishPrincipal Scientific Liaison
USP
ES988326_BP1117_003.pgs 11.08.2017 00:44 ADV blackyellowmagentacyan
4 BioPharm International www.biopharminternational.com November 2017
Contents
BioPharmINTERNATIONAL
BioPharm International integrates the science and business of
biopharmaceutical research, development, and manufacturing. We provide practical,
peer-reviewed technical solutions to enable biopharmaceutical professionals
to perform their jobs more effectively.
COLUMNS AND DEPARTMENTS
BioPharm International ISSN 1542-166X (print); ISSN 1939-1862 (digital) is published monthly by UBM LLC 131 W. First Street, Duluth, MN 55802-2065. Subscription rates: $76 for one year in the United States and Possessions; $103 for one year in Canada and Mexico; all other countries $146 for one year. Single copies (prepaid only): $8 in the United States; $10 all other countries. Back issues, if available: $21 in the United States, $26 all other countries. Add $6.75 per order for shipping and handling. Periodicals postage paid at Duluth, MN 55806, and additional mailing offices. Postmaster Please send address changes to BioPharm International, PO Box 6128, Duluth, MN 55806-6128, USA. PUBLICATIONS MAIL AGREEMENT NO. 40612608, Return Undeliverable Canadian Addresses to: IMEX Global Solutions, P. O. Box 25542, London, ON N6C 6B2, CANADA. Canadian GST number: R-124213133RT001. Printed in U.S.A.
BioPharm International is selectively abstracted or indexed in: • Biological Sciences Database (Cambridge 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)
Cover: Dmitry Lobanov/Shutterstock.com
6 From the Editor
CPhI Pharma Awards honor companies and individuals driving the pharma industry forward. Rita Peters
8 Regulatory Beat
FDA seeks to focus on problematic facilities and inform firms quickly about site problems. Jill Wechsler
10 Perspectives on Outsourcing
Recent acquisitions are creating CDMOs with scale that rivals global bio/pharma.Jim Miller
52 Product Spotlight
53 New Technology Showcase
53 Ad Index
54 Ask the Expert
The level of formality in change control may be holding back your SOP progress, according to Siegfried Schmitt, principal consultant at PAREXEL.
DRUG DELIVERY
Delivering Biologics
in Prefilled Syringes
Adeline SiewSiliconization is a key process
step in the manufacturing
of prefilled syringe systems. 14
EXPRESSION SYSTEMS
Platform Technologies
Improve Protein
Expression
Cynthia ChallenerPlatform technologies facilitate
development and accelerate
commercialization of protein
therapeutics. 20
DOWNSTREAM PROCESSING
Connector Integrity
in Single-Use
Biomanufacturing Systems
Feliza MirasolConnectors are a critical element
in the process optimization of
single-use bioprocessing systems. 24
MANUFACTURING
ADC Development
Robust Despite
Lackluster Performance
Feliza MirasolDespite the disappointing therapeutic
performance of ADCs thus far, the
pipeline still boasts promising prospects. 28
CLEANING VALIDATION
AND MONITORING
Evaluating Surface
Cleanliness Using a
Risk-Based Approach
Elizabeth Rivera and Paul LopolitoRinse sample analysis or visual
inspection can be correlated to surface
cleanliness to replace surface sampling. 36
CLINICAL TRIAL LOGISTICS
Moving Toward
Direct-to-Patient Models
Agnes ShanleyDespite GxP and data-management
challenges, pharma is moving toward
new models for clinical trial logistics. 48
Volume 30 Number 11 November 2017
FEATURES
The Science & Business of Biopharmaceuticals
INTERNATIONAL
November 2017
Volume 30 Number 11
DELIVERING BIOLOGICS IN PREFILLED SYRINGES
EXPRESSION SYSTEMS
PLATFORM TECHNOLOGIES
IMPROVE PROTEIN
EXPRESSION
CLEANING VALIDATION
EVALUATING SURFACE
CLEANLINESS USING A
RISK-BASED APPROACH
CLINICAL TRIAL LOGISTICS
MOVING TOWARD
DIRECT-TO-PATIENT
MODELS
www.biopharminternational.com
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6 BioPharm International www.biopharminternational.com November 2017
From the Editor
CPhI Pharma
Awards honor
companies and
individuals driving
the pharma
industry forward.
Awards Recognize Bio/Pharma Industry Contributions
Recipients of the 14th annual 2017 CPhI Pharma Awards were announced
on Oct. 24, 2017 at an awards ceremony at the CPhI Worldwide trade
show in Frankfurt, Germany. More than 200 entries were received in
2017—twice the number of entries in 2016—and included innovations in
products and services for drug formulation, development, manufacturing, drug
delivery, packaging, and distribution. In addition, bio/pharma executives and
companies were honored for their business, scientific, and social contributions.
The awards were expanded to nearly 20 categories for 2017 to reflect the
increased diversity of attendees at CPhI Worldwide, the organizers report.
Separate awards were presented for innovation in formulation and excipients.
New categories recognized sustainability practices, export promotion, over-
the-counter drugs, patient centricity, and IT, mHealth, and digitalization.
The entries were reviewed by a panel of independent judges from
pharma, industry suppliers, testing labs, and the media, including BioPharm
International. A list of finalists was announced in September 2017. The winners
were revealed during a gala awards ceremony.
The 2017 CPhI Pharma Award recipients are as follows:
Analysis, Testing, and Quality Control—FlexiQuot: New disruptive technology
that revolutionizes sample storage and handling, 1CryoBio
API Development—Development of a new, efficient synthesis of ospemifene,
Cambrex
Bioprocessing—Modular automated sampling technology (MAST) platform
for the biopharma industry, Capsugel/Bend Research (Lonza)
CEO of the Year—Richard Chin, CEO of KindredBio
Contract Services and Outsourcing—Modified supercritical anti-solvent
(mSAS) technology for accelerated product development, Crystec Ltd.
Corporate Social Responsibility—HepC battle, Laboratories Pharma5
Drug Delivery Devices—Single-use inhaler (DPI) Perlamed-BLISTair, Perlen
Packaging
Excipients—Opadry QX for tablet film coating, Colorcon
Export Promotion—Waste water treatment plants, Rachana Overseas Inc.
Formulation—Orbis’ Optimum Platform: Delivering dispersed dosage forms
with functional coatings in a single manufacturing step, Orbis Biosciences
IT, mHealth, and Digitilization—Biocorp’s line of connected products, Biocorp
Manufacturing Technology and Equipment—MicroJet Reactor technology with
efficient control on particle size and homogeneity of particle size distribution,
MJR PharmJet
OTC—Innovation in wart treatment, Pronova Laboratories
Packaging—Side actuation device: Innovation in ophthalmic drug-delivery
devices, Aero Pump GmbH
Patient Centricity—Target My Hives, ERT
Pharma Company of the Year, SME—BenevolentAI
Regulatory Procedures and Compliance—Quality and Regulatory-A Means for
Value Creation, Piramal Enterprises
Supply Chain, Logistics, and Distribution—Industry’s first compliance and dig-
ital information platform for the EU Falsified Medicines Directive, TraceLink
Sustainability Initiative of the Year—AptarGroup’s Landfill Free Certification:
promoting efficiencies and the conservation of natural resources in a global
manufacturing setting, AptarGroup.
The editors congratulate the awards finalists and winners. Additional infor-
mation about the winning technologies will be published in future issues of
BioPharm International and on www.biopharminternational.com.
CPhI and BioPharm International are UBM plc brands. ◆
Rita Peters is the
editorial director of
BioPharm International.
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8 BioPharm International www.biopharminternational.com November 2017
Regulatory Beat
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To ensure the quality and safety of drugs,
biologics, and medical products more
efficiently and effectively, FDA is making
significant changes in its plant inspection pro-
gram, including more attention to imports and
to foreign producers of drugs for American con-
sumers. An aim is to target manufacturing over-
sight to more high-risk operations and free up
resources for greater scrutiny of foreign facilities
in the process. Agency officials also seek to bet-
ter coordinate and clarify the roles of field inves-
tigators and staff from FDA’s Center for Drug
Evaluation and Research (CDER) (as well as other
agency review centers) in selecting sites, weigh-
ing compliance action, and communicating
inspection findings to firms. And increased FDA
collaboration with foreign regulatory inspector-
ates promises to reduce redundant site visits and
increase oversight of violative situations.
FIELD REALIGNMENTAfter several years of planning, FDA’s Office of
Regulatory Affairs (ORA), which manages the
agency’s 5000 field inspectors, officially imple-
mented its Program Alignment (PA) initiative
in May 2017. This major reorganiza-
tion shifts ORA from a geographi-
cally-based inspection operation to
a program aligned by commodities
and vertically integrated, with more
specialized investigators able to iden-
tify and provide more timely infor-
mation on critical manufacturing
issues. Specialized inspection cadres
for drugs, biologics, medical devices,
food, bioresearch monitoring, and
tobacco continue to operate out of
ORA’s 20 district offices across the
United States, with certain offices
housing program managers that lead
product inspection teams (1).
Drugs regulated by CDER and the Center for
Veterinary Medicine (CVM), for example, are
managed by the Office of Pharmaceutical Quality
Operations (OPQO), directed by long-time ORA
official Alonza Cruse. He oversees four divi-
sions of pharmaceutical quality operations, each
headed by a regional manager, plus a division
for quality programs (for compounders and pre-
approval inspections) and a division for foreign
inspections, Cruse explained at the PDA/FDA reg-
ulatory conference in September 2017. The aim
is to achieve more consistent and timely inspec-
tions with reduced uncertainty for industry.
Similarly, ORA’s Office of Biological Products
Operations, headed by Ginette Michaud, has two
operating divisions to oversee the production
of blood products, tissues, vaccines, and other
products regulated by the Center for Biologics
Evaluation and Research (CBER). The Office
of Bioresearch Monitoring Operations under
Chrissy Cochran also has two divisions, while
the Office of Medical Devices and Radiological
Health Operations has three divisions.
A key goal of the reorganization is to enhance
communication and collaboration between field
inspectors and center product specialists. This
approach for drugs is spelled out in a “Concept of
Operations” white paper released in August 2017
(2). The 20-page report maps out how ORA and
CDER staffers will collaborate in the planning
and conduct of inspections and the communica-
tion of findings to manufacturers, with decision
trees for managing each of the four types of
inspections. Increased integration of drug review
and facility evaluations aims to achieve more
consistency and certainty in regulatory decisions,
commented FDA Commissioner Scott Gottlieb (3).
For preapproval inspections (PAIs), a CDER
team, including staffers from the Office of Process
and Facilities (OPF) in the Office of Product
Quality (OPQ), prepares an integrated quality
FDA Overhauls Inspection Process and Field OperationsFDA seeks to focus on problematic facilities and inform firms quickly about site problems.
Jill Wechsler
is BioPharm International’s
Washington editor,
Chevy Chase, MD, 301.656.4634,
November 2017 www.biopharminternational.com BioPharm International 9
Regulatory Beat
assessment. This assessment reviews
information in an application on
facilities, processes, and microbiol-
ogy, plus past inspection reports, to
determine whether a PAI is needed
for each site listed in the submission.
ORA leads any necessary inspection,
with CDER participation, and com-
municates findings to the assessment
team. A similar process is involved in
planning for and conducting post-
approval facility inspections, which
may occur following manufacturing
changes, particularly for a facility
where a PAI has not taken place.
For GMP surveillance inspec-
tions, OPQ’s Office of Surveillance
(OS) collaborates with ORA to
determine the need, timing, and
scope of site visits, based on a facil-
ity’s inspection history, type of
products produced, and risks previ-
ously reported. ORA investigators
generally conduct these inspec-
tions, informing CDER’s Office of
Compliance (OC) if they observe
questionable situations. ORA also
leads for-cause inspections, inter-
acting with CDER’s OPQ and OC.
To ensure timely inspections of
facilities listed in new drug appli-
cations, FDA and industry agreed
in the new prescription drug user
fee program to delay application
approval if a sponsor fails to iden-
tify all relevant sites in a submis-
sion. The aim is to provide complete
facility information for ORA to have
sufficient time to inspect and evalu-
ate relevant production sites. The
Generic Drug User Fee Amendments
(GDUFA II) further establish a pre-
submission correspondence pro-
cess that requires manufacturers of
critical drugs qualifying for priority
approval to submit information on
planned production facilities two
months before filing the applica-
tion—again, to support timely
inspection of relevant production
sites in tight timeframes.
A more efficient field inspection
program also aims to communicate
inspection findings to manufactur-
ers more quickly. GDUFA II specifies
that FDA will provide surveillance
inspection findings to facility own-
ers within 90 days of completing a
site visit, beginning October 2018,
and CDER officials expect to apply
that goal to all drugs. The aim is for
ORA to submit recommendations
to CDER within 45 days of post-
approval and surveillance inspec-
tions so that staff can follow up
quickly with the manufacturer.
INTERNATIONAL COLLABORATIONThe need to oversee the growing
number of overseas pharmaceuti-
cal manufacturers also is prompt-
ing US and European regulatory
authorities to collaborate more on
drug inspection activities. FDA and
the European Medicines Agency
(EMA) are moving forward with
a Mutual Recognition Agreement
(MRA) that will permit partici-
pants to rely more on each other’s
inspection reports. By reducing the
need to inspect all of more than
1000 registered drug production
facilities in Europe, FDA would
avoid duplicate site visits and free
up resources to support greater
oversight of firms in China, India,
and other nations.
US and EU officials signed an
agreement in March 2017 to extend
and conclude the MRA negotiating
process by July 2019 (4). The pro-
cess involves FDA observing how
EU member states inspect local
facilities, and for EU officials to
audit FDA’s inspection program.
The two authorities also agreed
in August 2017 to protect confi-
dential information in inspection
reports from public disclosure,
which is important for sharing
full inspection reports needed to
decide whether or not to visit sites
on each other’s inspection sched-
ules. The EU completed its assess-
ment of FDA inspection operations
in July 2017, and FDA hopes to fin-
ish its audits of the 28 EU member
states by mid-2019.
The current MRA initiative
applies to GMP surveillance inspec-
tions for most drugs and biotech
therapies, but could be extended
to vaccines and veterinary prod-
ucts in the future. An important
side-benefit of the final agreement
may be to end EU batch inspection
of US-made products shipped to
Europe. In the future, pre-approval
inspections might be covered in
certain situations, prompting FDA
and EU officials to examine how
PAIs differ or are the same in the
two regions. FDA’s need to com-
plete such inspections in limited
timeframes could lead to an agree-
ment that permits FDA or EMA to
request that a capable authority
conduct a PAI by a certain date.
More information on the MRA is
available on FDA’s website (5, 6).
REFERENCES 1. FDA, ORA Program Division Boundary
Maps and Fact Sheets, FDA.gov, www.fda.gov/AboutFDA/CentersOffices/Of-ficeofGlobalRegulatoryOperationsand-Policy/ORA/ucm557997.htm
2. FDA, Integration of FDA Facility Eval-uation and Inspection Program for Human Drugs: a Concept of Opera-tions, CDER, June 2, 2017, www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperation-sandPolicy/ORA/UCM574362.pdf
3. S. Gottlieb, “New Steps To Strengthen FDA’s Inspection And Oversight Of Drug Manufacturing,” FDAVoice blog, FDA.gov, https://blogs.fda.gov/fdavoice/index.php/2017/08/
4. FDA, “Mutual Recognition promises new framework for pharmaceutical in-spections for United States and European Union,” News Release, March 2, 2017, www.fda.gov/newsevents/newsroom/pressannouncements/ucm544357.htm.
5. FDA, Frequently Asked Questions/The Mutual Recognition Agreement, March 2, 2017, www.fda.gov/down-loads/aboutfda/centersoffices/officeof-globalregulatoryoperationsandpolicy/ucm544394.pdf
6. FDA, Office of Global Regulatory Op-erations and Policy (GO), www.fda.gov/aboutfda/centersoffices/officeofglobal-regulatoryoperationsandpolicy/default.htm. ◆
10 BioPharm International www.biopharminternational.com November 2017
Perspectives on Outsourcing
Do
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This has been another big year for acqui-
sitions in the contract development and
manufacturing organization (CDMO)
industry. In the first three quarters of 2017,
there have been 25 deals in which a CDMO
was the acquisition target (see Figure 1). With
just three months left in 2017, the final num-
ber of deals is likely to trail 2016 (34 CDMO
acquisitions), but the total value of the transac-
tions is likely to exceed $20 billion, which will
far exceed 2016’s total. Average deal multiples
look to be about 13.5x EBITDA (earnings before
interest, taxes, depreciation, and amortization),
a big premium above the 10x multiple at which
private equity investors typically value acquisi-
tions; a number of deals have come in at mul-
tiples in the 15x–25x range.
Aside from the sheer size of the transactions,
deals in 2017 are most notable because they
may have finally created some CDMOs with the
scale, breadth, and financial wherewithal to be
strategic manufacturing partners to global bio/
pharma companies. Global bio/pharma com-
panies represent the last frontier
for CDMOs: they outsource only
approximately 25% of their drug
product manufacturing require-
ments, compared to 70–80% for
small and mid-size bio/pharma
companies, and they use CDMOs
to manufacture fewer than 15% of
their biologics products.
CDMOs are fighting ingrained
culture and deep pockets when
trying to get global bio/pharma
companies to outsource more of
their manufacturing requirements,
but they are also handicapped by
scale and scope. An average size
global bio/pharma company (top
25 by revenue) has approximately
$20 billion in revenues and $3.5–4.0 billion in
cost of goods, plus as much as another $1 bil-
lion for developing and manufacturing clini-
cal candidates. That means the manufacturing
requirements of that average global bio/pharma
company are two to three times the revenues
of the three largest CDMOs, which all had rev-
enues of $1.5–2 billion prior to the latest round
of acquisitions. Even those largest CDMOs had
limited capabilities (only API, no dose; or strong
solid oral dose, limited injectable, and API), and
companies in the next tier of CDMOs ($500 mil-
lion–$1 billion range) had even more limited
capabilities and/or significant financial issues.
Global bio/pharma companies are struggling
to manage complex supply chains with hun-
dreds of vendors, but the limited scale and
scope of most CDMOs left the global companies
with few choices for consolidating their sup-
ply base without becoming too big a piece of
a given CDMO’s business. Thanks to the latest
round of acquisitions, however, the industry
now has some participants that, either on their
own or in concert with their parent companies,
have the scale, scope of capability, and finan-
cial sophistication to be taken more seriously
by global bio/pharma companies. Consider the
Creating
large-scale suppliers
will be crucial to
cracking the global
bio/pharma market.
CDMO Acquisitions Build Strategic Supplier BaseRecent acquisitions are creating CDMOs with scale that rivals global bio/pharma.
Jim Miller is president of PharmSource,
A GlobalData Company, and
publisher of Bio/Pharmaceutical
Outsourcing Report,
tel. 703.383.4903,
Twitter@JimPharmSource,
www.pharmsource.com.
This lab manager is:
Enjoying a long lunch
Catching up with coworkers
Analyzing 1,536 samples
All of the above
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12 BioPharm International www.biopharminternational.com November 2017
Fig
ure
co
urt
esy o
f th
e a
uth
or
Perspectives on Outsourcing
implications of some of the major
deals in 2017.
LONZA–CAPSUGEL Capsugel’s $1 billion in revenues
pushes Lonza’s total revenues past
the $5-billion threshold, giving it
manufacturing scale equivalent
to a $25 billion bio/pharma com-
pany. It also expends its scope by
bringing dose form capabilities,
including softgels and solubility-
enhancing technologies such
as spray-drying, and its market-
leading hard gelatin capsule busi-
ness; all of those are key inputs for
prescription pharmaceuticals and
nutraceuticals and a big part of any
bio/pharma company’s procure-
ment spend.
THERMO FISHER–PATHEONCombining Patheon with Thermo
Fisher’s clinical supplies business
fills a major gap in Patheon’s ser-
vice portfolio and creates a CDMO
with $3 billion in revenue, compa-
rable in size to Lonza’s pharma and
biotech segment. Patheon is now
better-positioned in the market for
clinical development, manufactur-
ing, and packaging services, which
is becoming more important as a
feeder into a CDMOs commercial
manufacturing pipeline. As impor-
tantly, Patheon is now a significant
part of a $20-billion supplier of
life-sciences products and services
to the bio/pharma industry, rather
than a $2-billion standalone CDMO.
CARLYLE GROUP–AMRIAcquisitions by private equity firms
aren’t usually viewed as strategic,
but a deal with a firm of the size
and reputation of Carlyle could be
transformational for AMRI. Carlyle
will bring more financial savvy
and operational focus to the com-
pany, which should strengthen it
for the long term. The transfor-
mational opportunity will come
about if Carlyle is able to bring in
an executive team of significant
stature and experience to drive
the company to the next level, as
Blackstone did for Catalent and JLL
Partners did for Patheon.
CATALENT–COOK PHARMICA Catalent’s acquisition of Cook
Pharmica, despite its nearly $1-bil-
lion price tag, is not as transforma-
tional as some of the other recent
deals: the company already has a
growing biomanufacturing busi-
ness, and the near-term revenue
increment is much smaller than in
the other cases. However, the deal
makes Catalent a more complete
provider in the biopharmaceuticals
market as the addition of North
American injectables and bioman-
ufacturing capacity complement
its existing biomanufacturing and
analytical capabilities.
EUROFINS–MULTIPLE CDMOS Eurofins is worth noting not
because of any one large deal but
because of the way it has built a
CDMO offering through a series
of small acquisitions. Eurofins
built its GMP analytical services
capability around its acquisition of
Lancaster Laboratories in 2011, but
in the past two years, it has broad-
ened its chemistry, manufacturing,
and controls (CMC) portfolio into
process development, formulation,
and clinical manufacturing ser-
vices by acquiring companies like
Sinesis Life Sciences (Netherlands),
Advantar Laborator ies (USA),
Alphora Research (Canada), and
Amatsigroup (France and Belgium).
Eurofins, with revenues exceeding
$2.5 billion, may be able to lever-
age its strong position providing
analytical and bioanalytical ser-
vices to global bio/pharma com-
panies to get more of its clients’
development business.
The current financial market
environment has been favorable
to large-scale acquisition activity,
and one might expect to see a few
more large deals that consolidate
the top end of the CDMO industry.
However, the number of large and
attractive acquisition targets is lim-
ited, which will limit the number
of transformational deals in the
near term. There is no doubt, how-
ever, that creating large-scale sup-
pliers will be crucial to cracking
the global bio/pharma market. ◆
Discovery, 9
Clinical, 7
SM API, 6
Bio API, 5
Develop, 5
Dose, 9
Source: PharmSource Strategic Advantage database.
Figure 1: Bio/pharma acquisitions in 2017, as of October 2017. SM is small
molecule.
Do you know whom to trust with
your complex compound?
By the time your compound gets to clinical development, you’ve already
invested years of painstaking work. Yet the next phase is filled with unpredictability
and challenges. So what can you do to help smooth your compound’s path to clinic
and beyond?
With Vetter, you get the advantages of working with a partner who knows how to
take your compound from preclinical to clinical to commercial manufacturing:
Q Expertise in the development of a broad range of drugs, including sensitive biologics
Q Technology, processes, and resources to achieve developmental milestones
Q Clinical manufacturing facilities in the US and Germany
When it comes to your injectable compound, turn to the partner
trusted by top biopharmaceutical companies. Turn to Vetter.
Answers that workwww.vetter-pharma.com
US inquiries: [email protected] �• Asia Pacific inquiries: [email protected] �•
Japan inquiries: [email protected] �• EU and other international inquiries: [email protected]
14 BioPharm International www.biopharminternational.com November 2017
Dm
itry
Lo
ban
ov/S
hu
tters
tock.c
om
Biologics are fast becoming the
driving force of the pharmaceu-
tical industry. Because the pri-
mary route of administration
for most biologics is still by injection,
there is a demand for advanced drug-
delivery systems that offer convenience
and ease of administration. Prefilled
syringes have gained strong acceptance
as delivery systems for injectable drugs,
especially in the treatment of chronic
conditions that require repeated admin-
istration of the medication.
ADVANTAGES OF PREFILLED SYRINGES“Prefilled syringes make injection
easier and safer for both doctors and
patients by ensuring the patient always
receives the right dosage,” says Fabian
Stöcker, head of Strategic Marketing &
Innovation, Schott. “Additionally, pre-
filled syringes work well with increasingly
popular safety devices and auto-injection
systems, making injections easy, safe, and
convenient.” He notes that pharmaceuti-
cal companies also stand to benefit from
prefilled syringes. “Compared to vials,
they can reduce overfill, which can be
particularly costly in biopharmaceuticals.
Also, customized delivery systems and
prefilled syringes are helping pharma-
ceutical companies in the biotech indus-
try deliver personalized drugs tailored to
smaller patient populations,” Stöcker says.
Prefilled syringes can potentially
offer better patient experiences than
traditional means, observes Graham
Reynolds, vice-president and general
manager, Global Biologics at West
Pharmaceutical Services, Inc. “There is
Delivering Biologics in Prefilled Syringes
Adeline Siew, PhD
Siliconization is a key process
step in the manufacturing
of prefilled syringe systems.
Drug Delivery
November 2017 www.biopharminternational.com BioPharm International 15
some degree of variability when
removing a drug product from a
vial with a conventional dispos-
able needle and syringe. With a
prefilled syringe system, the very
nature of its design eliminates
the withdrawal step and deliv-
ers the drug product directly to
the patient, which can result in
a more accurate dose of the drug
with less exposure to needles,”
he explains.
Reynolds adds that because some
biologic drug products are in short
supply and can be very costly to
produce, manufacturers are seek-
ing innovations to minimize waste.
“Prefilled syringes, with their pre-
measured dosage, have the poten-
tial to reduce dosing errors and
increase patient compliance while
potentially saving manufacturers
money,” he says. “Unlike single- or
multi-dose vials that may require
drug product overfill by as much
as 30% to ensure adequate with-
drawal, a prefilled syringe can vir-
tually eliminate the need for excess
overfill, thus conserving expensive
drug products. This is important
where manufacturing and product
costs are high and bulk manufac-
turing capacity is limited.”
GLASS VERSUS PLASTICGlass prefilled syringes continue
to dominate the market, but there
is a shift toward the increasing use
of plastic as an alternative material
for prefilled syringes because of
its robustness against breakabil-
ity while delivering consistent sta-
bility and performance for many
drug products. The two types of
polymers mainly used to make
plastic syringes are cyclo olefin
polymer (COP) and cyclo olefin
co-polymer (COC).
Stöcker acknowledges that glass
and polymer both have their
strengths. “The right material for
a syringe depends on the appli-
cation,” he says. “The excellent
barrier properties of glass and
regulatory ease make it the first
choice for drug manufacturers,
but the polymer’s stability and
inert properties, as well as its wide
design options, make it an attrac-
tive choice as well.” Stöcker cites
the example of the anticoagulant
heparin, which has been stored in
glass prefilled syringes for decades
without any major recalls or drug
contamination cases, making glass
an easy choice. Dermal fillers,
on the other hand, are typically
highly viscous substances that
need to be stored in packaging
that allows for consistent gliding
force and a robust luer lock, which
is integrated in a polymer syringe.
In this case, polymer is the mate-
rial of choice, according to him.
Stöcker recommends a holistic
evaluation along the three Ps—
product, process, and patient—to
find the best solution. He explains
that a number of aspects needs to
be considered, such as:
• W hether or not the d r ug
requires particularly inert pack-
aging materials
• The importance of design flex-
ibility, tighter tolerances, and
superior break resistance
• Whether or not integration with
safety devices or auto-injectors
is needed
• The compatibility of the pack-
aging with different f i l l ing
machines
• Regulatory pathways for drug
approval
• Patient comfort and needs.
Reynolds adds that the selection
of the drug container starts with an
understanding of the potential inter-
actions between the drug and the
system. He points out that certain
biologics may be sensitive to silicone
oil or tungsten, which are found in
many glass syringes. “Certain poly-
mer syringe systems, such as West’s
Daikyo Crystal Zenith syringe sys-
tem, provide container systems free
from silicone oil, tungsten, and other
extractables,” he says.
For the majority of drugs, glass
remains the preferred material;
however, Reynolds notes that in
certain circumstances, a polymer
syringe may offer unique advan-
tages. “Evaluation of both options
at an early stage can help to iden-
tify the pros and cons of both,”
he highlights. “In addition, the
selection of either glass or poly-
mer syringes can be influenced
by other factors such as storage
temperatures (polymer systems
offer advantages at extremely
low temperatures), potent ia l
risks of breakage, and, in cases
where a device is used, precision.
Functionality and dimensional
tolerances can also be key factors
in order to reduce the risk from
incorrect function of the injec-
tion system.”
DEVELOPMENT CONSIDERATIONS The development of biologic drug
products in prefilled syringes has
attracted a lot of interest within
the bio/pharmaceutical industry
because of the win–win situation
for both end-users and manufac-
turers. But besides formulation
considerations and compatibility
between the drug product and its
primary packaging, there are other
technical challenges that have to
be addressed such as functionality
issues and syringe siliconization.
“A drug product’s formulation is
comprised of multiple raw materi-
als, as are the components of pre-
filled syringes. It is ultimately the
compatibility of these systems that
will help to qualify the system for
its intended use,” says Reynolds.
“Components of prefilled systems
typically include pistons, syringe
bar rels, needles, and needle
shields—all of which must be com-
patible as a system and with the
drug product.”
According to Reynolds, the pre-
filled syringe component with the
maximum drug product contact
area is the syringe barrel, which
Drug Delivery
16 BioPharm International www.biopharminternational.com November 2017
can have a major influence on
drug product quality. The compat-
ibility of the drug product with
the barrel’s contact surface is cru-
cial to the drug product quality, he
explains, while the break loose and
glide forces are key to the adminis-
tration of the drug.
SILICONIZATIONSiliconization is a key process
step in the manufacturing of
prefilled syringe systems, high-
lights Tillmann Burghardt, team
manager, Manufacturing Science
and Process Development, Vetter
Pharma-Fertigung GmbH & Co.
KG. “It involves not only the coat-
ing of syringe barrels, but also any
rubber parts and the needle itself
with a thin layer of pure silicone
oil or distinct silicone oil/water
emulsions, respectively. This pro-
cess facilitates the assembly of
the syringe parts and promotes
ease of use and injection,” he says.
Burghardt explains that the sili-
cone oil acts as a lubricant that
provides certain properties cru-
cial for drug administration. “The
silicone layer forms a hydrophobic
surface so that the solution within
the syringe drains better and sup-
ports recovery rate accuracy. The
oil layer also has a barrier func-
tion—it prevents absorption of
the compound by the container.
The drug formulation is, there-
fore, protected f rom react ive
surface mediated chemical modifi-
cations,” he says.
According to Bernd Zeiss, man-
ager, Technical Support Medical
Systems, Gerresheimer, all prefilled
glass syringes today are silicon-
ized in some way. Siliconization
is essential to process capabil-
ity. “Without silicone oil as a
lubricant, prefilled syringe sys-
tems based on glass do not work
because the plunger stopper would
not move properly,” he notes.
“Extremely high gliding forces
would prevent the emptying and
make it impossible to carry out a
smooth and comfortable injec-
tion. The plunger stopper could get
stuck in the middle of the injec-
tion because direct contact between
glass and the currently used elas-
tomers causes very high friction
forces. Only appropriate siliconiza-
tion can overcome this friction.”
SILICONE OIL COMPATIBILITY WITH THE BIOLOGIC FORMULATIONBurghardt points out that sili-
cone itself is non-toxic, biocom-
patible, and insoluble in water;
therefore, it has limited impact
on the formulation. “As an inte-
g ra l component of pre f i l led
syringes, the use of silicone oil in
drug-delivery systems has been
clinically tested for decades and
commercially proven in billions
of patients,” he says.
Zeiss, however, cautions that
a few biologics may react to the
silicone oil, but adds that not all
biologics react this way. For this
reason, dedicated stability studies
of any newly developed formula-
tion with the intended syringe
need to be carried out, he high-
lights. According to Zeiss, in rare
cases where too much protein
binds to the siliconized glass sur-
face, or if silicone oil-protein aggre-
gates are formed in the liquid itself,
the efficacy of the injectable for-
mulation may be compromised.
“In such cases, immunogenic
effects cannot be excluded,” he
says. “And the safety of the drug
could be impaired.”
One modern tool to mea-
sure silicone oil-induced protein
aggregation is microflow imaging
(MFI), notes Zeiss. “The amount
of particles found in the formula-
tion provides an indicator of the
sensitivity of the protein toward
silicone oil. By applying MFI, the
amount and shape of particles
in the formulation can be deter-
mined. Free silicone oil will form
round droplets while any odd
shapes seen indicate protein aggre-
gation,” he explains.
Burghardt highlights that sili-
conization involves introducing
supplementary material into the
prefilled syringe system, in addition
to the actual injected compound.
“Therefore, before choosing a sili-
conization technology, companies
have to consider various factors,” he
says. “As the silicone coating is not
covalently bonded to its substrate, it
is susceptible to change over time.
Storage conditions and transport
stress, in particular, temperature and
agitation, can affect the layer and
its interaction with the syringe sur-
face over time. Silicone layers can
also interfere with analytical assays
because they might release subvis-
ible particles to the liquid phase.
The migration of such silicone oil
droplets at parts per million (ppm)
level into the compound is a known
phenomenon. Therefore, each new
compound requires individual com-
patibility and stability assessments.”
SILICONIZATION METHODSSiliconization methods use either
pure silicone oil or distinct silicone
oil emulsions. Burghardt notes that
pure silicone oil is still the most
commonly used technology for a
prefilled syringe. “It can be applied
by wipe down or dynamic spray-
ing processes and can also be used
for glass and polymer systems,”
he says. “This medium allows for
Drug Delivery
Prefilled
syringes have gained
strong acceptance as
delivery systems for
injectable drugs.
November 2017 www.biopharminternational.com BioPharm International 17
Drug Delivery
various types of sterilization proce-
dures such as autoclaving, ethylene
oxide treatment, or gamma irradia-
tion. It is also used for rubber com-
ponents, needles, and the syringe
barrel itself.”
Zeiss concurs that the standard
approach used until today is the
spray siliconization method with
silicone oil. “Medical-grade oil is
sprayed into the barrel using spe-
cial diving nozzles that distribute
the coating inside the syringe. If
required, different siliconization
levels can be applied, depend-
ing on the customer needs,” Zeiss
explains. Burghardt adds that this
process supports layer uniformity
from the cone toward the flange
of the barrel. However, he notes
that temperature-sensitive poly-
mer systems in general, as well as
glass syringes with diameters less
than 0.5 cm, are restricted to the
conventional static spray process,
which involves spraying from out-
side the barrel to avoid nozzle to
glass contact within the syringe.
The second method is baked-on
siliconization. Zeiss explains that
in this process, an oil-water emul-
sion is sprayed into the barrel and
subsequently baked on the inner
barrel surface in a dedicated heat
chamber. “Water is evaporated,
and the silicone oil is fixed to the
glass surface,” Zeiss says.
According to Burghardt, the use
of silicone oil emulsions is gain-
ing growing importance, but he
points out that this method is only
indicated for glass barrel systems
because it requires a dry heat steril-
ization step. “The syringe is heated
to more than 300 °C to evaporate
the water of the emulsion and help
bond the silicone oil to the ster-
ilized syringe. These silicone oil
emulsions can be applied by either
static or dynamic spraying nozzles
to the glass barrel.”
Zeiss highlights that baked-on
siliconization leads to dramatically
lower residual-free silicone in the
prefilled syringe. The method was
originally developed for ophthal-
mic applications, according to him,
but turns out to be well suited for
sensitive biologics.
OPTIMIZING THE SILICONIZATION PROCESSInsufficient or excessive siliconiza-
tion can cause issues in the func-
tional performance of the prefilled
syringe. “It is crucial to evaluate
the ideal siliconizing process on
the basis of the given compound
and the anticipated fill and finish
steps with regard to possible post-
fill treatments,” Burghardt stresses.
“The topology of the initial sili-
cone coating is determined by
which siliconization technology
is used. However, the impact of
pH and ionic strength of the filled
compound formulation, as well as
storage temperature and transport
stress or potential lyophilization
processes, should not be underesti-
mated during process development.
Thorough analytical testing has to
be considered to elicit the amount
and distribution of the silicone oil
on the syringe body surfaces both
prior to and after filling.”
Burghardt explains that various
analytical methods can be used to
examine the amount and distribu-
tion of silicone inside the system.
“For example, one can measure total
extracts of silicone oil from empty
barrels by Fourier transform infra-
red spectrometry, or optically assess
the uniformity and thickness of the
layer by reflectometry,” he says. “The
overall functionality of the entire
system can be evaluated by tensile
force measurements on both empty
and filled units, thus, simulating the
later application process. Simple flow
microscopy technology is applied for
detecting subvisible particles in liq-
uid solutions after incubation in the
desired prefilled syringe, allowing for
particle classification by count, size,
and shape.”
Zeiss notes that siliconization can
be optimized in many ways. “Over
the past 10 years, the use of diving
nozzles in spray siliconization have
led to much lower amounts of sili-
cone in the syringes. Manufacturers
have also constantly improved and
optimized the baked-on process,”
Zeiss says. “The lower the lubrica-
tion levels in a syringe, the more
critical the interface between bar-
rel and elastomer stopper becomes.
Finally, choosing a modern plunger
stopper makes a good syringe sys-
tem complete.” According to Zeiss,
Gerresheimer has carried out a
comprehensive test campaign com-
paring all kinds of available plunger
stoppers in combination with spray-
siliconized and baked-on silicon-
ized syringes. He adds that it is not
only important to lower and opti-
mize siliconization itself, but also
apply a system approach to evaluate
which syringe plunger combina-
tion is the best. “In addition, the
amount of product to be filled into
the syringe and the plunger stop-
per placement method are part of
this equation. Today, low silicone
syringe systems with very good
gliding behavior of the stopper can
be offered,” Zeiss says. ◆
Because most biologics
are administered by
injection, there is a
demand for advanced
drug-delivery
systems that offer
convenience and ease
of administration.
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Copyright © 2017 IQVIA. All rights reserved.
Research & Development | Real-World Value & Outcomes
HUMAN DATA SCIENCE
20 BioPharm International www.biopharminternational.com November 2017
An
na K
ireie
va
/Sh
utt
ers
tock.c
om
Speed to market is essential in
the biopharmaceutical industry
today. Manufacturers are seek-
ing mechanisms for increasing
efficiencies and reducing costs without
compromising the safety and efficacy
of their drug products. In addition to
exploring novel production methods
such as continuous processes and dis-
posable production technology, manu-
facturers also heavily invest in platform
technologies for protein expression that
will not only facilitate the development
of biologic drug candidates, but also
increase yield and speed to market.
A PLATFORM OF BENEFITSPlatform technologies for protein
expression that have been successfully
used to produce biologic drug sub-
stances (i.e., substances that have made
it to late-stage clinical trials and com-
mercialization after being subjected
to regulatory scrutiny) can thus be
considered safe, according to Menzo
Havenga, CEO at Batavia Biosciences. In
addition, any technologies underlying
these platforms have at that stage been
well-studied, making them predictable,
and predictability creates manufactur-
ing comfort. They are also expected
to speed up the development of novel
specific molecules based on the use of
chemistry, manufacturing, and con-
trols (CMC) standards and by leveraging
capabilities and capacities, notes Beate
Mueller-Tiemann, head of business
integration and innovation at Sanofi.
“Consequently, platform expression
technologies may lead to substantial
Platform Technologies Improve Protein Expression
Cynthia Challener
Platform technologies
facilitate development
and accelerate commercialization
of protein therapeutics.
Cynthia A. Challener, PhD
is a contributing editor to
BioPharm International.
Expression Systems
November 2017 www.biopharminternational.com BioPharm International 21
benefits in terms of speed to mar-
ket, assuming CMC aspects are on
the critical path, and reduced cost
of goods manufactured (COGM),”
she states.
In addition, new technologies
for genomic engineering of cells
for the production of therapeutic
proteins are “opening up a new
world of possibilities to tailor-
make protein-based drugs with
appropriate post-translat ional
modifications that meet the needs
of the pharmaceutical industry,
physicians, and ultimately patients
in need of novel medications,”
notes Bjørn Voldborg, director of
CHO cell-line development at the
Novo Nordisk Foundation Center
for Biosustainability.
IMPROVING EFFICIENCY, YIELD, AND FUNCTIONALITYThere are a large number of fac-
tors to be taken into account in
the development of new platform
technologies for protein expression
ranging from the choice of cell
line, expression plasmid design,
cultivation medium, growth con-
ditions, equipment, scalability,
stability, and matching purifica-
tion capability, to name but a few.
Primary drivers to the develop-
ment of a new therapeutic protein
platform are the desire to improve
efficiency and productivity, the
need to increase the agility of
manufacturing, and the fact that
complex non-natural proteins are
not well-expressed in the current
systems such as Chinese hamster
ovary (CHO) cell lines, according
to Mueller-Tiemann.
Improving yield has always
been and will continue to be one
of the key drivers for a technol-
ogy platform to be successful,
explains Havenga, although clearly
agility, product quality, and regu-
latory acceptance are highly sig-
nificant. Next to yield, the stability
of protein-producing cell clones
remains an issue to be studied as
well. Furthermore, Havenga points
out that the use of novel platform
technologies for protein expression
has not yet resulted in significant
reductions in consumer prices.
“The goa l beyond mak ing
some of these new entities viable
is achieving a significant reduc-
tion in COGM, thus increasing the
affordability of biotherapeutics and
improving overall healthcare eco-
nomics,” agrees Mueller-Tiemann.
With respect to the impact of
technology, the main driver for
recent advances in the devel-
opment of protein expression
platforms is the discovery of
CRISPR-Cas9-based genome edit-
ing, according to Voldborg. “This
technology has made it possible
to specifically engineer genes in
existing hosts to improve their
properties and performance and
to add completely new functional-
ity,” he observes. There is one hur-
dle yet to overcome, however; the
intellectual property landscape
surrounding the CRISPR-Cas9
approach is unresolved, which
makes it less attractive for use in
industrial settings.
PROMISING DEVELOPMENTSVoldborg expects that most thera-
peutic proteins will continue to
be produced using well-known
platforms (e.g., CHO cells and
Escherichia coli [E. coli] bacteria),
but with the addition of engi-
neered versions that may over-
come the drawbacks of earlier
non-engineered versions of these
platforms. “I have to say, however,
that the possibility to specifically
delete or insert genes by demand
using CRISPR-Cas9 technology is
a game-changer in the field.” He
adds that combining genetic engi-
neering tools like CRISPR/CAS9
with bioinformatics to identify
optimum sequences using a bio-
mimetic approach could make a
difference. Tools enabling modifi-
cation of metabolic pathways for
glycosylation in algae and yeast
glycosylation are also noteworthy.
“These approaches offer avenues
for designing better fit-for-purpose
molecules not only in terms of
their activity and safety, but also
with respect to desirable CMC
attributes,” says Voldborg.
The availability of several molec-
ular biology tools developed in
the recent past by the scientific
community in diverse applica-
tions beyond biopharmaceuticals
is starting to make a difference,
agrees Muel ler-Tiemann. She
notes that there are several plat-
form approaches based on diverse
host systems that seem promising
for the expression of therapeutic
proteins due to their increased
productivity and ability to be
genetically engineered toward spe-
cific molecule characteristics and
levels of expression.
In add it ion, accord ing to
Mueller-Tiemann, the simplic-
ity of the culture media required
for their growth presents oppor-
tunities from a cost-reduction
perspective. Use of chemically
defined media also makes the risk
of exposure to zoonotic adventi-
tious agents extremely unlikely.
“High-quality, defined, animal-free
reagents and cell-culture products
help biomanufacturers eliminate
the risk of contamination that has
been associated with animal- and
human-serum-derived media,”
agrees Scott Deeter, president and
CEO of Ventria Bioscience. Cell-free
systems, which are currently at the
earliest stage of development, could
be important in the long term,
according to Mueller-Tiemann.
Advances in process equip-
ment are also expected to have
an impact, according to Havenga.
He points to the use of high-cell-
density, fixed-bed bioreactors for
adherent cell culture as an excit-
ing new development. “With
these bioreactors, it is possible to
increase cell densities from 10–20
Expression Systems
22 BioPharm International www.biopharminternational.com November 2017
million cells per milliliter in typi-
cal bioreactors to an impressive
100–200 million cells per milli-
liter, resulting in significant sav-
ings in facility costs due to the
reduction in required floor space,”
he explains.
OVERCOMING CELLULAR COMPLEXITYWhile a lack of suitable genome
engineering tools is no longer a bot-
tleneck for improvement of protein
expression platforms, biologic drug
manufacturers still face many chal-
lenges. The perfect system is not
around the corner. Understanding
and tools for better engineering
the overall metabolism of host
cells with the capability to bal-
ance protein generation in several
different phases with cell growth
and survival will remain a key
research focus, according to Mueller-
Tiemann. “Significant progress has
been made, but a lot has yet to be
discovered,” she asserts.
Adds Voldborg: “Cellular expres-
sion systems are highly complex,
and we still lack knowledge of the
cellular machinery that is used to
transcribe, translate, fold, modulate,
and finally secrete desired protein
products.” He does note, however,
that the use of computer-based mod-
els and big data analysis are being
used to improve this knowledge.
For Havenga, continuing issues
with the stability of expression cell
lines and clonality associated with
gene amplification technologies,
such as dihydrofolate reductase
(DHFR) selection, remain a con-
cern. “The problem here is loss of
expression, and [the use of] tech-
nologies that do not involve gene
amplification, such as the STEP
technology developed by Batavia
Biosciences, is one approach to
addressing this problem,” he says.
ENGINEERING CHO CELLSThe platform technology developed
at The Novo Nordisk Foundation
Center for Biosustainability at the
Technical University of Denmark
is focused on engineering cell lines
according to the needs of the phar-
maceutical industry working with
protein-based therapeutics, says
Voldborg. “We have been able to
engineer cell lines that solve a lot of
the problems and challenges expe-
rienced by the industry,” he says.
As one example, Voldborg points to
engineered CHO cell lines that can-
not produce lactate, thereby nearly
eliminating the need for pH adjust-
ment via base addition during cell
culture. “With these expression sys-
tems, it will be possible to conduct
much longer fed-batch runs and
significantly increase the amount
of product that can be made from
each production run.” The center
has also developed cell lines engi-
neered to produce proteins with
tailor-made, highly homogenous
glycoprofiles, highly homogenous
cell lines that exhibit reduced host-
cell protein secretion, and cell lines
resistant to certain virus infections.
At Sanofi, establishing differen-
tiating CHO expression systems is
a clear goal for the company, says
Mueller-Tiemann. Sanofi is also
pursuing process intensification for
high-throughput, semi-continuous
manufacturing in the short term.
PLASMID-BASED EXPRESSIONBatavia Biosciences’ plasmid-based
STEP technology increases protein
expression in CHO cells by at least
10-fold, taking just 12 weeks to gen-
erate stable cell clones, according to
Havenga. A cytomegalovirus (CMV)
promoter drives the transcription of
one mRNA from which two proteins
are translated (i.e., the protein of
interest [product] and a functionally
impaired Zeocin selection marker).
As the impaired Zeocin selection
marker needs to be expressed in a
CHO cell to high levels for the cell
to survive the antibiotic pressure,
that cell per definition also makes
high levels of the desired product.
The platform rapidly achieves
high protein-expression levels
without the need for gene ampli-
fication. In addition, cell clones
developed thus far with STEP
(n=12) have all proven to be stable
in the expression of the desired
product for more than 60 pas-
sages in the absence of selection
pressure, according to Havenga.
“In the rapidly growing market
of recombinant proteins and
antibodies, our STEP technology
provides a tool to complete pre-
clinical phases at higher speed
with reduced costs and with a
higher success rate,” he asserts.
Regulatory approval of the STEP
technology is expected in 2018 at
the latest, according to Havenga,
with first products on the market
using STEP in 2024.
PLANT-BASED EXPRESSIONVent r ia Biosc ience ’s propr i -
etary ExpressTec technology is a
plant-based expression system.
Recombinant proteins, peptides,
multi-subunit molecules, mono-
clonal antibodies, fusion proteins,
and enzymes are manufactured
within a growing plant using sun-
light, soil, water, and air as raw
materials, according to Deeter. He
adds that products manufactured
using this expression platform
are cost-effective and free of ani-
mal, human, and bacterial con-
taminants, which is an important
safety factor.
“ExpressTec also delivers mean-
ingful advantages by making
molecules that would be diffi-
cult to produce in other systems,
enabling new product opportuni-
ties that were not previously avail-
able. Ventria is in the process of
doubling our production capacity
with the platform to meet grow-
ing needs in developing new bio-
therapeutics, cell-culture media
reagents for biomanufacturing,
and industrial and animal nutri-
tion enzymes,” says Deeter. ◆
Expression Systems
The Next EvolutionFor the past 75 years, Kerry has evolved with the market trends in cell culture. As our customers’ needs changed we have expanded our product portfolio to encompass technologies needed to meet the evolving needs of the bio-pharma market globally.
AmpliCHO CD medium is our latest evolution.
�Îáȶ�,K����Σ�¶õÎ�¶è����ÕÎáÈ£ð£Èć��³£Î¶��È��³£Î¶��ÈÈćȇ�£ėÏ£��Σ�¶õÎ�ð³�ð��Õ£è�not contain supplements. It is optimized for extended growth and enhanced recombinant protein production for CHO suspension cultures.
e³£��£Ï£ėðè�Õ�õè¶Ï®��Îáȶ�,K����Σ¶õÎ:㔑 ^¶®Ï¶ė��ÏðÈć�³¶®³£ä�ð¶ð£äè㔑 Low osmolality㔑 Extended viable density and cell viability㔑�Animal component free (ACF)㔑�Compatible with complex, defined, and CD supplements and feed
Learn more at Kerry.com
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24 BioPharm International www.biopharminternational.com November 2017
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Single-use technology has become
more widely adopted in bio-
pharmaceutical manufactur-
ing, shifting from acceptance of
the technology to standardization (1).
Optimizing single-use systems and main-
taining quality are as much functions of
the types and configuration of the con-
nector components as they are a func-
tion of overall process design.
A single-use system is at the mercy of
its weakest link, which centers around
the connectors used to unify the manu-
facturing assembly, such as valves, joint
connectors, and blockers, among others.
CRITICAL CONNECTORSIn single-use systems, criticality exists
wherever a connection is made so that
product can flow through. The drugs and
therapies being developed are valuable,
so any failure in the system will lead to
an expensive loss, notes Scott Herskovitz,
vice-president of sales and marketing at
Qosina, a Ronkonkoma, NY-based pro-
vider of stock components for medical
devices.
Connection types vary depending on
the classification of the manufacturing
environment in which the connection is
being made, says Todd Andrews, global
sales and business development manager,
Bioprocessing, Colder Products Company
(CPC), a provider of quick disconnect
couplings, fittings, and connectors for
plastic tubing based in St. Paul, MN.
“Any connection where product ste-
rility could be compromised is impor-
tant. Critical connections can be located
upstream where the end user is trying to
Connector Integrity in Single-Use Biomanufacturing Systems
Feliza Mirasol
Connectors are a critical
element in the process optimization of single-use
bioprocessing systems.
Downstream Processing
November 2017 www.biopharminternational.com BioPharm International 25
protect the cell line, or downstream
where patient health could be
affected. The best defense against
a potential breach in sterility is
employing connectors that are well
validated, robust, easy to use, and
highly reliable,” Andrews says.
The importance of sterile connec-
tors in the single-use bioprocessing
system revolves around their ability
to help maintain volume and prod-
uct flow.
Their impact, as well the impact
of other attachments such as tub-
ing, to the system must be assessed
as they may significantly change
the system volume. This in turn
can potentially lead to erroneous
results when testing the system for
sterility (2), according to the Bio-
Process Systems Alliance (BPSA), an
industry association that promotes
and accelerates the adoption of sin-
gle-use manufacturing technologies
used in the production of pharma-
ceuticals and vaccines. Connectors
and tubing should be assessed in
qualification studies to determine
their impact on the system, the
BPSA said in a report (2).
For example, the diameter, wall,
thickness, length, and material
type of the tubing used should
all be taken into account because
these properties can affect the
stiffness of the tubing under pres-
sure. This can have an effect on
pressure measurements, said the
BPSA in its report. In addition, the
organization recommends that
any permeable membranes, such
as vent filters or hydrophobic peel
strips, on connectors should be
isolated from the tested single-
use system by shut-off valves or
clamps (2).
The management of these connec-
tor elements is an important aspect
of process optimization because the
development of new drugs and ther-
apies in single-use systems requires
components that are made to a
higher standard than those used in
other industries, Herskovitz says. In
particular, the materials with which
various connectors are made must be
able to withstand exposure to chemi-
cals without introducing bioburden
or other chemicals into the final
product.
Furthermore, connections should
reflect the manufacturing environ-
ment in which they are used as well
as the risk associated with those
connection. In a highly classified
environment, such as ISO Class 5,
Downstream Processing
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26 BioPharm International www.biopharminternational.com November 2017
for example, open connectors, such
as quick connects, are acceptable.
In this case, the environment
has less inherent risk than a lower-
class environment, according to
Andrews. More and more, how-
ever, drug manufacturers are seek-
ing connections outside of highly
classified environments to improve
flexibility and reduce overhead. In
these situations, manufacturers are
moving toward sterile connectors,
Andrews notes.
The particular configuration of
connectors in the bioprocessing
network depends on the applica-
tion, quantity, and price, Herskovitz
says. “Molded connections give a
higher level of confidence than
zip ties, but there is a higher cost
involved and a lengthier develop-
ment time to configure and pro-
duce,” he remarks.
“Genderless” connectors simplify
use and the inventory management
of system components. In a gen-
derless connector, each connector
half is the same design, eliminating
the traditional “male” and “female”
connections where each side is
unique, adds Andrews.
Genderless connectors avoid issues
associated with male/female connec-
tions, such as accidentally specifying
the same gender on each half and
requiring more stock keeping units
(SKUs), to ensure sufficient inventory
of male and female components for
proper matching, he says.
An example of the former situa-
tion would be having male connec-
tors on both the bag assembly and
the tube manifold, which would
not allow a proper connection. This
is typically discovered at the point
of use, to the detriment of the oper-
ator. To remedy the situation, an
operator might then need to create
a makeshift tube assembly—assum-
ing that components are readily
available—sterilize it, and attempt
a connection, all of which delay
manufacturing and affect produc-
tion efficiency, Andrews explains.
In the latter situation, genderless
connectors reduce the number of
SKUs needed at the component and
finished-system levels. Fewer SKUs
simplify ordering and reduce the
burden on inventory control, which
contributes to lower overhead costs
and shorter lead times for single-use
systems, Andrews says.
CONNECTOR CRITERIA AND COST CONSIDERATIONSThere are certain key criteria for the
types and quantity of connectors to
use in a single-use system, includ-
ing the quality of material from
which the connectors are made, the
manufacturing environment, and
testing data, to ensure the compo-
nents will not introduce bioburden
or leachables/extractables into the
product, says Herskovitz.
Andrews highlights other criteria
that should be considered in select-
ing the right connectors. One of
them is ease of use: in an industry
where the primary cause of failure is
operator error, well-designed connec-
tors are important for reducing the
opportunities for operator mistakes.
Downstream Processing
Different Ways to Connect
One element meant to ensure the integrity of connections in the bioprocessing network are connector sealants, or
retainers, which include tie wraps, Oetiker clamps, BarbLocks, and overmolding. The benefits and disadvantages of
these sealants are highlighted in an article published on October 25, 2017 on BioPharmInternational.com by Graeme
Proctor, product manager (single-use technologies) at Parker Hannifin, a diversified manufacturer of motion and control
technologies and systems (1).
The benefits of tie wraps include low cost and versatility as well as the ability to use with them with all types of
materials. Similarly, Oetiker clamps are usable with all types of materials and offer 360-degree compression; however,
they are more expensive than tie wraps. BarbLocks, in comparison, also offer 360-degree compression and repeatable
automated connection force, but are even more expensive and have more limited sizing than Oetiker clamps. Another
sealant method, overmolding, involves a process where a single part, or component, is created by combining two or more
different materials. During the manufacturing process, the first material (substrate), is typically covered either partially
or fully by the other materials, which are known as the overmold materials (2). The cheapest option would be to have no
retainer at all, but Proctor concluded in the article that the use of an external retainer is essential.
References
1. G. Proctor, “Connectors and Sealing Mechanisms—and Their Impact on Process Protection,” BioPharmInternational.com, www.
biopharminternational.com/connectors-and-sealing-mechanisms-and-their-impact-process-protection, accessed Oct. 25, 2017.
2. Creative Mechanisms, “Everything You Need to Know About Overmolding Prototypes,” www.creativemechanisms.com/blog/
overmolding-prototype-design-development, accessed Oct. 18, 2017.
November 2017 www.biopharminternational.com BioPharm International 27
Downstream Processing
To test a connector’s ease-of-use, operators should
be allowed to attempt installing the connections with
minimal training. The operators who are putting
together the connections on the floor are the best gauge
of ease-of-use in real-life manufacturing conditions,
Andrews asserts.
Durability is another key criterion; do the connectors
still function properly when used in less-than-perfect
conditions? “Some connectors, for example, function
adequately if there is zero side-load or tension in the
line. However, these conditions are hard to achieve in
real-world applications. Robust connectors will work
well in a variety of circumstances,” says Andrews.
Other key connector criteria are integrated function-
ality and availability. For example, biomanufacturers
should seek out connectors that deliver the required
functionality and performance without the need for
extra equipment or processes.
Secondary equipment such as welders, sanitary
clamps, or machined fixtures add complexity and
become potential sources of problems or mistakes,
Andrews explains. In terms of availability, some con-
nector manufacturers offer connectors as part of
higher-cost single-use systems that include other com-
ponents—such as filters, bags, and tubing—that are not
needed or wanted.
“For cost and process efficiencies, obtain connectors
from connector specialists dedicated to delivering the
specific types of connectors required for your system,”
he states.
The cost consideration for using disposable versus
sterilizable/reusable connectors is another factor in the
adoption of single-use systems. In evaluating the costs
between disposable and reusable connectors, an impor-
tant consideration is the total cost of use versus initial
acquisition costs alone, Andrews says.
For example, disposable connectors may have higher
direct, per-unit costs, but they eliminate other costs
that are normally associated with reusable connectors,
such as: water required to clean and sterilize the con-
nector, typically in the form of steam or water-for-injec-
tion (WFI); costly electrical power and utilities needed
to generate steam and WFI; and downtime required to
clean and sterilize reusable equipment between usages.
“With disposables, manufacturing can be up and
running immediately after replacing the disposable
assembly,” remarks Andrews.
“This is a classic question addressing the entire sin-
gle-use movement,” says Herskovitz. “The consideration
is volume. If you are manufacturing a billion doses, it is
more cost effective to go the traditional route. However,
the trends have been toward small batches of targeted
therapies that serve a much smaller population. This
has been where single-use systems have shined.”
The saving of time and money on cleaning and vali-
dation is important, but this means rapid changeover
between batches, he notes. Using disposable connec-
tors also reduces water and waste and eliminates cross-
contamination.
“Manufacturers also have greater flexibility when
using mobile single-use designs over pre-existing stain-
less-steel facilities. Single-use equipment can be dupli-
cated with less effort and cost and can help you keep
manufacturing closer to end-users. Stainless-steel facili-
ties can take time to build; single-use is cheaper and
quicker,” Herskovitz states.
REFERENCES 1. T. Andrews, “The Standardization of Single-Use Components
for Bioprocessing,” CPC White Paper 7003, https://content.
cpcworldwide.com/Portals/0/Library/Resources/Literature/
WhitePapers/Documents/CPC_WhitePaper_standardization_
of_single-use_components.pdf, accessed Oct. 18, 2017.
2. Bio-Process Systems Alliance, “Design, Control,
and Monitoring of Single-Use Systems for Integrity
Assurance,” http://bpsalliance.org/wp-content/
uploads/2017/07/Integrity-assurance-of-single-use-
systems-FINAL-7.7.17.pdf, accessed Oct. 20, 2017. ◆
In-line Sensors to Meet Your Single UseProcess Monitoring Requirements
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28 BioPharm International www.biopharminternational.com November 2017
mo
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hu
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Focus on the development of
a nt ib o dy d r ug conjugate s
(ADCs) remains robust as drug
companies continue to invest
resources in this area of therapeutics.
The road to market has been diffi-
cult, however, with only three ADC
products approved for sale by FDA in
the United States as of October 2017.
This has not stopped ADC develop-
ers, though, and the biopharmaceutical
pipeline is populated with ADC candi-
dates under development.
THE PROMISE OF CONJUGATIONADCs are part of a relatively new class
of targeted cell immunotherapeutics
that represent a major step in develop-
ing precision drugs (1). The target for
ADCs has primarily been cancer, and
the cytotoxic agents that are used in
ADCs are typically more potent than
currently used anti-cancer drugs (1).
The ADC construct combines a
targeted monoclonal antibody (mAb)
with a cytotoxic agent, linked together
with a stable linker technology. An
ADC enables the specific delivery of
chemotherapeutics to tumors while
avoiding systemic exposure to the
cytotoxic compound (1).
Because the stable linkers conju-
gate cytotoxic molecules to the mAb,
ADCs can remain inactive while in
circulation within the patient’s body.
The agent is internalized by the tumor
cell after it is bound to the cell by the
mAb end of the ADC molecule. Inside
the tumor cell, the ADC breaks down
into its components, which releases
ADC Development Robust Despite Lackluster Performance
Feliza Mirasol
Despite the disappointing
therapeutic performance of ADCs thus far,
the pipeline still boasts promising prospects.
Manufacturing
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30 BioPharm International www.biopharminternational.com November 2017
the cytotoxic agent inside the cell,
thereby killing it (1).
“The potential of ADCs has been
enhanced by a greatly expanded
knowledge of ADC technology,
cancer biology, and pharmacology.
It is projected that the global
market for ADCs will reach $2.8
billion by 2018,” said Mirella
Zulueta, business development
director at Oncomatryx, a Spain-
based biopharmaceutical company
focused on tumor stroma, in a
company blog (1).
ADCS ON THE MARKET NOWCurrently, there are only three
ADCs approved by FDA for the US
market. These three, from Pfizer,
Roche, and Seattle Genetics, are all
indicated for treating cancers.
P f i zer ’s product, Mylota rg
(gemtuzumab ozogamicin), was
approved in 2017, nearly a decade
after an initial approval in 2000 (2).
Soon after its first approval by FDA
in 2000, Pfizer voluntarily with-
drew Mylotarg from the market
because the company was unable
to verify a clinical benefit and
because of safety concerns. The
more recent approval authorizes
the use of the drug for treating
acute myeloid leukemia (AML).
Roche’s product, Kadcyla (trastu-
zumab emtansine), was approved
by FDA in 2013. It is indicated for
treating HER2-positive, metastatic
breast cancer. The drug is among
Roche’s top-10 selling products,
earning 2016 sales of CHF 831 mil-
lion (US$844 million) (3).
Seat t le Genet ic s’ produc t ,
Adcetris (brentuximab vedotin),
was approved in 2011. It is indi-
cated for treating classical Hodgkin
lymphoma (cHL) and systemic
anaplastic large cell lymphoma
(ALCL). Adcetris had 2016 sales of
approximately $266 million (4).
OPTIMISM IN THE PIPELINEDespite the promise of ADCs as
an alternative therapeutic for can-
cers, response rates to these drugs
in clinical trials have been typ-
ically low, and in addition, tox-
icity issues have been common.
This has led to an unfavorable
attitude toward ADCs for some
industry participants. Overall,
however, the industry continues
to believe in the clinical benefits
of these drugs (1). Some examples
of ADCs in clinical development
include candidates from Seattle
Genetics, Immunomedics, and
Roche. In addition, companies
such as Mersana Therapeutics and
Oncomatryx are using different
approaches to ADC development.
S e a t t l e G e n e t i c s . S e a t t l e
Genetics is among the companies
deve lopi ng a p ipe l i ne t hat
highlights ADCs (5). In addition
to having Adcetris on the market
for cHL and ALCL, the company
is also further developing the ADC
for other indications, including
in three Phase III clinical studies
to evaluate its potential in earlier
l ines of treatment within its
already approved indications (6).
In addition, the company is
developing brentuximab vedotin,
the active ingredient in Adcetris,
in many additional types of CD30-
expressing lymphomas, including
cutaneous T- cel l lymphoma,
mat u re T- ce l l ly mphomas —
c o m m o n l y r e f e r r e d t o a s
peripheral T-cell lymphoma—and
B-cell lymphomas (6).
Seattle Genetics is developing
b r e n t u x i m a b v e d o t i n i n
c o l l a b o r a t ion w i t h Ta ke d a
Pharmaceutical, under which
S e a t t l e G e n e t i c s h a s t h e
commercialization rights in the
US and Canada while Takeda
has commercial izat ion r ights
in the rest of the world. Joint
worldwide development costs are
funded equally between the two
companies, except in Japan where
Takeda has full responsibility for
development costs (6).
Seattle Genetics has an ADC
candidate in Phase II development
as well: denintuzumab mafodotin.
This candidate is in two Phase
II trials for relapsed/refractory
and frontline diffuse large B-cell
lymphoma (7). Also approaching
Phase II development is enfortumab
vedotin, an ADC that the company
is co-developing with Japanese
pharmaceut ical f i rm Astel las
Pharma. This ADC is expected
to go into a Phase II tr ial in
metastatic urothelial cancer in
the second half of 2017 and has
been undergoing a Phase I trial
evaluating its safety and antitumor
activity in escalating doses for
metastatic urothelial cancer (8).
Seattle Genetics also has several
other ADC programs in early-stage
clinical development, including
candidates for cervical cancer,
metastatic breast cancer, metastatic
u rothe l ia l cancer, re lapsed/
refractory aggressive B-cell non-
Hodgkin lymphoma, relapsed/
refractory AML, and relapsed/
refractory multiple myeloma (5).
Immunomedics. Immunomedics,
a clinical-stage biopharmaceu-
tical company based in Morris
Plains, NJ, specializes in anti-
body-based therapeutics and has
two ADCs in clinical develop-
ment. Sacituzumab govitecan is a
Phase II ADC candidate in devel-
opment for metastatic triple-neg-
ative breast cancer (TNBC) and
metastatic solid cancers, includ-
ing lung, urothelial, and esopha-
geal (9). Labetuzumab govitecan
is the second ADC, also in Phase
I I cl inical development. It is
Manufacturing
The industry continues
to believe in the
clinical benefits of
these drugs.
The Parenteral Drug Association presents the...
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32 BioPharm International www.biopharminternational.com November 2017
being developed for metastatic
colorectal cancer (9).
In February 2016, FDA granted
breakthrough therapy designation
to sacituzumab govitecan for the
TNBC indication. The agency also
awarded the ADC a fast-track des-
ignation. If approved, the ADC will
join Eisai’s eribulin, for treating
metastic liosarcoma, and Novartis’
ofatumumab, for treating recur-
rent or progressive chronic lym-
phocytic leukemia, both of which
were approved in 2016 (10).
Roche. Although it is not cur-
rently conducting clinical develop-
ment of new ADCs in its pipeline,
Roche is further developing its
already-approved ADC, Kadcyla, by
pairing it up in clinical trials with
other anti-cancer agents.
In one Phase III clinical trial,
the company is studying Kadcyla
in combination with its anti-breast
cancer biologic Perjeta (pertu-
zumab) as an adjuvant treatment
for early-stage HER2-positive breast
cancer. In a Phase II trial, the com-
pany is evaluating the combined
use of Kadcyla with its anti-cancer
biologic Tecentriq (atezolizumab)
as a second-line treatment for
HER2-positive metastatic breast
cancer. The company plans to
submit regulatory filings for these
indications in 2020 or later (11).
In addition to these combina-
tion-use clinical trials, Roche is also
conducting two Phase III clinical
trials for Kadcyla in the third-line
and adjuvant treatment of HER2-
positive metastatic breast cancer.
The company plans to file a regula-
tory submission for the adjuvant
treatment indication in 2020 or
later, but has not specified a time-
line for regulatory filing of the
third-line treatment indication (11).
DIFFERENT APPROACHESTO BUILDING AN ADCDue to past failures in efficacy,
safety, and tolerability, other ADC
developers are looking deeper into
the ADC conundrum to come up
with different approaches on how
an ADC can be made and what it
should do. Two examples include
a company that developed a water-
soluble polymer that can enhance
the effectiveness of an ADC and
another company that chooses a
target outside of, but significantly
associated with, tumor cells.
Mersana Therapeutics. Cambridge,
MA-based Mersana Therapeutics, a
clinical-stage company, is develop-
ing an ADC pipeline across mul-
tiple tumor types. Its lead ADC
candidate, XMT-1522, is in Phase
I clinical development for tumors
expressing the HER2 antigen (12).
The candidate is built on the
company’s lead ADC platform,
Dolaflexin, which consists of a
biodegradable, biocompatible,
and water-soluble polymer, called
Fleximer, and multiple molecules
of the company’s proprietary drug
payload, auristatin, which are
attached to Fleximer by a linker
specifically designed to work with
this polymer (13). Takeda has the
rights to XMT-1522 outside the
US and Canada under a strate-
gic partnership it entered with
Mersana in February 2013 (14).
Mersana’s technology aims to
enhance the efficacy, safety, and
tolerability of ADCs. Because its
polymer is highly water soluble,
it can be used to surround the
cytotoxic payload and compensate
for the payload’s poor solubility,
thus minimizing aggregation and
maintaining the ADC’s stability
while in circulation (13). Multiple
molecules of this polymer-payload
construction (Dolaflexin) can then
be attached to the chosen mAb,
which results in an ADC with a sig-
nificantly increased payload capac-
ity, according to the company.
Mersana’s approach di f fers
from other ADC technologies in
which the cytotoxic payload is
directly conjugated to the mAb
using a linker. With the compa-
ny’s Dolaflexin platform, ADCs
can be produced that carry a drug-
to-antibody (DAR) ratio between
12 to 15—a three to four-fold
increase in DAR compared to tra-
ditional ADC constructs—and
still maintain pharmacokinetics
and drug-like properties within an
acceptable range, as demonstrated
in animal models (13).
In addition to its XMT-1522
lead candidate, the company
is also developing XMT-1536,
another ADC c reated on it s
Dolaf lexin platform, which is
in the pre-clinical phase and for
which an investigation new drug
application was f iled. The lat-
ter is targeting tumors express-
ing the NaPi2b antigen, which is
highly expressed in 75% to 90%
of non-squamous non-small cell
lung cancer and epithelial ovar-
ian cancer cells (12).
T he N a P i 2 b a nt i ge n w a s
eva luated as a ta rget for an
ADC (lifastuzumab vedotin) by
Genentech, a Roche company
(12). Mersana expects to enter
into clinical trials for XMT-1536
in early 2018.
In addition to these two ADC
programs in development, as
wel l as two other early drug
discovery-stage ADC programs,
M e r s a n a p a r t n e r e d w i t h
EMD Serono, the life-sciences
business of Merck KGa A, in
Manufacturing
Due to past failures in
efficacy, safety, and
tolerability, other ADC
developers are looking
deeper into the ADC
conundrum.
November 2017 www.biopharminternational.com BioPharm International 33
Manufacturing
2014 to develop next-generation
A DCs using Mersana’s A DC
technolog y (15). Mersana is
generating Fleximer-ADCs using
mAbs provided by EMD Serono.
Mersana will also conduct drug
d i s c ove r y a nd p r e - c l i n ic a l
development activ it ies, while
EMD Serono will be responsible
for cl inical development and
commercialization of any products
that result, as per an exclusive
license granted by Mersana (15).
S i m i la r ly, Me r s a na ha s a
col laborat ion with Takeda to
develop ADCs. In February 2016,
the companies expanded an
already existing collaboration
between them. The expanded
de a l p rov ide s Ta ke d a w it h
additional access to Mersana’s
F l e x i m e r t e c h n o l o g y (14) .
Me r s a na ha s a n opt ion to
co-develop and co-commercialize
programs from its partnership
w i t h Ta k e d a w h e n P h a s e
I c l i n i c a l d e v e l o p m e nt i s
completed. The companies will
also co-develop new cytotoxic
payloads to use in ADCs (14).
Oncomatryx. The Spanish ADC-
focused company, Oncomatryx,
specializes in precision drugs that
target the tumor stroma, that is,
the supportive microenvironment
that surrounds tumor cells.
Oncomatryx’s approach is to
develop precision drugs that tar-
get proteins located in the tumor
microenv ironment, which it
believes is a novel route to cancer
treatment because it is directed at
stromal cells that propagate the
invasiveness, immune suppression,
and drug resistance of tumor cells,
rather than directed at the epithe-
lial cells of the tumor (16).
The company has developed
a pipeline of ADCs, as well as
antibodies and human-derived
proteins, that target the tumor-
associated stroma. For its ADC
deve lopme nt , t he compa ny
is developing antibodies that
specifically target two stromal-
cell membrane proteins, MTX5
and MTX3 (17,18).
The first of these targets, MTX5,
is a membrane glycoprotein found
in f ibroblasts associated with
cancer. However, Oncomatryx’s
approach is not to block MTX5,
because blocking this protein was
shown to be ineffectual in previ-
ous Phase II studies. Instead, the
company’s approach is to use the
protein as a cancer-associated-fibro-
blast-specific vehicle to internalize
cytotoxic molecules because MTX5
is naturally capable of internalizing
molecules (16). Similarly, the other
target, MTX3, is a membrane pro-
tein found in endothelial cells that
also possesses a natural ability to
internalize molecules (17).
The cytotoxic payloads that
Oncomatryx is developing are
cytolysin and nigrin. The com-
pany has designed three cytolysin
molecules that will be conjugated
to mAbs. With nigrin, the com-
pany has developed two payloads:
a nigrin b–A chain molecule and a
recombinant version of the nigrin
b–A chain. Nigrin b is a plant
toxin derived from the bark of an
elder plant (Sambucus nigra) (19).
The company’s first ADC clini-
cal candidate, OMTX705, is being
developed for pancreatic cancer and
invasive lung and breast cancer.
The company has already run pre-
clinical trials on the candidate (20).
REFERENCES 1. M. Zulueta, “Antibody Drug Conjugates
Against Tumor Stroma: The Beginning
of the End?,” http://oncomatryx.
com/antibody-drug-conjugates-
beginning/, accessed Oct. 23, 2017.
2. Pfizer, “Pfizer Receives FDA Approval
for Mylotarg (gemtuzumab ozogamicin),”
Press Release (Sep. 1, 2017).
3. Roche, “Annual Report 2016,” www.
roche.com/dam/jcr:ee2f197f-5487-
4629-9e28-66b77c9cbbab/en/
ar16e.pdf, accessed Oct. 20, 2017.
4. SEC, “Seattle Genetics Form
10-K,” http://services.corporate-ir.
net/SEC.Enhanced/SecCapsule.
aspx?c=124860&fid=14839381,
accessed Oct. 20, 2017.
5. Seattle Genetics, “Strong Development
Pipeline,” www.seattlegenetics.com/
pipeline, accessed Oct. 23, 2017.
6. Seattle Genetics, “Brentuximab
Vedotin,” www.seattlegenetics.
com/pipeline/brentuximab-vedotin,
accessed Oct. 23, 2017.
7. Seattle Genetics, “Denintuzumab
Mafodotin,” www.seattlegenetics.
com/pipeline/denintuzumab-
mafodotin, accessed Oct. 23, 2017.
8. Seattle Genetics, “Enfortumab
Vedotin,” www.seattlegenetics.
com/pipeline/enfortumab-vedotin,
accessed on Oct. 23, 2017.
9. Immunomedics, “Pipeline,” www.
immunomedics.com/pipeline-demo.
shtml, accessed Oct. 24, 2017.
10. BioPharm International,
“Immunomedics Receives
Breakthrough Therapy
Designation for Breast Cancer
Antibody-Drug Conjugate,”
www.biopharminternational.
com/immunomedics-receives-
breakthrough-therapy-
designation-breast-cancer-
antibody-drug-conjugate-0,
accessed Oct. 24, 2017.
11. Roche, “Product Development
Portfolio,” www.roche.com/
research_and_development/
who_we_are_how_we_work/pipeline.
htm, accessed Oct. 24, 2017.
12. Mersana Therapeutics, “Pipeline,”
www.mersana.com/pipeline,
accessed Oct. 23, 2017.
13. Mersana Theraputics, “Our
Technology,” www.mersana.
com/our-technology#dolaflexin,
accessed Oct. 23, 2017.
14. Takeda Pharmaceutical, “Mersana
Therapeutics and Takeda
Expand Partnership to Advance
Development of Fleximer Antibody-
Drug Conjugates and XMT-1522,”
Press Release (Feb. 3, 2016).
15. BioPharm International, “EMD Serono
and Mersana to Develop Next-
Generation Antibody-Drug Conjugates,”
www.biopharminternational.com/
emd-serono-and-mersana-develop-
next-generation-antibody-drug-
conjugates, accessed Oct. 24, 2017.
16. Oncomatryx, “Our Battlefield,
the Stroma,” http://oncomatryx.
com/targeting-tumor-stroma/,
accessed Oct. 24, 2017.
17. Oncomatryx, “Targets: MTX5 &
MTX3,” http://oncomatryx.com/
antibody-drug-conjugates/targets-
mtx5-mtx3/, accessed Oct. 24, 2017.
18. Oncomatryx, “Antibodies: MTX5 &
MTX3,” http://oncomatryx.com/
antibody-drug-conjugates/antibodies-
mtx5-mtx3/, accessed Oct. 24, 2017.
19. Oncomatryx, “Payloads: Cytolysin &
Nigrin,” http://oncomatryx.com/antibody-
drug-conjugates/payloads-cytolysin-
nigrin/, accessed Oct. 24, 2017.
20. Oncomatryx, “Pipeline,” http://
oncomatryx.com/pipeline/,
accessed Oct. 24, 2017. ◆
SPONSORED BY
Cell Culture Media Lot-To-Lot Variability: Can We Control It?
An Executive
Summary
The importance of taking into account
variability in cell culture media.
Biopharmaceutical manufacturers are constantly seeking to gain more control over protein
quality and process consistency. Both chemically defined media and biologically derived
peptones can contribute to variability in cell culture processing due to impurities and
inherent lot-to-lot variability. BioPharm International recently sat down with Graziella Piras, PhD,
a scientific application manager at BD Life Sciences, to discuss variability in cell culture media
and how to reduce this variability, in both complete and chemically defined media formulations.
BioPharm International: We hear a lot
about variability in cell culture media.
How does this variability affect the
bioprocessing industry?
Piras: This is a critical question in our industry.
A bioprocess will depend on several factors.
The cell line from which a biological drug is
produced is very important, particularly how it
is derived and generated as well as its stability.
In addition, there is also the process itself,
how it is controlled through all parameters,
and the cell culture media, which has many
components. Some chemically defined media
have more than 80 components, which can
be sources of variability. Therefore, defining
the concentration of each component is very
important as well as controlling what goes
into the medium to ensure no impurities are
present that could derail the process.
Med ium can be supp lemented w i th
peptones, which are derived from natural
products such as plants or yeast, and can
introduce some inherent variability. We want
to make sure we can control that and define
the parameters to always produce the same
amount of protein from the cell line and ensure
the efficacy and safety of the biological drug
being produced. This is at the center of pro-
cess control: making sure we always produce
a consistent amount of protein and with an
appropriate quality profile.
BioPharm International: Are peptones
the major source of variability in com-
plete media formulations?
Piras: Peptones are certainly a potential
source of variability. But what we have found
is that the chemical components of the media
itself can also be a major source of variability.
For instance, if we are using a peptone-
containing media, we will have the peptone
in addition to the base medium that contains
numerous chemically defined components.
Some impurities, like trace metals (e.g.,
manganese), in chemically defined compo-
nents can have a drastic effect on protein
quality. Therefore, whether the variability
stems from peptones or chemically defined
medium components, it’s very important to
control it.
Graziella Piras, PhD Scientific Application Manager
BD Life Sciences
CELL CULTURE MEDIA LOT-TO-LOT VARIABILITY: CAN WE CONTROL IT?
BioPharm International: Understanding what is driving
your cell culture process is important. What exactly are
these key drivers and how do you identify them?
Piras: This is key to the approach we have developed at BD. If
we focus on a process where we are using peptones that are
composed of over 50 components, to really understand what
is driving the process, we want to nail down the key, specific
components that will positively or negatively affect the process.
In our experience, we have found that not everything is impor-
tant and that every process is unique and will depend on the
presence and proper concentration of just a few components.
We analyze each component within the peptones and
generate a statistical model to establish a statistical correla-
tion between each analyte and the performance. We then
reduce the system to just those few components that show a
statistical correlation with key performance parameters. At the
center of this approach is defining which components cause
the variability versus the ones that just correlate with vari-
ability. We see some components, for example, that fluctuate
slightly but are not correlating with the variability. By using
a statistical model, we can establish which ones cause the
variability. We also find that key drivers have a narrow range
of optimal performance and that is what we need to define.
We have examples where copper needs to be between 1 and
2.5 ppm in a very tight range of lower order ppm. We don’t
just accumulate analytical data, but apply a statistical model
and develop a predictive tool to identify which parameter is
causing the variability.
BioPharm International: How do you get to this statis-
tical model that you mentioned?
Piras: We use an iterative process in which the model will
analyze the statistical significance of the impact of each
component that is present in a chemically defined medium or
a peptone and establish a correlation. If a component drives
the process and may affect variability, the model will assign
that component a high coefficient. If the component is not
driving the process, the model will eliminate that component.
Finally, the model will eliminate all the components that do not
correlate with the performance and variability.
The next important step is to assess the causative nature
of those key drivers. This is done by generating peptones
in which those potential key drivers are modulated beyond
the natural variation. By modulating the amount of a potential
driver, we can demonstrate its causative nature. If the compo-
nent further positively or negatively affects the variability, then
that is a good indication that this is a key driver of variability.
The last step is then to lock in the model and demonstrate
that this is a predictive tool to identify lots of peptones with
a very high likelihood of working in the customer’s process.
BioPharm International: Can you apply this method-
ology to reduce variability in chemically defined media
as well as complete media?
Piras: Any cell culture medium has impurities and this meth-
odology can be applied to a peptone-containing medium or
a chemically defined medium where, even though the com-
ponents are defined, each component may bring in impurities.
Our methodology can identify the variability in both.
BioPharm International: And once you have defined the
key drivers, how does BD help to manage the variability?
Piras: Once we have the key drivers, we can screen lots of
chemically defined media or peptones and make sure that
they fit the model for that specific process. In this way, we
can provide material that works very well early on rather than
having to go through extensive screening using a complex
biological process. The idea is to prescreen the material
before it is used in large- or small-scale models to save time
and resources.
36 BioPharm International www.biopharminternational.com November 2017
TR
AIM
AK
/Sh
utt
ers
tock.c
om
Regulated companies that use
automated cleaning applications
have always struggled with cor-
relating rinse sample quality or
visual inspection to surface cleanliness.
The process typically involves perform-
ing 100% spray coverage testing, rinse
recovery testing, specific or non-specific
analytical method qualification, surface
sampling and recovery testing of the
sampling technique, and visual inspec-
tion performed during the cleaning vali-
dation. Each element of the justification
needs to be reviewed and evaluated dur-
ing the cleaning process design stage
to defend a lean approach in continu-
ously monitoring the cleaning process. A
risk-based approach, supplemented with
laboratory studies and information from
published literature, can be leveraged in
the justification to reduce testing dur-
ing cleaning qualification and continu-
ous monitoring stages without impacting
quality. Laboratory results from total
organic carbon (TOC) and conductivity
rinse sample for an alkaline detergent
along with determining visible residue
limits using multiple concentrations,
light intensity, viewing angles, inspec-
tors, and distances have been used by
multiple biopharmaceutical companies.
This approach has helped correlate rinse
sample quality or visual inspection and
justify a lean approach to continuously
monitoring surface cleanliness.
CLEANING VALIDATION REGULATORY GUIDANCEFDA’s 1998 cleaning validation guidance
document focuses on general aspects
and qualification of the cleaning pro-
cess (1). The design and post-validation
Evaluating Surface Cleanliness Using a Risk-Based Approach
Elizabeth Rivera
and Paul Lopolito
Rinse sample analysis or visual
inspection can be correlated
to surface cleanliness to
replace surface sampling.
Paul Lopolito is a senior technical
services manager and Elizabeth
Rivera is a technical services manager,
both at the Life Sciences Division of
STERIS Corporation in Mentor, Ohio.
Cleaning Validation and Monitoring
November 2017 www.biopharminternational.com BioPharm International 37
AL
L F
IGU
RE
S A
RE
CO
UR
TE
SY
OF
TH
E A
UT
HO
RS
monitoring aspects are factored
into the validation process, but
are not specified in the regulatory
guide nor in the industry practices.
Today, this is referred to as the old
or traditional approach to valida-
tion. Other countries used a simi-
lar approach to provide guidance
to the industry of the regulatory
expectations regarding cleaning
and cleaning validation (2–3).
In 2011, FDA issued a revised pro-
cess validation guidance document
that introduced a concept known
today as the product lifecycle model
(4). This model separates the various
steps and activities of validation into
three stages: process design, process
qualification, and continuous pro-
cess verification. Since then, the life-
cycle model has become the “gold
standard” for all types of processes
including cleaning validation; it pro-
vides a better understanding of the
design and monitoring of the clean-
ing process (see Figure 1) and, con-
sequently, it ensures a more robust
cleaning validation program.
Along with the process lifecycle
approach, other guides have been
issued by FDA and the International
Council for Harmonization (ICH),
which include the concepts of
quality by design (QbD), risk man-
agement, and process analytical
technology (PAT) (5, 6). The pur-
pose of these guidance documents
is to promote enhanced under-
standing of products and processes,
to build quality into manufactur-
ing, and to provide the basis for
continuous improvement of prod-
ucts and processes. Figure 2 shows
the correlation between these doc-
uments and the lifecycle model.
Consequently, the lifecycle model
places more attention on under-
standing the process and its design,
and continued monitoring of the
operation to ensure the expected
results. By comparison, the old vali-
dation approach placed most efforts
on qualifying the process rather
than understanding it.
Cleaning in the GMP industry is
a critical process intended to prevent
or, in more modern terms, reduce
risk of contaminating the subsequent
product with undesirable residues
that may impact patient safety. For
that reason, it is important to make
the right connection between rinse
sampling and/or visual inspection to
surface cleanliness. Reducing the risk
requires good understanding of the
cleaning process. Some aspects of the
lifecycle model must be considered
to ensure that surface cleanliness not
only is feasible and consistent but
also relates to patient safety. Figure 3
depicts a workflow that helps bridge
the gap between sampling to surface
cleanliness, which will be discussed
in more detail.
REVIEW ENGINEERING DESIGN AND COVERAGE TESTINGThe design of the process equip-
ment must be considered to ensure
that the cleaning recommendations
Cleaning Validation and Monitoring
Figure 1. Example of cleaning validation activities in a lifecycle model.
Figure 2. Correlation between the lifecycle model, International Council
for Harmonization (ICH), and process analytical technology (PAT) guidance
documents.
DESIGN VALIDATION MONITOR
Process equipment Readiness check: Periodic reviewProcess controlsContinuous monitoring
Cleaning documentation
Personnel training
– Process equipment– Utilities system– Analytical method
UtilitiesCleaning methods
Cleaning parametersResidue detection
Acceptance criteria
Roadmap to the cleaning validationLifecycle approach
Stage 1:Cleaning process
Design
Stage 3:Continued cleaningProcess verification
Changes
Changes
Stage 2:Cleaning process
PerformanceQualification
Co
nfi
rmC
on
firm
ICHQ8
ICHQ9
ICHQ2
ICHQ10
ICHQ10
PAT
38 BioPharm International www.biopharminternational.com November 2017
can be successfully scaled-up from
laboratory-scale experiments. For
automated clean-out-of-place (COP)
and clean-in-place (CIP) applica-
tions, it is important to review cov-
erage and flow velocity in vessels
and piping, drainability of the wash
and rinse solutions, surface finish,
and materials of construction (7–9).
Spray devices should cover all the
surfaces that they are intended to
clean. These types of devices can
be fixed or dynamic. Riboflavin
(vitamin B2) testing using 0.2 g/L
vitamin B2 and an ultraviolet (UV)
light ensures that the spray device
gives full coverage during the wash
and rinse steps. For vertical tanks,
the flow rate of a static spray device
should be about 2.5–3 gallons per
minute per feet of internal tank
diameter (10). Vessel inserts such as
agitators, probes, and baffles may
be challenging to clean in place and
hence, coverage testing becomes
more crucial to designing for a suc-
cessful cleaning.
Flow rates in piping are important
for proper coverage of solutions, as is
providing turbulent flow. The flow
velocity in piping should be five feet
per second (approximately 1.5 m/s)
to prevent air entrapment at vertical
elbows. Dead legs should be mini-
mized, and the length-to-diameter
ratio of less than or equal to 1.5 is
preferred. Dead legs should also be
oriented at an angle to allow for full
coverage and drainage during wash-
ing and rinsing.
The drainage of wash and rinse
solution is also important. Pooling in
vessels and piping may lead to micro-
bial blooms, biofilm, and carryover of
process and cleaning agent residues.
The mixing of the drain solution
(heel) can reduce residue deposition
on the side walls. Horizontal tanks,
equipment surfaces, and piping
should be sloped at 1/8–1/16 inches
per square foot (3.6–1.8 cm per
square meter) to allow full drainage.
The preferred materials of con-
struction in the pharmaceutical
industry are 304 and 316L stain-
less steel. Other materials of con-
struction are used throughout the
industry. The selection of materials
should be based on both the manu-
facturing process and on the clean-
ing procedure required for reducing
the amount of residue to safe levels.
Surface roughness as well as other
materials of constructions in use
should be included in the laboratory
studies to ensure that such levels do
not adversely impact cleanability
and recovery of residues.
CLEANING AGENT AND ANALYTICAL METHOD SELECTIONCleaning agents should be selected
based on laboratory studies that sim-
ulate the process soil, soil condition,
and cleaning method used, as well
as performing a supplier qualifica-
tion and technical support review.
Further consideration should be
given to formulation, toxicity, ana-
lytical method for residuals, rinsabil-
ity of components, stability of closed
and open containers, and assurance
that the product will be made con-
sistently over the life of the prod-
uct, which is often in decades for
cleaning agents intended for GMP
applications. Several cleaning agent
options are available, including
water, solvents, commodity chemi-
cals, and formulated cleaning agents
(11). Formulated cleaning agents are
blends of the latter components that
help improve cleaning performance
by incorporating several cleaning
mechanisms in solution. Table I
lists different components used in
designing cleaning agents (12).
A variety of analytical methods
are used to detect active ingredients,
degradation or byproducts, biobur-
den, endotoxin level, and cleaning
agent residues. The selection may be
based on multiple factors including
the analyte of interest, analytical
resources available, rinsability, and
carry-over risk.
The rinsability of a cleaning
agent is crucial in demonstrating
that the components within the
formulation rinse freely from the
surface with water. If the compo-
nents within the formulation rinse
at similar rates, then either non-
specific methods, such as conduc-
tivity or TOC, or specific methods,
such as ultra high-performance liq-
uid chromatography (UHPLC), can
be used (13, 14). If the components
Cleaning Validation and Monitoring
Figure 3. Workflow to bridge the gap between sampling and surface cleanliness.
Roadmap to the cleaning validationLifecycle approach
Review engineering design and coverage
testing
Rinse sampling and rinse recovery
Visual inspection and visible residue limit
Surface sampling
selection and swab
recovery
Cleaning parameters
and analytical method selection
Stage 1:Cleaning process
Design
Stage 3:Continued cleaningProcess verification
Stage 2:Cleaning process
PerformanceQualification
Co
nfi
rmC
on
firm
Changes
Changes
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40 BioPharm International www.biopharminternational.com November 2017
Cleaning Validation and Monitoring
do not rinse at similar rates, then
it is important to identify and set
residual limits based on the last-to-
rinse component. Refer to Figure 4
to compare rinsing results with
various analytical methods for
monitoring components within a
formulated cleaning agent (13).
Cleaning agents used for product
contact surfaces must have toxic-
ity information available, which is
important in determining safe lev-
els of cleaning agent residues. The
toxicity of components is important,
especially if they are the last to rinse
from the surface or if they display
mutagenic, reproductive, carcino-
genic, developmental, or chronic tox-
icity. In the case of cleaning agents,
the sum of components may have
increased or decreased toxicity com-
pared to individual components, and
toxicity of the cleaning agent should
be available from the suppliers.
SURFACE CLEANLINESSThe ability to sample the surface for
cleanliness is the preferred technique
to demonstrate the equipment is
ready to manufacture the next batch
of product, a new product, or to pro-
ceed with the next manufacturing
process step. Surface testing, however,
requires a significant amount of time
to: prepare the equipment for sam-
pling; prepare and source sampling
tools; sample the surfaces; transport
samples for testing; test samples; and
review results of testing.
In addition to the amount of time
required for sampling and testing,
there is allocation of labor for sam-
pling and testing, often scheduling
between multiple departments, and
more importantly lost time that
could be used for manufacturing or
sampling and testing critical steps
within the manufacturing process.
The selection of sampling sites and
test methods and performing sur-
face sampling recovery will help in
significantly reducing or even elimi-
nating routine surface sampling to
demonstrate surface cleanliness.
Selection of sampling sites
The European Union GMP guideline,
Annex 15 section 10.11, cites that
cleaning validation protocols should
specify or reference the locations to
be sampled, specify the rationale for
the selection of these locations, and
define the acceptance criteria (15). A
documented sampling and testing
plan must be prepared describing:
location of samples (and rationale),
number of samples per location,
sampling test methods used, wetting
agent, and surface area sampled.
The use of diagrams, such as the
one illustrated in Figure 5, provides
the operator with a better picture
of the sampling areas to focus on
(16). They also aid in understanding
the rationale behind the sampling
site selection. Figure 5, for example,
shows the interior of a vessel with
multiple accessories that reduce
the coverage provided through the
spray device (top circumference)
in a CIP system. The shaded area
in the vessel represents the nor-
mal process air-to-liquid interface,
which is often an area where solids
settle onto the surface and form a
scum-like ring on the walls.
Sampling sites should be defined
based upon the geometry and
design of the equipment, materi-
als of construction, hard-to-clean
areas, and locations that may have
a higher risk to product contamina-
tion (i.e., risk assessment), or they
may be based on historical refer-
ence from similar equipment on
Figure 4. Monitoring of cleaning agent residues on surface.
TOC is total organic carbon.
100.095.090.085.080.075.070.065.060.055.050.045.040.035.030.025.020.015.010.0
5.00.0
Percent residue removal
TOC
Sodium (IC)
Potassium (IC)
Titration
Organic Acid
Chelant
Rinse Time, Seconds
% R
em
oved
15
30
45
Table I. Components in formulated cleaners.
Component Function
Water Solvent for salts, polar materials; carrier for additives
SurfactantWet, solubilize, emulsify, disperse, lubricate, soften, release, detergent,
level, corrosion inhibitor, couple, foam, foam stabilizer, disinfectant
Chelants Tie up calcium, iron, and other metals
Solvent Solubilize
Bases Alkalinity source, hydrolysis
Acids Acidity source, hydrolysis
Builders Assist in detergency; multifunctional
Dispersants Suspend solids
Antimicrobials Kill, reduce microbes
Oxidant Oxidize, kill microbes
November 2017 www.biopharminternational.com BioPharm International 41
site (i.e., benchmark). The ribofla-
vin testing used for spray device
qualification in CIP systems also
helps in identifying areas that must
be sampled due to limited coverage.
Risk-based surface sampling
locations and testing performed
A risk assessment should be per-
formed to minimize the number of
sampling sites. Table II is an exam-
ple of a list of sampling sites and
assigned risk factors.
A risk assessment should also be
performed to minimize the number
of tests performed, such as micro-
Cleaning Validation and Monitoring
A large biopharmaceutical manufacturer was designing a new
facility for the final compounding and filling of their product.
This standard parenteral facility consists of an automated
parts washer, steam sterilizer, automated vial washer,
depyrogenation tunnel, filling machine, closure machine
to insert stoppers, capping machine, and product labeler.
This product was being filled by a contract manufacturing
organization (CMO), which was using only water for cleaning.
During the design phase of the cleaning program, coupon
testing was performed by coating the finished product onto
stainless-steel coupons and evaluating the cleaning with water
and a formulated alkaline cleaning agent to remove the finished
product. Water-only cleaning at ambient to 80 oC was not
sufficient to yield a visual clean and water-break free surface.
Cleaning the coupons with water was successful in meeting
the gravimetric testing of around 1–2 mcg/cm2. In support of
a visual inspection program of the items being washed in the
parts washer, a visible residue limit (VRL) study was performed
on the final drug product as well as on a formulated alkaline
cleaning agent on stainless-steel and glass surfaces.
The VRL study procedure consisted of precleaning and
drying 304 stainless-steel coupons with a 2B finish as well
as borosilicate-glass coupons. The roughness of the 304
stainless coupons was comparable to the 316L stainless-
steel specifications for the filling parts. The formulated acid
and alkaline cleaning agents as well as the finished product
were compatible with 304 stainless steel, so the use of
these coupons as a test substrate versus 316L was justified.
The test samples were serially diluted, and 1 mcl of diluted
sample and 20 mcl of low TOC de-ionized (DI) water were
applied over a 1-cm2 area. The sample was then allowed to
air-dry at ambient temperature for at least 16 hours.
After drying, the coupons were inspected by two analysts,
in duplicate, at one of the following distances (0.45 m, 1.0
m, and 1.5 m); lighting conditions (250 lux, 500 lux, and
1000 lux); viewing angles (30o, 45o, and 90o); and with and
without a viewing mirror. A light meter (Cooke Corporation
Cal-Light 400 lux), digital protractor, and 1–5 mcl syringe
(Hamilton) were used in the study. The acceptable results
for both analysts on two coupons per set for the formulated
alkaline cleaning agent are noted in Sidebar Figure 1. The
borosilicate glass surface was used in the construction of the
viewing endcap on the final formulation compounding tank, so
the higher VRL observed was not critical.
Visual inspection training
The visual inspection procedure as well as the inspector
qualification study consisted of precleaning and visual
inspection of the coupons before spiking. An analyst
receives a yearly eye exam with 20/20 vision (glasses
or contact lenses are acceptable), wears safety glasses
during visual inspection, and is informed that some coupons
may not contain a sample. This procedure is used to try to
eliminate phantom residues or false positives.
The coupons were placed flat on a table in front of a
fume hood in groups of three, and the inspector stood back
approximately 0.85 m and inspected the coupons at a 50o
angle. The groups of three coupons were mixed in order
as seen in Sidebar Table I. The lighting in the room was
between 500 and 1000 lux.
An acceptable result is that the inspector identifies all
coupons with a loading of 10 mcg/cm2 and 12 out of 15 of
the remaining coupons.
Visible residue limit case study
Table I. Visual inspection training test matrix example.
Coupon set 1 7 mcg/cm2 10 mcg/cm2 Blank
Coupon set 2 10 mcg/cm2 5 mcg/cm2 10 mcg/cm2
Coupon set 3 Blank 7 mcg/cm2 5 mcg/cm2
Coupon set 4 5 mcg/cm2 Blank 7 mcg/cm2
Coupon set 5 10 mcg/cm2 7 mcg/cm2 10 mcg/cm2
Figure 1. Visible residue limit (VRL) results for the
formulated alkaline cleaning agent.
Increase in light to 1000 lux no issues, VRL at 1:600Increased distance resulted in difficulty using mirror and operator variabilityAdjustment in angle improved VRL but increased difficulty in using mirrorAn angle of 90 degrees without mirror had a VRL at 1:600Glass substrate was difficult and displayed variability even at lower
concentrations (1:10, 1:20 and 1:50)
42 BioPharm International www.biopharminternational.com November 2017
Cleaning Validation and Monitoring
bial, detergent, or active ingredient
testing. For example, a TOC swab
may be able to demonstrate removal
of the large molecule API as well as
the cleaning agent used. A single
UHPLC swab may be able to dem-
onstrate the removal of multiple
detergents that are used in separate
wash steps of the cleaning proce-
dure (17). Applying a scientific,
risk-based rationale can drastically
reduce the number of samples taken
as well as testing performed.
Surface sampling recovery studies
Surface sampling recovery studies
using swabs, wipes, or direct sam-
pling techniques should be per-
formed as part of the design stage
to ensure that testing of the surface
can meet predefined acceptance
criteria. Surface sampling should
define the swab or wipe used, sur-
face location sampled, surface area
sampled, material of construction
of the surface, number and condi-
tion of the swab(s) or wipe(s), sam-
ple storage and stability conditions,
swab or wipe diluent, and sam-
pling accessories; qualified analysts
should perform the testing. The
surface sampling recovery study
should also consider, if applicable,
the swab or wipe wetting solu-
tion and various spiked amounts
on the surface. The spiked amount
and design of the surface sampling
recovery test should challenge the
sampling and analytical procedure.
The analysis of swab recovery from
various active pharmaceutical ingredi-
ents as well as cleaning agent residues
from a single site using various materi-
als of constructions (including metals,
plastics, and elastomers) supported
that stainless steel could be used as a
representative surface for swab recov-
ery (18). Forsyth, et. al. pooled recov-
ery factors from 16 sites, 29 different
materials, and hundreds of samples.
The reported recovery factor from a
formulated alkaline cleaning agent,
CIP 100 detergent, from 316 stainless
steel was 93% (18).
VISUAL INSPECTIONVisual inspection is important to
ensure that the equipment looks
sufficiently clean to proceed with
analytical testing. There are limita-
tions, similar to surface sampling,
with routine visual inspections, such
as large equipment or lengths of pip-
ing, as well as the time and resources
required for proper visual inspection.
Visual inspection can be defined
as the process of using the unaided
eye as the sensing mechanism from
which judgments can be made
about the condition of a unit to be
inspected. A visual non-uniformity
on equipment surfaces may present
as an interruption of the normal pat-
tern or grain either by residue or dis-
coloration in amount as perceived by
the unaided eye. This non-unifor-
mity could be on the surface, such
Figure 5. Sampling site selections.
Table II. Risk assessment of surface sampling locations. MOC is material of construction.
Sampling Location
Critical Site: Potential large
contaminant area
Hot Spot (historically
hard to clean)
Affinity to MOC or
surface finish
Role in process likely to lead to difficult residue
Cleanability of location/
coverage and access
Ranking
Sidewall 1 1 1 1 1 5
Bottom outlet valve 5 3 3 1 1 13
Dome lid 1 1 1 1 5 9
Instrument port 1 5 3 1 5 15
Sampling port 5 5 3 1 1 15
Agitator 1 1 1 1 3 7
EVENT OVERVIEW
In mAb purification, viral clearance is a requirement of
downstream processing of biologics, especially those
derived from microbial expression systems that contain
endogenous host cell endotoxin. Viral clearance studies,
which verify virus removal, do not have a set standard
method. Depending on the potential viral contaminant
load in its source materials, a unique method to reduce the
viruses must be designed. In this presentation, different
resin chromatography modes—such as hydrophobic
interaction chromatography (HIC), ion exchange
chromatography (IEX) and mixed mode—are studied and
compared to verify the effectiveness of viral removal in
mAb purification.
Who Should Attend
■ Chief Medical Officer
■ Downstream process development scientists for mAb
purification
■ Downstream process development managers for mAb
purification
■ Supply chain managers for downstream process
manufacturing
For questions, contact Ethan Castillo at [email protected]
Sponsored by
Presented by
Presenters
Bill EvansProcess Chromatography Technical SpecialistTosoh Bioscience LLC
Moderator: Rita PetersEditorial DirectorBioPharm International
Key Learning Objectives
■ Learn about resin selection for viral
clearance in mAb purification
■ Learn about the effectiveness of
different resins for viral clearance in mAb
purification
■ Learn about viral clearance methods
without jeopardizing the yield or purity of
mAb
Viral Clearance in mAb Purification: A Deeper Look at Resin Selection
LIVE WEBCAST Thursday, November 16, 2017 at 11am EST | 8am PST | 4pm GMT | 5pm CET
Register for free at www.biopharminternational.com/bp_p/resin
44 BioPharm International www.biopharminternational.com November 2017
as visible residue, particulate matter,
pooling of liquid, or rouge (oxides) or
within the surface, such as scratches,
corrosion, or etching.
During the design and qualifica-
tion stages of the lifecycle model, a
correlation between visual inspec-
tion, surface sampling, and rinse
sampling should be performed, so
that a visual inspection or rinse
sample can be scientifically justified
to determine that the equipment,
piping, or parts are cleaned. Visual
inspection as the method to assess
for cleanliness is ideal for small parts
or open process equipment that are
easy to inspect. However, “visually
clean” as the only acceptance cri-
terion will require a justifiable, sci-
entific rationale that will need to
be defended when inspected (15).
Several published articles have eval-
uated the use of visual inspection
procedures and the role of visible
cleanliness in control of critical vari-
ables, as well as establishing visible
residue limits of select analytes.
Visible residue limits
In 1993, Fourman and Mullen
specified a visual limit of small-
molecule active ingredients of 1
to 4 mcg/cm2 (19), and this article
was referenced in the FDA guide
to cleaning validation (1) as well
as Parenteral Drug Association
(PDA) technical report 29 (20).
Forsyth et al. have published sev-
eral articles that include testing
and defining critical variables as
well as presenting various case
studies. The case studies include
spiking a 1 cm2 surface with resi-
due at various concentrations and
on different substrates. Once the
residue is dried, it can then be
inspected visually at different
distances, angles, light intensi-
ties, with the use of mirrors, and
by different analysts (21, 22). By
defining the operators’ qualifi-
cations, visual inspection tools
and conditions, procedures, and
training and retraining activities,
a company can quantify and vali-
date the visual inspection proce-
dure. The Sidebar describes a VRL
case study for a biopharmaceuti-
cal facility.
RINSE SAMPLINGRinse sampling is commonly used
to evaluate surface cleanliness of
closed production equipment, hoses,
and piping commonly cleaned by
CIP systems (23–25). The advan-
tages of rinse sampling are that the
entire surface can be sampled, with
no disassembly of equipment and
no direct sampling of the surface,
and that rinse sample analysis via
conductivity, TOC, UV, and other
Cleaning Validation and Monitoring
Figure 6. First rinse recovery study; linearity between conductivity to
concentration of a formulated alkaline cleaning agent.
Figure 7. Second rinse recovery study; linearity between total organic carbon
(TOC) and concentration of a formulated alkaline cleaning agent.
November 2017 www.biopharminternational.com BioPharm International 45
Cleaning Validation and Monitoring
methods in-line or on-line can be
adapted to PAT technologies. The
disadvantages of rinse sampling are
that the analyte measured may not
be soluble in the rinse solution, rins-
ing may not pick up the residue due
to poor coverage during rinsing, and
the analyte may be too diluted in
the rinse solution volume.
Rinse recovery studies
Rinse recovery studies can be used
in addition to assessing the solubil-
ity of the active ingredient in the
rinse solution. The studies are per-
formed by adding a specified con-
centration, around the acceptable
limit, of the residue on the surface.
The selection of the residue, condi-
tioning of the residue, surface mate-
rial, roughness of the surface, rinse
solution, volume of rinse solution
per surface area, rinse solution tem-
perature, and flow rate should all be
considered in setting up a rinse solu-
tion recovery study.
Two rinse recovery studies are dis-
cussed as examples. The first rinse
recovery case study includes a lin-
earity between concentration and
conductivity of a formulated alka-
line cleaning agent (Figure 6) as well
as the recovery factor from stain-
less steel, polytetrafluoroethylene
(PTFE), rubber, and glass surfaces
(Table III). The second rinse recov-
ery case study includes a linearity
between concentration and TOC of
a formulated alkaline cleaning agent
(Figure 7) as well as the recovery fac-
tor from stainless steel, PTFE, rub-
ber, and glass surfaces (Table IV).
Three lots of the formulated alka-
line cleaning agent were diluted at
various concentrations between 1
and 100 ppm by volume using DI
water and tested at ambient tem-
perature. A conductivity meter
(Radiometer/Copenhagen CDM83)
was used, and the conductivity
probe was standardized following
the manufacturer’s recommenda-
tions with 50 and 100 mcS/cm stan-
dards prior to testing. Temperature
Table III. Conductivity and pH results, 24-hour air-dried samples; SS is stainless steel.
Sample Identification Conductivity mS / cmAverage Percent
Recovery, %Relative Standard
Deviation, %pH
SS 5.608
66.1 0.1
8.05
SS 5.360 8.11
SS 5.387 8.08
Teflon 5.276
66.5 0.3
8.43
Teflon 5.361 8.55
Teflon 5.804 8.30
Rubber 4.915
63.6 0.3
8.44
Rubber 5.460 7.80
Rubber 5.362 7.93
Glass 5.081
63.0 0.2
6.85
Glass 5.378 7.44
Glass 5.121 7.29
Table IV. Total organic carbon (TOC) results, 24-hour air-dried samples. SS is stainless steel.
Sample
Identification
TOC
experimental,
ppb C
TOC
theoretical
(at 100 %
Recovery), ppb C
Net TOC, ppb CPercent
Recovery, %
Average
Percent
Recovery, %
Relative
Standard
Deviation, %
SS 463 355 327 92.2
95.2 2.6SS 475 353 339 96.1
SS 488 362 352 97.2
Teflon 708 341 370 108.6
98.7 31.5Teflon 762 342 424 124.1
Teflon 564 356 226 63.5
Rubber 505 358 263 73.4
95.5 20.0Rubber 595 350 353 100.8
Rubber 525 356 400 112.3
Glass 452 354 290 82.0
92.7 9.4Glass 512 352 350 99.5
Glass 503 353 341 96.5
46 BioPharm International www.biopharminternational.com November 2017
Cleaning Validation and Monitoring
compensation was not used for this
testing. The conductivity to concen-
tration curve is reported in Figure 6.
Three lots of the formulated
alkal ine cleaning agent were
diluted at various concentrations
between 0.1 and 5 ppm C by vol-
ume using DI water and tested at
ambient temperature. A laboratory
TOC analyzer (Sievers 900) was
used for testing, and the TOC ana-
lyzer was standardized following
the manufacturer’s recommenda-
tions with reference standards for
sucrose and benzoquinone. The
TOC to concentration curve is
reported in Figure 7.
Rinse recovery testing was per-
formed by applying 1 +/-0.1 g of
the prepared 0.24% w/w formu-
lated alkaline cleaning agent to
about 100 cm2 area of one side of
the stainless steel, PTFE, glass, and
rubber coupons using an analyti-
cal balance (Mettler Toledo XS).
Solution was applied in drops
to provide a uniform coverage.
Samples were air-dried on the
coupons in a horizontal position.
After drying, 300 mL of DI water at
ambient temperature was poured
from a squeeze bottle over the cou-
pon so that the flow cascades down
the face of the coupon for approxi-
mately 30 seconds. The collected
rinse water was agitated for 30 sec-
onds to ensure uniformity, then 39
mL was poured into a labeled TOC
vial, sealed, and measured for TOC
(Sievers 900 laboratory TOC ana-
lyzer). The TOC recovery results are
reported in Table IV. The remain-
ing sample (39 mL) was measured
for conductivity (Fisher Scientific
AB30 conductivity meter). The
conductivity recovery results are
reported in Table III.
CONCLUSIONSurface cleanliness is crucial in
ensuring that process residue,
cleaning agent residue, and bio-
burden do not adversely affect the
safety, quality, and potency of the
drug manufactured. Surface clean-
liness can be determined through
surface sampling, rinse sampling,
and visual inspection. The pre-
ferred method is surface sampling
through swabbing, wiping, or
direct measurement. Surface sam-
pling can add production delays,
increased sampling costs, and
often increased safety risk to the
analyst. If the engineering of the
equipment, coverage testing of the
equipment, and cleaning agent
and analytical method selection
have been well vetted during the
design and qualification stages of
the lifecycle approach, then rinse
sampling or visual inspection can
be successfully used to demon-
strate surface cleanliness. Attention
to detail and application of a risk-
based approach during the design
stage can provide justification for
using either rinse sampling or
visual inspection in determining
surface cleanliness.
ACKNOWLEDGEMENTThe authors a re g ratef u l to
Amanda Deal for excellent techni-
cal assistance in performing the
VRL study as well as the first and
second rinse recovery case studies.
REFERENCES 1. FDA, Guide to Inspections Validation
of Cleaning Processes (July 1993).
2. Health Canada, Guide-0028 Cleaning
Validation Guidelines (Jan. 2008).
3. PIC/S, PE-006-3 Validation Master Plan
Installation and Operational Qualification
Non-Sterile Process Validation
Cleaning Validation (Sept. 2009).
4. FDA, Process Validation: General
Principles and Practices (Jan. 2011).
5. FDA, Guide for Industry. PAT—A
Framework for innovative pharmaceutical
development, manufacturing, and
quality assurance (Sept. 2004).
6. ICH, Harmonised Tripartite
Guideline—Q9 Quality Risk
Management (Nov. 2005).
7. E. Rivera, “Basic equipment-
design concepts to enable cleaning
in place: Part I,” Pharm. Tech.
Equipment and Processing Report
(June 15, 2011), www.pharmtech.
com/basic-equipment-design-
concepts-enable-cleaning-place-
part-i, accessed Oct. 10, 2017.
8. G. Verghese and P. Lopolito,
“Cleaning Engineering and Equipment
Design,” in Cleaning and Cleaning
Validation Volume I, P. Pluta Ed. (DHI
Publishing and the Parenteral Drug
Association, 2009) pp 123-150.
9. J. Voss, Cleaning and Cleaning
Validation: A Biotechnology Perspective
pp 1-39 (PDA, Bethesda, MD, 1996).
10. ASME, Bioprocessing Equipment
(BPE) p. 52 (2012).
11. G. Verghese and N. Kaiser,
“Cleaning Agents and Cleaning
Chemistry, Chapter 7” in Cleaning
and Cleaning Validation Volume
I, P. Pluta Ed. (Davis Healthcare
International and Parenteral Drug
Association, 2009) pp 103-121.
12. P. Lopolito, “Critical Cleaning for
Pharmaceutical Applications, Chapter
17” in Handbook for Critical Cleaning
Applications, Processes and Controls,
Second Edition, B. Kanesgsberg and
E. Kanesgsberg, Eds. (CRC Press,
Taylor & Francis Group, 2011).
13. H.J. Kaiser, J.F. Tirey, and D.A.LeBlanc,
J. Val. Tech. 6 (1) 424-436 (1999).
14. H. J. Kaiser and B. Ritts,
“Validation of Analytical Methods
Used in Cleaning Validation,” J.
Val. Tech. 10 (3) (May 2004).
15. European Commission, Good
Manufacturing Practice Medicinal
Products for Human and Veterinary
Use —Annex 15, Qualification
and Validation (2015).
16. P. Lopolito and E. Rivera, “Cleaning
Validation: Process Lifecycle Approach,”
in Contamination Control in Healthcare
Product Manufacturing, Vol 3. R.
Madsen and J. Moldenhauer, Eds.
(DHI Publishing, PDA Books, 2014).
17. M. Gietl, B. Meadows, and P. Lopolito,
“Cleaning Agent Residue Detection with
UHPLC” Pharm. Manufacturing (April,
2013) www.pharmamanufacturing.
com/articles/2013/1304_
SolutionsTroubleshooting/,
accessed Oct. 10, 2017.
18. R. L. Forsyth, J.C. O’Neill, and
J.L. Hartman, Pharm. Tech. 31
(10) 103-116 (2007).
19. G. L. Fourman and M.V. Mullen,
Pharm. Tech. 17 (4) 54-60 (1993).
20. PDA, Technical Report No. 29 (Revised
2012) Points to consider for cleaning
validation. (Bethesda, MD, 2012).
21. R.J.Forsyth, V. Van Nostrand,
and G.P. Martin, Pharm. Tech.
28 (10) 58-72 (2004).
22. D. A. LeBlanc, J. Pharm. Sci.
Tech. 56 (1) 31-36 (2002).
23. D. A. LeBlanc, Rinse sampling for
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48 BioPharm International www.biopharminternational.com November 2017
A a
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Clinical trials pose major man-
ufacturing and distribution
challenges, which have been
magnified by the trend to out-
source more operations. The success of
any clinical trial demands strong adher-
ence to GxPs—required good current
practices in manufacturing, clinical,
distribution, and documentation. The
end goal, says Matthew Caponi, senior
director of North American depot and
production services at PAREXEL, is pro-
viding assurance that the rights, safety,
and wellbeing of patients are protected,
and that the results of the trial will be
unbiased and credible.
A number of factors, including
increasing complexity of drug forms
and increased reliance on outsourcing,
has made it more difficult to optimize
manufacturing, packaging, and distri-
bution for clinical trials.
In addition, a growing number of
manufacturers are moving from tradi-
tional to direct-to-patient clinical trial
designs, a shift that will change basic
Moving Toward Direct-to-Patient Models
Agnes Shanley
Despite GxP and data-
management challenges, pharma is
moving toward new models
for clinical trial logistics.
Clinical Trial Logistics
A growing number of CRLs
reflects dosage complexity
and a clinical-to-cGMP
disconnect at some
companies.
communication, logistics, and the
way that manufacturing, patient
compliance, and logistics data are
exchanged. This article examines
some current trends and changes
that can be expected in clinical
trial logistics in the near future.
MANUFACTURING DELAYSOn the manufacturing side, fail-
ure to maintain GMP standards
at the clinical stage is resulting in
an increased number of new drug
approval delays. In 2016, for exam-
ple, FDA issued a record number of
complete response letters (CRLs)
for new drugs under development.
CRLs detail problems found at pre-
approval facility inspections for new
drug applications (NDAs) and require
that manufacturers or contract part-
ners fix these issues before the NDA
approval process can continue.
According to John Jenkins,
retired director of the Office of
New Drugs in FDA’s Center for
Drug Evaluation and Research
(CDER), the agency issued 14 CRLs
for new drugs (1) in 2016, and five
involved cGMP issues at contract
development and manufactur-
ing organization (CDMO) or con-
tract manufacturing organization
(CMO) partner facilities (2).
Some of these cGMP deficiencies
are due to tight timelines and the
fact that formulations are becom-
ing more complex, especially as
drug development shifts from an
emphasis on small molecules to
one on biologics, says Sanjay Vyas,
corporate vice-president, global
head of clinical trial supplies and
logistics at PAREXEL.“Clinicians
want a simple dose to adminis-
ter the most robust and efficient
drug formulation, but some dos-
age forms must be administered
intravenously instead of orally.”
In addition, he says, a number of
new APIs require a difficult syn-
thesis, and the resulting drug prod-
ucts can require special storage and
cold-chain handling.
PATIENT-CENTERED PACKAGINGNot all that long ago, many oral,
solid-dose products were shipped
in corrugate, and temperature
monitoring was not even needed,
says Vyas. “Today, a biologic must
be moved in shippers using phase-
change material of far more robust
and technical design, with temper-
ature monitoring devices to ensure
and demonstrate environmental
control,” he says. “All of these spe-
cific requirements must be sup-
ported by a supply logistics chain
that can ensure that the material
is maintained exactly as required
as it moves along the supply
chain—the chain of custody must
be unbroken and documented as
such,” he adds.
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Packaging for clinical trials must
not only support the required stor-
age conditions but also enhance
patient compliance and ease of use,
as well as efficient logistics, says
Vyas. “A blister card that clearly
shows the morning and evening
dose as part of its design will work
better than a series of bottles pre-
sented to the patient, each with
different dosing instructions,” he
says, adding that smaller, less com-
plicated packs will help support
logistics efforts.
BLINDING CHALLENGESBeyond basic manufacturing, the
most challenging part of any clini-
cal trial is maintaining the practice
of double blinding, which helps
to ensure unbiased trial results by
preventing patients, healthcare pro-
viders, and those who collect and
analyze trial data from knowing
whether each individual subject
in the trial has received the actual
drug being studied or a placebo.
The challenges posed by blinding
requirements run from manufac-
turing to dosage-form selection,
packaging, and distribution. “The
range of potential unblinding or at
least complicating factors is enor-
mous, and as varied as the products
themselves,” says Caponi.
Even numbering the kits to be
used by each individual patient in
a clinical trial requires strategy. If
the randomization and trial supply
management (RTSM) or interac-
tive response technology (IRT) sys-
tem being used is not configured
with blinding in mind, it will be
possible for sites to see trends in
the dispensation of kit numbers
and identify kits that are different
from another, explains Tony Street,
PAREXEL’s head of global portfolio
leadership for clinical trial supplies
and logistics. “The use of scram-
bled rather than sequential num-
bers eliminates this risk, but this
approach can present operational
challenges at the warehouse if the
selection of kits is completely ran-
dom,” he says.
Street suggests using a hidden
sequence number that will not
be visible on the kit, which will
allow depot and warehouse staff to
know the order in which kits will
be requested, so that packing can
be done most efficiently. “When
selecting your RTSM/IRT vendor,
it is essential that you work with
a team that fully understands the
process at study sites and the GMP/
GCP implications of system set up.
Something as small as the sequen-
tial numbers utilized on a patient
kit can jeopardize the credibility
of an entire clinical trial program,”
says Street.
AVOIDING THE NEED FORDOUBLE DUMMY TRIAL DESIGNIn trials where two compounds
are being compared, a double
dummy approach may be required,
in which each of the drugs and
its placebo are given distinctive
forms, for example, different col-
ors for oral solid-dosage forms and
their placebos.
However, careful and early
planning can eliminate the need
for this approach, says Caponi.
“An early decision on dosage form
may prevent the need to resort to
double dummy designs, in turn,
reducing the total number of dos-
age forms manufactured, as well
as the labels produced, packag-
ing components used, and sim-
plifying overall packaging design
strategy. “The end result is a
dosing regimen that is easier for
the patient to maintain and less
expensive to produce,” he says.
For oral solid-dosage forms, the
best solution for blinding may
be as simple as over encapsulat-
ing the product comparator with
the same size capsule, Caponi says.
“Injectables present another whole
spectrum of issues—questions to
ask include: Does your syringe
look the same or can it be some-
how blinded to the comparator?
Is the actual product visually the
same color?” he says.
It’s especially important to be
aware of issues that can result
when blinded drugs for clinical tri-
als are manufactured on existing
commercial lines, a practice that
is becoming more common, and
will become to be widespread in
the future.
Caponi recalls a case in which
transdermal pouches were pro-
duced at various clinical strengths
on a single commercial produc-
tion line. Each of the pouches was
marked so that it could be traced
back to the production line, a use-
ful practice for commercial opera-
tions. However, when the material
was received by the clinical sup-
plies packager, something had
to be done to blind these marks,
because each mark indicated a dif-
ference in strength for each pouch
manufactured on that line.
DIRECT-TO-PATIENT TRIALSThe move from traditional to
direct-to-patient clinical trials (in
which patients take the medica-
tion independently in their own
homes) is gaining ground, and
is likely to result in fundamen-
tal changes in the way products
are packaged and distributed and
how product data are transferred.
“Distribution and medical adher-
ence will now be more closely
intertwined with the design of the
clinical trial itself and the loca-
Clinical Trial Logistics
Early planning can
reduce the clinical
trial complexity and
the need for double-
dummy designs.
November 2017 www.biopharminternational.com BioPharm International 51
Clinical Trial Logistics
tions of the distribution of the
drugs,” says James Streeter, global
vice-president of life-sciences prod-
uct strategy at Oracle.
In formulation and drug deliv-
ery, ease of use and safety will
become even more important,
because patients themselves, rather
than healthcare providers, will be
administering dosing, says Vyas.
As a result, products such as infu-
sions or those that need to be
reconstituted at the point of use
will need to be reformulated, he
says, while packaging design will
have to become even more stream-
lined. Biologics manufacturers will
also be under greater pressure to
develop products that remain sta-
ble under a wider range of tem-
peratures and conditions, he adds.
LAST-MILE PLANNING IS CRUCIALInstead of sending large shipments
to investigator sites, manufactur-
ers will now be sending multiple,
smaller shipments to patients, Vyas
says, and logistics planning and
patient monitoring data will need
to be linked. Planning the last mile
of drug delivery to the patient’s
home from either the manufactur-
ing plant or the storage depot will
become more challenging, he says,
because each country has its own
different product stability require-
ments as well as different geogra-
phies and climates.
“For the clinical supply pro-
vider, orchestrating an integrated
technology and data sharing capa-
bility becomes highly important
to ensure that not only the right
drugs reach the right patient safely
and on time, but also that patient
information remains blinded from
the sponsor to support regulatory
requirements,” says Vyas. Proactive
supply chain planning, agility, and
integrated technology will be key
to success.
In the direct-to-patient world,
shipping controls and tracking will
be handled through new methods
that will involve direct contact
with patients. Third-party vendors
will interact with patients who will
get supplies either directly at home
or at their local pharmacies, says
Oracle’s Streeter.
Tracking and controlling who
gets these drugs will shift from
one central operation to individ-
ual operations, and regulators will
require that patient adherence data
be aligned with distribution con-
trol, Streeter predicts. In fact, he
says, distribution, patient adher-
ence, and overall clinical trial data
will no longer be managed sepa-
rately, but together, because opera-
tions teams running the clinical
trials will need all three types of
data to optimize trial control. In
addition, although investigators
will still be responsible for patient
safety, their operations will also
need to be monitored.
FROM THE PACKAGE TO THE DOSEBlinding and packing the phar-
maceuticals used in clinical trials
will no longer be controlled at the
package level, but at the level of
the individual dose, says Streeter,
who adds that social media will
make blinding more challenging,
because patients may inadvertently
share information with each other
about drugs and their packaging.
The need to ensure that dosage
form and packaging appear iden-
tical will be crucial. Individual
dosage forms and their packaging
will require unique identifiers, and
each will need to be monitored
closely, he says.
Sponsors will have to have the
technology required for tracking
and monitoring as part of each
clinical trial design and as part
of their overall data-management
toolkit, Streeter says. “We won’t
be tracking data at the individual
patient’s kit level, but at the level
of the individual pill, and data will
become part of overall operations
data, so a much more coordinated
approach to data management will
be needed,” he says.
A ROLE FOR BLOCKCHAIN?Data lineage and even blockchain
methodologies will be required so
that manufacturers will be able
to trace each drug, its packaging,
and shipments precisely, Oracle’s
Streeter says. As a result, he says,
data requirements will explode,
requiring large amounts of storage
space, analytics and machine learn-
ing software to manage and mine.
“Evidence-based medicine has
become the norm in the medical
field today, and, as the need grows
for real-world evidence in clinical
trials, so will the need to break
down the silos that still separate
manufacturing, patient compli-
ance, and logistics data. Together,
these forms of data will provide
better overall control, and promise
to reduce the overall costs of clini-
cal trials in the future,” he says.
REFERENCES 1. J. Jenkins, “A Review of CDER’s Novel
Drug Approvals for 2016,” FDAVoice,
January 4, 2017, www.blogs.fda.gov/
fdavoice/index.php/2017/01/a-review-
of-cders-novel-drug-approvals-for-2016/
2. A. Thayer, “The Complete
Response Letter: The Mail No
One Wants to Receive,” cen.acs.
org, May 15, 2017, www.cen.acs.
org/articles/95/i20/complete-
response-letter-mail-one.html ◆
As patient ease-of-use
becomes paramount,
drugs that must be
reconstituted at the
point of use will need to
be reformulated.
52 BioPharm International www.biopharminternational.com November 2017
PRODUCT SPOTLIGHT
Pump Head for Shear-Sensitive Pumping
The Masterflex L/S Cytoflow pump head from Cole Parmer is suited for use in biopharma and microbiology applications. The pump was developed for pumping live cells and shear-sensitive fluids, and
is compatible with all Masterflex L/S drives that accept two or more pump heads. The pump head has a large-diameter rotor
resulting in high flow rates at low motor speeds, and is available in two- and three-roller configurations. Two-roller heads offer higher flow rates, and three-roller heads deliver less pulsation. In addition to the high flow rates at low motor speeds, the pump head has a convex roller for cell viability. According to the company, performance in live-cell applications has been verified by independent test data.
Cole-Parmerwww.ColeParmer.com
Dip-Molded Plastisol Y ConnectorsQosina has added a variety of Y connectors manufactured from plastisol, also known as liquid polyvinyl chloride (PVC), a material used to make flexible components. According to the company, plastisol is Class VI approved and BPA and latex free. These connectors are produced through a dip-molding process rather than traditional injection molding.The company offers standard and universal plastisol
Y connectors. The universal style can be cut to accommodate 3/32, 1/8, 3/16, and 1/4 in. OD tubes. There are 15 different Y connector configurations, sample assortment kits, and custom design services available to meet requirements for a range of projects.
Qosinawww.Qosina.com
Analytical Data System UpdateAn updated version of Shimadzu’s LabSolutions analytical data system incorporates additional functions to comply with data integrity regulations, and to support development and quality inspection procedures. The software features an operating environment for complete data management and security in networked laboratories and can be used with traditional peak integration methods. Users can switch between traditional and new peak integration methods during analysis, allowing the selection of an appropriate peak integration method for the circumstance. This includes selecting a traditional method for compatibility with past data.
A peak integration algorithm in the software can quantify overlapping peaks more accurately, the company reports. The intelligent peak deconvolution analysis (i-PDeA II), which uses analyte UV spectral information obtained by the PDA detector, has been improved and can be used to show data traces for single components more accurately than with the conventional peak purity method, enabling accurate quantitative values, even for co-eluting peaks.
Shimadzuwww.shimadzu.com
Temperature-Controlled Shipping SolutionAlmac Group has expanded availability of the Almac Pod, a temperature-controlled shipping solution service for biologics and other temperature-sensitive products, to the United States as part of the company’s end-to-end, global supply chain management solution. Originally released in Europe, the service is compliant with good distribution practices and comes in three models: protected, optimized, and dynamic.The protected model is qualified for up to 96 hours
against thermal challenges by the International Safe Transit Association and is available in -15 °C to -25 °C, +2 °C to +8 °C, and +15 °C to +25 °C temperature ranges. The optimized model is also qualified for up to 96 hours of protection, eliminates temperature excursions, is suited for reuse with no shippers left at the clinical site, and requires no disposal. The dynamic model features upgraded operational processing capacity and flexibility, and uses a phase-change material to offer increased thermal protection. It can be immediately placed into appropriate storage at each point of packing and in-transit. For this model, Almac has the ability to perform a year-round pack out of clinical shipments.
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November 2017 www.biopharminternational.com BioPharm International 53
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Ask the Expert
Da
mia
n P
alu
s/s
hu
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rsto
ck.c
om
The level of formality in change control may be holding back your SOP progress, according to Siegfried Schmitt, principal consultant at PAREXEL.
Q: We have one established change control
process, and this process is applied to all
planned changes, including changing
standard operating procedures (SOPs). On aver-
age, it takes far too long to complete the pro-
cess. For example, just preparing a line-by-line
description of the rationales for each individual
change in the text of the SOP can take sev-
eral weeks. The result is that we often have to
operate according to draft versions of SOPs, as
changes must be implemented faster for opera-
tional or safety reasons. How can we expedite
this process?
A:You have correctly interpreted the regu-
lations, which require you to establish
change control, or as International Council
for Harmonization (ICH) Q10 calls it, change
management (1), and to have documented pro-
cedures, most likely in the form of SOPs (2). The
issue seems to lie in the way change control is
applied (i.e., the level of formality).
A formal change control process, which as you
describe can take weeks or months to complete
(e.g., for the replacement of a filling line), typically
consists of these steps:
• Change request
• Feasibility assessment
• Technical review
• Input by regulatory affairs
• Review by quality assurance (QA)
• Approval of change
• Implementation of change
• Verification of change effectiveness
• Close-out of the change request.
Notwithstanding the formality of the process,
a change control process should be effective (1),
meaning it is user-friendly, simple, and with
minimal cycle time for decisions. This is aligned
with the concept in ICH Q10 that the level of
effort and formality should be commensurate
with the level of risk.
Your example of preparing a line-by-line
description of the rationales for each individ-
ual change in the text of the SOP gives a good
idea of the level of formality you apply at
present. A change to a SOP will be requested
by the owner of the procedure covered by the
SOP. So this person needs this change and
is thus in a position to assess the technical
and operational feasibility of the change very
well. More importantly, the requester is per-
fectly well aware of the reasons (i.e., the ratio-
nale for each change in the document). For
these reasons, it is standard industry practice
to provide a summary rationale, not a line-
by-line explanation in the revised document
(e.g., change due to revision in the applicable
regulations).
It is also easy for reviewers to see changes to
the revised draft document as these are created
with word processors in ‘track changes’ mode.
This normally provides sufficient information
for the reviewers and approvers. One issue often
encountered at this step in the change process is
the number of reviewers and approvers that have
to sign off on the document. In effective organi-
zations, this is kept to a minimum (i.e., two or
three signatures).
The solution to your problem is to review the
level of formality applied, especially in the docu-
mentation of the change and the reasons for the
change. There is no reason why a change to a
SOP cannot be completed in a compliant, con-
trolled, and formal manner in as short a time as
one working day.
REFERENCES 1. ICH, Q10 Pharmaceutical Quality System (ICH, June 2008),
www.ich.org.
2. European Commission, EudraLex Volume 4, Part I,
Chapter 4 Documentation, https://ec.europa.eu/health/
documents/eudralex/vol-4_en ◆
Change Control for Standard Operating Procedures
Siegfried Schmitt is principal consultant
at PAREXEL.
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