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DELIVERING
BIOLOGICS
IN PREFILLED
SYRINGES
EXPRESSION SYSTEMS CLEANING VALIDATION CLINICAL TRIAL LOGISTICS

PLATFORM TECHNOLOGIES EVALUATING SURFACE MOVING TOWARD
IMPROVE PROTEIN CLEANLINESS USING DIRECT-TO-PATIENT
EXPRESSION A RISK-BASED APPROACH MODELS
©2017 America’s Biopharmaceutical Companies. GoBoldly.com
BIOPHARMACEUTICAL RESEARCHERS HAVE UNEARTHED

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ZIKA, YOU’RE NEXT.
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replication could help blaze the trail in tackling a host of deadly viruses.
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BioPharm
I N T E R N AT I O N A L
The Science & Business of Biopharmaceuticals
EDITORIAL EDITORIAL ADVISORY BOARD

Editorial Director Rita Peters rita.peters@ubm.com BioPharm International’s Editorial Advisory Board comprises distinguished
specialists involved in the biologic manufacture of therapeutic drugs,
Senior Editor Agnes M. Shanley agnes.m.shanley@ubm.com
diagnostics, and vaccines. Members serve as a sounding board for the
Managing Editor Susan Haigney susan.haigney@ubm.com editors and advise them on biotechnology trends, identify potential
Science Editor Feliza Mirasol feliza.mirasol@ubm.com authors, and review manuscripts submitted for publication.
Science Editor Adeline Siew, PhD adeline.siew@ubm.com
K. A. Ajit-Simh Hanns-Christian Mahler
Manufacturing Editor Jennifer Markarian jennifer.markarian@ubm.com President, Shiba Associates Head Drug Product Services
Associate Editor Amber Lowry amber.lowry@ubm.com Lonza AG
Art Director Dan Ward dward@hcl.com Madhavan Buddha
Freelance Consultant Jerold Martin
Contributing Editors Jill Wechsler, Jim Miller, Eric Langer,
Independent Consultant
Anurag Rathore, and Cynthia A. Challener, PhD Rory Budihandojo
Correspondent Sean Milmo (Europe, smilmo@btconnect.com) Director, Quality and EHS Audit
Hans-Peter Meyer
Boehringer-Ingelheim
Lecturer, University of Applied Sciences
ADVERTISING Edward G. Calamai and Arts Western Switzerland,
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European Sales Manager Linda Hewitt linda.hewitt@ubm.com President and CEO David Radspinner
European Senior Sales Executive The Chrai Associates Global Head of Sales—Bioproduction
Stephen Cleland stephen.cleland@ubm.com Thermo Fisher Scientific
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BioPharm
I N T E R N AT I O N A L
BioPharm International integrates
the science and business of
biopharmaceutical research, development,
Contents and manufacturing. We provide practical,
peer-reviewed technical solutions
Volume 30 Number 11 November 2017 to enable biopharmaceutical professionals
to perform their jobs more effectively.
FEATURES
DRUG DELIVERY DOWNSTREAM PROCESSING CLEANING VALIDATION
Delivering Biologics Connector Integrity AND MONITORING
in Prefilled Syringes in Single-Use Evaluating Surface
Adeline Siew Biomanufacturing Systems Cleanliness Using a
Siliconization is a key process Feliza Mirasol Risk-Based Approach
step in the manufacturing Connectors are a critical element Elizabeth Rivera and Paul Lopolito
of prefilled syringe systems. 14 in the process optimization of Rinse sample analysis or visual
single-use bioprocessing systems. 24 inspection can be correlated to surface
cleanliness to replace surface sampling. 36
EXPRESSION SYSTEMS
Platform Technologies MANUFACTURING
Improve Protein ADC Development CLINICAL TRIAL LOGISTICS
Expression Robust Despite Moving Toward
Cynthia Challener Lackluster Performance Direct-to-Patient Models
Platform technologies facilitate Feliza Mirasol Agnes Shanley
development and accelerate Despite the disappointing therapeutic Despite GxP and data-management
commercialization of protein performance of ADCs thus far, the challenges, pharma is moving toward
therapeutics. 20 pipeline still boasts promising prospects. 28 new models for clinical trial logistics. 48
COLUMNS AND DEPARTMENTS
6 From the Editor 10 Perspectives on Outsourcing

CPhI Pharma Awards Recent acquisitions are
honor companies and creating CDMOs with scale
individuals driving the that rivals global bio/pharma.
pharma industry forward. Jim Miller
Rita Peters
52 Product Spotlight
8 Regulatory Beat
FDA seeks to focus 53 New Technology Showcase
on problematic facilities Volume 30 Number 11
and inform firms quickly

53 Ad Index INTERNATIONAL
about site problems. 54 Ask the Expert

www.biopharminternational.com
Jill Wechsler The level of formality in change

control may be holding back
your SOP progress, according
DELIVERING
to Siegfried Schmitt, principal BIOLOGICS
IN PREFILLED
consultant at PAREXEL. SYRINGES
EXPRESSION SYSTEMS CLEANING VALIDATION CLINICAL TRIAL LOGISTICS

PLATFORM TECHNOLOGIES EVALUATING SURFACE MOVING TOWARD
IMPROVE PROTEIN CLEANLINESS USING A DIRECT-TO-PATIENT
EXPRESSION RISK-BASED APPROACH MODELS
Cover: Dmitry Lobanov/Shutterstock.com
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)
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
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4 BioPharm International www.biopharminternational.com November 2017

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From the Editor
Awards Recognize Bio/Pharma Industry Contributions
R
ecipients 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.
Rita Peters is the New categories recognized sustainability practices, export promotion, over-
editorial director of the-counter drugs, patient centricity, and IT, mHealth, and digitalization.
BioPharm International. The entries were rev iewed by a panel of independent judges f rom
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.
CPhI Pharma The 2017 CPhI Pharma Award recipients are as follows:
Analysis, Testing, and Quality Control—FlexiQuot: New disruptive technology
Awards honor that revolutionizes sample storage and handling, 1CryoBio
API Development—Development of a new, efficient synthesis of ospemifene,
companies and Cambrex
Bioprocessing—Modular automated sampling technology (MAST) platform
individuals driving for the biopharma industry, Capsugel/Bend Research (Lonza)
CEO of the Year—Richard Chin, CEO of KindredBio
the pharma Contract Services and Outsourcing—Modified supercritical anti-solvent
(mSAS) technology for accelerated product development, Crystec Ltd.
industry forward. 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. ◆

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Regulatory Beat
FDA Overhauls Inspection

Process and Field Operations
FDA seeks to focus on problematic facilities
and inform firms quickly about site problems.
T
o ensure the quality and safety of drugs, Drugs regulated by CDER and the Center for
biologics, and medical products more Veterinary Medicine (CVM), for example, are
efficiently and effectively, FDA is making managed by the Office of Pharmaceutical Quality
significant changes in its plant inspection pro- Operations (OPQO), directed by long-time ORA
gram, including more attention to imports and official Alonza Cruse. He oversees four divi-
to foreign producers of drugs for American con- sions of pharmaceutical quality operations, each
sumers. An aim is to target manufacturing over- headed by a regional manager, plus a division
sight to more high-risk operations and free up for quality programs (for compounders and pre-
resources for greater scrutiny of foreign facilities approval inspections) and a division for foreign
in the process. Agency officials also seek to bet- inspections, Cruse explained at the PDA/FDA reg-
ter coordinate and clarify the roles of field inves- ulatory conference in September 2017. The aim
tigators and staff from FDA’s Center for Drug is to achieve more consistent and timely inspec-
Evaluation and Research (CDER) (as well as other tions with reduced uncertainty for industry.
agency review centers) in selecting sites, weigh- Similarly, ORA’s Office of Biological Products
ing compliance action, and communicating Operations, headed by Ginette Michaud, has two
inspection findings to firms. And increased FDA operating divisions to oversee the production
collaboration with foreign regulatory inspector- of blood products, tissues, vaccines, and other
ates promises to reduce redundant site visits and products regulated by the Center for Biologics
increase oversight of violative situations. Evaluation and Research (CBER). The Office
of Bioresearch Monitoring Operations under
FIELD REALIGNMENT Chrissy Cochran also has two divisions, while
After several years of planning, FDA’s Office of the Office of Medical Devices and Radiological
Regulatory Affairs (ORA), which manages the Health Operations has three divisions.
agency’s 5000 field inspectors, officially imple- A key goal of the reorganization is to enhance
mented its Program Alignment (PA) initiative communication and collaboration between field
in May 2017. This major reorganiza- inspectors and center product specialists. This
tion shifts ORA from a geographi- approach for drugs is spelled out in a “Concept of
cally-based inspection operation to Operations” white paper released in August 2017
a program aligned by commodities (2). The 20-page report maps out how ORA and
and vertically integrated, with more CDER staffers will collaborate in the planning
specialized investigators able to iden- and conduct of inspections and the communica-
tify and provide more timely infor- tion of findings to manufacturers, with decision
mation on critical manufacturing trees for managing each of the four types of
VisionsofAmerica/Joe Sohm/Getty Images
issues. Specialized inspection cadres inspections. Increased integration of drug review

for drugs, biologics, medical devices, and facility evaluations aims to achieve more
food, bioresearch monitoring, and consistency and certainty in regulatory decisions,
Jill Wechsler tobacco continue to operate out of commented FDA Commissioner Scott Gottlieb (3).
is BioPharm International’s ORA’s 20 district offices across the For preapproval inspections (PAIs), a CDER
Washington editor, United States, with certain offices team, including staffers from the Office of Process
Chevy Chase, MD, 301.656.4634, housing program managers that lead and Facilities (OPF) in the Office of Product
jillwechsler7@gmail.com. product inspection teams (1). Quality (OPQ), prepares an integrated quality

Regulatory Beat
assessment. This assessment reviews ers more quickly. GDUFA II specifies T he c u r rent M R A in it iat ive
information in an application on that FDA will provide surveillance applies to GMP surveillance inspec-
facilities, processes, and microbiol- inspection findings to facility own- tions for most drugs and biotech
ogy, plus past inspection reports, to ers within 90 days of completing a therapies, but could be extended
determine whether a PAI is needed site visit, beginning October 2018, to vaccines and veterinary prod-
for each site listed in the submission. and CDER officials expect to apply ucts in the future. An important
ORA leads any necessary inspection, that goal to all drugs. The aim is for side-benefit of the final agreement
with CDER participation, and com- ORA to submit recommendations may be to end EU batch inspection
municates findings to the assessment to CDER within 45 days of post- of US-made products shipped to
team. A similar process is involved in approval and surveillance inspec- Europe. In the future, pre-approval
planning for and conducting post- tions so that staff can follow up inspections might be covered in
approval facility inspections, which quickly with the manufacturer. certain situations, prompting FDA
may occur following manufacturing and EU officials to examine how
changes, particularly for a facility INTERNATIONAL COLLABORATION PAIs differ or are the same in the
where a PAI has not taken place. The need to oversee the growing two regions. FDA’s need to com-
For GMP surveillance inspec- number of overseas pharmaceuti- plete such inspections in limited
tions, OPQ’s Office of Surveillance cal manufacturers also is prompt- timeframes could lead to an agree-
(OS) collaborates with OR A to ing US and European regulatory ment that permits FDA or EMA to
determine the need, timing, and authorities to collaborate more on request that a capable authority
scope of site visits, based on a facil- drug inspection activities. FDA and conduct a PAI by a certain date.
ity’s inspection history, type of the European Medicines Agency More information on the MRA is
products produced, and risks previ- (EMA) are moving forward with available on FDA’s website (5, 6).
ously reported. ORA investigators a Mutual Recognition Agreement
generally conduct these inspec- (MR A) that will permit partici- REFERENCES
tions, informing CDER’s Office of pants to rely more on each other’s 1. FDA, ORA Program Division Boundary
Compliance (OC) if they observe inspection reports. By reducing the Maps and Fact Sheets, FDA.gov, www.
questionable situations. ORA also need to inspect all of more than fda.gov/AboutFDA/CentersOffices/Of-
leads for-cause inspections, inter- 1000 registered drug production ficeofGlobalRegulatoryOperationsand-
Policy/ORA/ucm557997.htm
acting with CDER’s OPQ and OC. facilities in Europe, FDA would
2. FDA, Integration of FDA Facility Eval-
To ensure timely inspections of avoid duplicate site visits and free uation and Inspection Program for
facilities listed in new drug appli- up resources to support greater Human Drugs: a Concept of Opera-
cations, FDA and industry agreed oversight of firms in China, India, tions, CDER, June 2, 2017, www.fda.gov/
in the new prescription drug user and other nations. downloads/AboutFDA/CentersOffices/
fee program to delay application US and EU officials signed an OfficeofGlobalRegulatoryOperation-
approval if a sponsor fails to iden- agreement in March 2017 to extend sandPolicy/ORA/UCM574362.pdf
3. S. Gottlieb, “New Steps To Strengthen
tify all relevant sites in a submis- and conclude the MRA negotiating FDA’s Inspection And Oversight Of
sion. The aim is to provide complete process by July 2019 (4). The pro- Drug Manufacturing,” FDAVoice blog,
facility information for ORA to have cess involves FDA observing how FDA.gov, https://blogs.fda.gov/fdavoice/
sufficient time to inspect and evalu- EU member states inspect local index.php/2017/08/
ate relevant production sites. The facilities, and for EU officials to 4. FDA, “Mutual Recognition promises
Generic Drug User Fee Amendments audit FDA’s inspection program. new framework for pharmaceutical in-
spections for United States and European
(GDUFA II) further establish a pre- The two authorities also agreed
Union,” News Release, March 2, 2017,
submission correspondence pro- in August 2017 to protect confi- www.fda.gov/newsevents/newsroom/
cess that requires manufacturers of dential information in inspection pressannouncements/ucm544357.htm.
critical drugs qualifying for priority reports from public disclosure, 5. FDA, Frequently Asked Questions/
approval to submit information on which is important for sharing The Mutual Recognition Agreement,
planned production facilities two full inspection reports needed to March 2, 2017, www.fda.gov/down-
months before filing the applica- decide whether or not to visit sites loads/aboutfda/centersoffices/officeof-
globalregulatoryoperationsandpolicy/
tion—again, to support timely on each other’s inspection sched-
ucm544394.pdf
inspection of relevant production ules. The EU completed its assess- 6. FDA, Office of Global Regulatory Op-
sites in tight timeframes. ment of FDA inspection operations erations and Policy (GO), www.fda.gov/
A more efficient field inspection in July 2017, and FDA hopes to fin- aboutfda/centersoffices/officeofglobal-
program also aims to communicate ish its audits of the 28 EU member regulatoryoperationsandpolicy/default.
inspection findings to manufactur- states by mid-2019. htm. ◆
November 2017 www.biopharminternational.com BioPharm International 9

Perspectives on Outsourcing
CDMO Acquisitions Build

Strategic Supplier Base
Recent acquisitions are creating CDMOs
with scale that rivals global bio/pharma.
T
his has been another big year for acqui- $20 billion in revenues and $3.5–4.0 billion in
sitions in the contract development and cost of goods, plus as much as another $1 bil-
manufacturing organization (CDMO) lion for developing and manufacturing clini-
industry. In the first three quarters of 2017, cal candidates. That means the manufacturing
there have been 25 deals in which a CDMO requirements of that average global bio/pharma
was the acquisition target (see Figure 1). With company are two to three times the revenues
just three months left in 2017, the final num- of the three largest CDMOs, which all had rev-
ber of deals is likely to trail 2016 (34 CDMO enues of $1.5–2 billion prior to the latest round
acquisitions), but the total value of the transac- of acquisitions. Even those largest CDMOs had
tions is likely to exceed $20 billion, which will limited capabilities (only API, no dose; or strong
far exceed 2016’s total. Average deal multiples solid oral dose, limited injectable, and API), and
look to be about 13.5x EBITDA (earnings before companies in the next tier of CDMOs ($500 mil-
interest, taxes, depreciation, and amortization), lion–$1 billion range) had even more limited
a big premium above the 10x multiple at which capabilities and/or significant financial issues.
private equity investors typically value acquisi-
tions; a number of deals have come in at mul-
tiples in the 15x–25x range. Creating
Aside from the sheer size of the transactions,
deals in 2017 are most notable because they
may have finally created some CDMOs with the
large-scale suppliers
scale, breadth, and financial wherewithal to be
strategic manufacturing partners to global bio/ will be crucial to
pharma companies. Global bio/pharma com-
panies represent the last frontier
for CDMOs: they outsource only
cracking the global
approximately 25% of their drug
product manufacturing require-
bio/pharma market.
ments, compared to 70 –80% for
small and mid-size bio/pharma Global bio/pharma companies are struggling
companies, and they use CDMOs to manage complex supply chains with hun-
to manufacture fewer than 15% of dreds of vendors, but the limited scale and
their biologics products. scope of most CDMOs left the global companies
CDMOs are fighting ingrained with few choices for consolidating their sup-
Jim Miller is president of PharmSource, culture and deep pockets when ply base without becoming too big a piece of
A GlobalData Company, and trying to get global bio/pharma a given CDMO’s business. Thanks to the latest
publisher of Bio/Pharmaceutical companies to outsource more of round of acquisitions, however, the industry
Don Farrall/Getty Images
Outsourcing Report, their manufacturing requirements, now has some participants that, either on their
tel. 703.383.4903, but they are also handicapped by own or in concert with their parent companies,
Twitter@JimPharmSource, scale and scope. An average size have the scale, scope of capability, and finan-
info@pharmsource.com, global bio/pharma company (top cial sophistication to be taken more seriously
www.pharmsource.com. 25 by revenue) has approximately by global bio/pharma companies. Consider the

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Perspectives on Outsourcing
implications of some of the major Figure 1: Bio/pharma acquisitions in 2017, as of October 2017. SM is small
deals in 2017. molecule.
LONZA–CAPSUGEL
Capsugel’s $1 billion in revenues
pushes Lonza’s total revenues past
the $5-billion threshold, giving it Dose, 9
manufacturing scale equivalent Discovery, 9
to a $25 billion bio/pharma com-
pany. It also expends its scope by
bringing dose form capabilities,
Develop, 5
including softgels and solubility- Clinical, 7
en ha nc i ng te c h nolog ies suc h
as spray-drying, and its market-
leading hard gelatin capsule busi- Bio API, 5
ness; all of those are key inputs for SM API, 6
prescription pharmaceuticals and
nutraceuticals and a big part of any
Source: PharmSource Strategic Advantage database.
bio/pharma company’s procure-
ment spend.
THERMO FISHER–PATHEON an executive team of significant Lancaster Laboratories in 2011, but

Combining Patheon with Thermo stature and experience to drive in the past two years, it has broad-
Fisher’s clinical supplies business the company to the next level, as ened its chemistry, manufacturing,
fills a major gap in Patheon’s ser- Blackstone did for Catalent and JLL and controls (CMC) portfolio into
vice portfolio and creates a CDMO Partners did for Patheon. process development, formulation,
with $3 billion in revenue, compa- and clinical manufacturing ser-
rable in size to Lonza’s pharma and CATALENT–COOK PHARMICA vices by acquiring companies like
biotech segment. Patheon is now Catalent’s acquisition of Cook Sinesis Life Sciences (Netherlands),
better-positioned in the market for Pharmica, despite its nearly $1-bil- Ad v a nt a r L ab or ator ie s ( U S A),
clinical development, manufactur- lion price tag, is not as transforma- Alphora Research (Canada), and
ing, and packaging services, which tional as some of the other recent Amatsigroup (France and Belgium).
is becoming more important as a deals: the company already has a Eurofins, with revenues exceeding
feeder into a CDMOs commercial growing biomanufacturing busi- $2.5 billion, may be able to lever-
manufacturing pipeline. As impor- ness, and the near-term revenue age its strong position providing
tantly, Patheon is now a significant increment is much smaller than in analytical and bioanalytical ser-
part of a $20-billion supplier of the other cases. However, the deal vices to global bio/pharma com-
life-sciences products and services makes Catalent a more complete panies to get more of its clients’
to the bio/pharma industry, rather provider in the biopharmaceuticals development business.
than a $2-billion standalone CDMO. market as the addition of North The current financial market
American injectables and bioman- environment has been favorable
CARLYLE GROUP–AMRI ufacturing capacity complement to large-scale acquisition activity,
Acquisitions by private equity firms its existing biomanufacturing and and one might expect to see a few
aren’t usually viewed as strategic, analytical capabilities. more large deals that consolidate
but a deal with a firm of the size the top end of the CDMO industry.
and reputation of Carlyle could be EUROFINS–MULTIPLE CDMOS However, the number of large and
transformational for AMRI. Carlyle Eu rof ins is wor t h not ing not attractive acquisition targets is lim-
Figure courtesy of the author
will bring more financial savvy because of any one large deal but ited, which will limit the number
and operational focus to the com- because of the way it has built a of transformational deals in the
pany, which should strengthen it CDMO offering through a series near term. There is no doubt, how-
for the long term. The transfor- of small acquisitions. Eurofins ever, that creating large-scale sup-
mational opportunity will come built its GMP analytical services pliers will be crucial to cracking
about if Carlyle is able to bring in capability around its acquisition of the global bio/pharma market. ◆

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Drug Delivery
Delivering Biologics
Adeline Siew, PhD
in Prefilled Syringes
Siliconization is
a key process
step in the
manufacturing
of prefilled
syringe
Dmitry Lobanov/Shutterstock.com
systems.
B
iologics are fast becoming the Innovation, Schott. “Additionally, pre-
driving force of the pharmaceu- filled syringes work well with increasingly
tical industry. Because the pri- popular safety devices and auto-injection
mary route of administration systems, making injections easy, safe, and
for most biologics is still by injection, convenient.” He notes that pharmaceuti-
there is a demand for advanced drug- cal companies also stand to benefit from
delivery systems that offer convenience prefilled syringes. “Compared to vials,
and ease of administration. Prefilled they can reduce overfill, which can be
syringes have gained strong acceptance particularly costly in biopharmaceuticals.
as delivery systems for injectable drugs, Also, customized delivery systems and
especially in the treatment of chronic prefilled syringes are helping pharma-
conditions that require repeated admin- ceutical companies in the biotech indus-
istration of the medication. try deliver personalized drugs tailored to
smaller patient populations,” Stöcker says.
ADVANTAGES OF PREFILLED SYRINGES Prefilled syringes can potentially
“P ref illed sy r inges make injec tion offer better patient experiences than
easier and safer for both doctors and traditional means, observes Graham
patients by ensuring the patient always Reynolds, vice-president and general
receives the right dosage,” says Fabian manager, Global Biolog ics at West
Stöcker, head of Strategic Marketing & Pharmaceutical Services, Inc. “There is

Drug Delivery
some degree of variability when regulatory ease make it the first For the majority of drugs, glass
removing a drug product from a choice for drug manufacturers, remains the preferred material;
vial with a conventional dispos- but the polymer’s stability and however, Reynolds notes that in
able needle and syringe. With a inert properties, as well as its wide certain circumstances, a polymer
prefilled syringe system, the very design options, make it an attrac- syringe may offer unique advan-
nature of its design eliminates tive choice as well.” Stöcker cites tages. “Evaluation of both options
the withdrawal step and deliv- the example of the anticoagulant at an early stage can help to iden-
ers the drug product directly to heparin, which has been stored in tify the pros and cons of both,”
the patient, which can result in glass prefilled syringes for decades he highlights. “In addition, the
a more accurate dose of the drug without any major recalls or drug selection of either glass or poly-
with less exposure to needles,” contamination cases, making glass mer syringes can be influenced
he explains. an easy choice. Dermal fillers, by other factors such as storage
Reynolds adds that because some on the other hand, are typically temperatures (polymer systems
biologic drug products are in short highly viscous substances that of fer adva ntages at ext remely
supply and can be very costly to need to be stored in packaging low te mp e r at u r e s), p ote nt i a l
produce, manufacturers are seek- that allows for consistent gliding risks of breakage, and, in cases
ing innovations to minimize waste. force and a robust luer lock, which where a device is used, precision.
“Prefilled syringes, with their pre- is integrated in a polymer syringe. Functionalit y and dimensional
measured dosage, have the poten- In this case, polymer is the mate- tolerances can also be key factors
tial to reduce dosing errors and rial of choice, according to him. in order to reduce the risk from
increase patient compliance while Stöcker recommends a holistic incorrect function of the injec-
potentially saving manufacturers evaluation along the three Ps— tion system.”
money,” he says. “Unlike single- or product, process, and patient—to
multi-dose vials that may require find the best solution. He explains DEVELOPMENT CONSIDERATIONS
drug product overfill by as much that a number of aspects needs to The development of biologic drug
as 30% to ensure adequate with- be considered, such as: products in prefilled syringes has
drawal, a prefilled syringe can vir- • W het her or not t he d r ug attracted a lot of interest within
tually eliminate the need for excess requires particularly inert pack- the bio/pharmaceutical industry
overfill, thus conserving expensive aging materials because of the win–win situation
drug products. This is important • The importance of design flex- for both end-users and manufac-
where manufacturing and product ibility, tighter tolerances, and turers. But besides formulation
costs are high and bulk manufac- superior break resistance considerations and compatibility
turing capacity is limited.” • Whether or not integration with between the drug product and its
safety devices or auto-injectors primary packaging, there are other
GLASS VERSUS PLASTIC is needed technical challenges that have to
Glass prefilled syringes continue • The compatibility of the pack- be addressed such as functionality
to dominate the market, but there ag i ng w it h d i f ferent f i l l i ng issues and syringe siliconization.
is a shift toward the increasing use machines “A drug product’s formulation is
of plastic as an alternative material • Regulatory pathways for drug comprised of multiple raw materi-
for prefilled syringes because of approval als, as are the components of pre-
its robustness against breakabil- • Patient comfort and needs. filled syringes. It is ultimately the
ity while delivering consistent sta- Reynolds adds that the selection compatibility of these systems that
bility and performance for many of the drug container starts with an will help to qualify the system for
drug products. The two types of understanding of the potential inter- its intended use,” says Reynolds.
polymers mainly used to make actions between the drug and the “Components of prefilled systems
plastic syringes are cyclo olefin system. He points out that certain typically include pistons, syringe
polymer (COP) and cyclo olefin biologics may be sensitive to silicone b a r r e l s, ne e d le s, a nd ne e d le
co-polymer (COC). oil or tungsten, which are found in shields—all of which must be com-
Stöcker acknowledges that glass many glass syringes. “Certain poly- patible as a system and with the
a nd poly mer bot h have t hei r mer syringe systems, such as West’s drug product.”
strengths. “The right material for Daikyo Crystal Zenith syringe sys- According to Reynolds, the pre-
a syringe depends on the appli- tem, provide container systems free filled syringe component with the
cation,” he says. “The excellent from silicone oil, tungsten, and other maximum drug product contact
barrier properties of glass and extractables,” he says. area is the syringe barrel, which

Drug Delivery
can have a major inf luence on make it impossible to carry out a shapes seen indicate protein aggre-
drug product quality. The compat- smooth and comfortable injec- gation,” he explains.
ibility of the drug product with tion. The plunger stopper could get
the barrel’s contact surface is cru- stuck in the middle of the injec-
cial to the drug product quality, he
explains, while the break loose and
tion because direct contact between
glass and the currently used elas-
Prefilled
glide forces are key to the adminis-
tration of the drug.
tomers causes very high friction
forces. Only appropriate siliconiza- syringes have gained
tion can overcome this friction.”
SILICONIZATION
Siliconization is a key process SILICONE OIL COMPATIBILITY
strong acceptance as
step i n t he ma nu fac t u r i ng of WITH THE BIOLOGIC FORMULATION delivery systems for
prefilled syringe systems, high- Burghardt points out that sili-
lights Tillmann Burghardt, team cone itself is non-toxic, biocom-
manager, Manufacturing Science patible, and insoluble in water; injectable drugs.
and Process Development, Vetter therefore, it has limited impact
Pharma-Fertigung GmbH & Co. on the formulation. “As an inte-
KG. “It involves not only the coat- g r a l c o mp o n e nt o f p r e f i l l e d Burghardt highlights that sili-
ing of syringe barrels, but also any syringes, the use of silicone oil in conization involves introducing
rubber parts and the needle itself drug-delivery systems has been supplementary material into the
with a thin layer of pure silicone clinically tested for decades and prefilled syringe system, in addition
oil or distinct silicone oil/water commercially proven in billions to the actual injected compound.
emulsions, respectively. This pro- of patients,” he says. “Therefore, before choosing a sili-
cess facilitates the assembly of Zeiss, however, cautions that conization technology, companies
the syringe parts and promotes a few biologics may react to the have to consider various factors,” he
ease of use and injection,” he says. silicone oil, but adds that not all says. “As the silicone coating is not
Burghardt explains that the sili- biologics react this way. For this covalently bonded to its substrate, it
cone oil acts as a lubricant that reason, dedicated stability studies is susceptible to change over time.
provides certain properties cru- of any newly developed formula- Storage conditions and transport
cial for drug administration. “The tion with the intended syringe stress, in particular, temperature and
silicone layer forms a hydrophobic need to be carried out, he high- agitation, can affect the layer and
surface so that the solution within lights. According to Zeiss, in rare its interaction with the syringe sur-
the syringe drains better and sup- cases where too much protein face over time. Silicone layers can
ports recovery rate accuracy. The binds to the siliconized glass sur- also interfere with analytical assays
oil layer also has a barrier func- face, or if silicone oil-protein aggre- because they might release subvis-
tion—it prevents absorption of gates are formed in the liquid itself, ible particles to the liquid phase.
the compound by the container. the efficacy of the injectable for- The migration of such silicone oil
The drug formulation is, there- mulation may be compromised. droplets at parts per million (ppm)
fore, prote c te d f rom reac t ive “In such cases, im mu nogen ic level into the compound is a known
surface mediated chemical modifi- effects cannot be excluded,” he phenomenon. Therefore, each new
cations,” he says. says. “And the safety of the drug compound requires individual com-
According to Bernd Zeiss, man- could be impaired.” patibility and stability assessments.”
ager, Technical Support Medical O ne mo d e r n to ol to me a -
Systems, Gerresheimer, all prefilled sure silicone oil-induced protein SILICONIZATION METHODS
glass syringes today are silicon- aggregation is microflow imaging Siliconization methods use either
ized in some way. Siliconization (MFI), notes Zeiss. “The amount pure silicone oil or distinct silicone
is essential to process capabil- of particles found in the formula- oil emulsions. Burghardt notes that
it y. “Without silicone oil as a tion provides an indicator of the pure silicone oil is still the most
lubricant, prefilled syringe sys- sensitivity of the protein toward commonly used technology for a
tems based on glass do not work silicone oil. By applying MFI, the prefilled syringe. “It can be applied
because the plunger stopper would amount and shape of particles by wipe down or dynamic spray-
not move properly,” he notes. in the formulation can be deter- ing processes and can also be used
“Extremely high gliding forces mined. Free silicone oil will form for glass and polymer systems,”
would prevent the emptying and round droplets while any odd he says. “This medium allows for

Drug Delivery
various types of sterilization proce- prefilled syringe. The method was Burghardt explains that various
dures such as autoclaving, ethylene originally developed for ophthal- analytical methods can be used to
oxide treatment, or gamma irradia- mic applications, according to him, examine the amount and distribu-
tion. It is also used for rubber com- but turns out to be well suited for tion of silicone inside the system.
ponents, needles, and the syringe sensitive biologics. “For example, one can measure total
barrel itself.” extracts of silicone oil from empty
Zeiss concurs that the standard OPTIMIZING THE barrels by Fourier transform infra-
approach used until today is the SILICONIZATION PROCESS red spectrometry, or optically assess
spray siliconization method with Insufficient or excessive siliconiza- the uniformity and thickness of the
silicone oil. “Medical-grade oil is tion can cause issues in the func- layer by reflectometry,” he says. “The
sprayed into the barrel using spe- tional performance of the prefilled overall functionality of the entire
cial diving nozzles that distribute syringe. “It is crucial to evaluate system can be evaluated by tensile
the coating inside the syringe. If the ideal siliconizing process on force measurements on both empty
required, different siliconization the basis of the given compound and filled units, thus, simulating the
levels can be applied, depend- and the anticipated fill and finish later application process. Simple flow
ing on the customer needs,” Zeiss microscopy technology is applied for
explains. Burghardt adds that this detecting subvisible particles in liq-
process supports layer uniformity Because most biologics uid solutions after incubation in the
from the cone toward the flange desired prefilled syringe, allowing for
of the barrel. However, he notes
that temperature-sensitive poly-
are administered by particle classification by count, size,
and shape.”
mer systems in general, as well as
glass syringes with diameters less injection, there is a Zeiss notes that siliconization can
be optimized in many ways. “Over
than 0.5 cm, are restricted to the the past 10 years, the use of diving
conventional static spray process,
which involves spraying from out-
demand for advanced nozzles in spray siliconization have
led to much lower amounts of sili-
side the barrel to avoid nozzle to
glass contact within the syringe. drug-delivery cone in the syringes. Manufacturers
have also constantly improved and
The second method is baked-on optimized the baked-on process,”
siliconization. Zeiss explains that
in this process, an oil-water emul-
systems that offer Zeiss says. “The lower the lubrica-
tion levels in a syringe, the more
sion is sprayed into the barrel and
subsequently baked on the inner
convenience and ease critical the interface between bar-
rel and elastomer stopper becomes.
barrel surface in a dedicated heat Finally, choosing a modern plunger
chamber. “Water is evaporated, of administration. stopper makes a good syringe sys-
and the silicone oil is fixed to the tem complete.” According to Zeiss,
glass surface,” Zeiss says. Gerresheimer has carried out a
According to Burghardt, the use steps with regard to possible post- comprehensive test campaign com-
of silicone oil emulsions is gain- fill treatments,” Burghardt stresses. paring all kinds of available plunger
ing growing importance, but he “The topology of the initial sili- stoppers in combination with spray-
points out that this method is only cone coating is determined by siliconized and baked-on silicon-
indicated for glass barrel systems which siliconization technology ized syringes. He adds that it is not
because it requires a dry heat steril- is used. However, the impact of only important to lower and opti-
ization step. “The syringe is heated pH and ionic strength of the filled mize siliconization itself, but also
to more than 300 °C to evaporate compound formulation, as well as apply a system approach to evaluate
the water of the emulsion and help storage temperature and transport which syringe plunger combina-
bond the silicone oil to the ster- stress or potential lyophilization tion is the best. “In addition, the
ilized syringe. These silicone oil processes, should not be underesti- amount of product to be filled into
emulsions can be applied by either mated during process development. the syringe and the plunger stop-
static or dynamic spraying nozzles Thorough analytical testing has to per placement method are part of
to the glass barrel.” be considered to elicit the amount this equation. Today, low silicone
Zeiss highlights that baked-on and distribution of the silicone oil syringe systems with very good
siliconization leads to dramatically on the syringe body surfaces both gliding behavior of the stopper can
lower residual-free silicone in the prior to and after filling.” be offered,” Zeiss says. ◆

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Commercialization | Technologies
Expression Systems
Platform Technologies
Improve Protein Expression
Cynthia Challener
Platform
technologies
facilitate
development
and accelerate
commercialization
Anna Kireieva/Shutterstock.com
of protein
therapeutics.
S
peed to market is essential in stances (i.e., substances that have made
the biopharmaceutical industry it to late-stage clinical trials and com-
today. Manufacturers are seek- mercialization after being subjected
ing mechanisms for increasing to regulatory scrutiny) can thus be
efficiencies and reducing costs without considered safe, according to Menzo
compromising the safety and efficacy Havenga, CEO at Batavia Biosciences. In
of their drug products. In addition to addition, any technologies underlying
exploring novel production methods these platforms have at that stage been
such as continuous processes and dis- well-studied, making them predictable,
posable production technology, manu- and predictability creates manufactur-
facturers also heavily invest in platform ing comfort. They are also expected
technologies for protein expression that to speed up the development of novel
will not only facilitate the development specific molecules based on the use of
of biologic drug candidates, but also chemistry, manufacturing, and con-
increase yield and speed to market. trols (CMC) standards and by leveraging
capabilities and capacities, notes Beate
A PLATFORM OF BENEFITS Mueller-Tiemann, head of business
Cynthia A. Challener, PhD Plat for m tech nolog ies for protei n integration and innovation at Sanofi.
is a contributing editor to expression that have been successfully “Consequently, platform expression
BioPharm International. used to produce biologic drug sub- technologies may lead to substantial

Expression Systems
benefits in terms of speed to mar- well. Furthermore, Havenga points glycosylation in algae and yeast
ket, assuming CMC aspects are on out that the use of novel platform glycosylation are also noteworthy.
the critical path, and reduced cost technologies for protein expression “These approaches offer avenues
of goods manufactured (COGM),” has not yet resulted in significant for designing better fit-for-purpose
she states. reductions in consumer prices. molecules not only in terms of
In addition, new technologies “ T he go a l b e yo nd m a k i n g their activity and safety, but also
for genomic engineering of cells some of these new entities viable with respect to desirable CMC
for the production of therapeutic is achieving a significant reduc- attributes,” says Voldborg.
proteins are “opening up a new tion in COGM, thus increasing the The availability of several molec-
world of possibilities to tailor- affordability of biotherapeutics and ular biology tools developed in
make protein-based drugs with improving overall healthcare eco- the recent past by the scientific
appropr iate post-t ra nslat iona l nomics,” agrees Mueller-Tiemann. community in diverse applica-
modifications that meet the needs With respect to the impact of tions beyond biopharmaceuticals
of the pharmaceutical industry, technology, the main driver for is starting to make a difference,
physicians, and ultimately patients recent adva nces in t he devel- ag r e e s Mue l le r-T ie m a n n. She
in need of novel medications,” opment of protein expression notes that there are several plat-
notes Bjørn Voldborg, director of plat for ms is t he d iscover y of form approaches based on diverse
CHO cell-line development at the CRISPR-Cas9-based genome edit- host systems that seem promising
Novo Nordisk Foundation Center ing, according to Voldborg. “This for the expression of therapeutic
for Biosustainability. technology has made it possible proteins due to their increased
to specifically engineer genes in productiv it y and abilit y to be
IMPROVING EFFICIENCY, existing hosts to improve their genetically engineered toward spe-
YIELD, AND FUNCTIONALITY properties and performance and cific molecule characteristics and
There are a large number of fac- to add completely new functional- levels of expression.
tors to be taken into account in ity,” he observes. There is one hur- I n a d d it i o n , a c c o r d i n g t o
the development of new platform dle yet to overcome, however; the Mueller-Tiemann, the simplic-
technologies for protein expression intellectual property landscape ity of the culture media required
ranging from the choice of cell su r rou nd ing t he CR ISPR- Cas9 for their growth presents oppor-
line, expression plasmid design, approach is unresolved, which tunities from a cost-reduction
cultivation medium, growth con- makes it less attractive for use in perspective. Use of chemically
ditions, equipment, scalability, industrial settings. defined media also makes the risk
stability, and matching purifica- of exposure to zoonotic adventi-
tion capability, to name but a few. PROMISING DEVELOPMENTS tious agents extremely unlikely.
Primary drivers to the develop- Voldborg expects that most thera- “High-quality, defined, animal-free
ment of a new therapeutic protein peutic proteins will continue to reagents and cell-culture products
platform are the desire to improve be produced using well-known help biomanufacturers eliminate
efficiency and productivity, the platforms (e.g., CHO cells and the risk of contamination that has
need to increase the agility of Escherichia coli [E. coli] bacteria), been associated with animal- and
manufacturing, and the fact that but with the addition of engi- human-ser um- der ived media,”
complex non-natural proteins are neered versions that may over- agrees Scott Deeter, president and
not well-expressed in the current come the drawbacks of earlier CEO of Ventria Bioscience. Cell-free
systems such as Chinese hamster non-engineered versions of these systems, which are currently at the
ovary (CHO) cell lines, according platforms. “I have to say, however, earliest stage of development, could
to Mueller-Tiemann. that the possibility to specifically be important in the long term,
Improv ing y ield has a lways delete or insert genes by demand according to Mueller-Tiemann.
been and will continue to be one using CRISPR-Cas9 technology is Adva nces i n process equ ip -
of the key drivers for a technol- a game-changer in the field.” He ment are also expected to have
og y platform to be successf ul, adds that combining genetic engi- an impact, according to Havenga.
explains Havenga, although clearly neering tools like CRISPR/CAS9 He points to the use of high-cell-
agility, product quality, and regu- with bioinformatics to identify density, fixed-bed bioreactors for
latory acceptance are highly sig- optimum sequences using a bio- adherent cell culture as an excit-
nificant. Next to yield, the stability mimetic approach could make a i ng new deve lopme nt. “ Wit h
of protein-producing cell clones difference. Tools enabling modifi- these bioreactors, it is possible to
remains an issue to be studied as cation of metabolic pathways for increase cell densities from 10–20

Expression Systems
million cells per milliliter in typi- Center for Biosustainability at the The platform rapidly achieves
cal bioreactors to an impressive Technical University of Denmark high protein- expression levels
100 –200 million cells per milli- is focused on engineering cell lines without the need for gene ampli-
liter, resulting in significant sav- according to the needs of the phar- fication. In addition, cell clones
ings in facility costs due to the maceutical industry working with developed thus far w ith ST EP
reduction in required floor space,” protein-based therapeutics, says (n=12) have all proven to be stable
he explains. Voldborg. “We have been able to in the expression of the desired
engineer cell lines that solve a lot of product for more than 60 pas-
OVERCOMING the problems and challenges expe- sages in the absence of selection
CELLULAR COMPLEXITY rienced by the industry,” he says. pressure, according to Havenga.
While a lack of suitable genome As one example, Voldborg points to “In the rapidly growing market
engineering tools is no longer a bot- engineered CHO cell lines that can- of re combi na nt prote i n s a nd
tleneck for improvement of protein not produce lactate, thereby nearly antibodies, our STEP technology
expression platforms, biologic drug eliminating the need for pH adjust- provides a tool to complete pre-
manufacturers still face many chal- ment via base addition during cell clinical phases at higher speed
lenges. The perfect system is not culture. “With these expression sys- with reduced costs and with a
around the corner. Understanding tems, it will be possible to conduct higher success rate,” he asserts.
and tools for better engineering much longer fed-batch runs and Regulatory approval of the STEP
the overall metabolism of host significantly increase the amount technology is expected in 2018 at
cells with the capability to bal- of product that can be made from the latest, according to Havenga,
ance protein generation in several each production run.” The center with first products on the market
different phases with cell growth has also developed cell lines engi- using STEP in 2024.
and survival will remain a key neered to produce proteins with
research focus, according to Mueller- tailor-made, highly homogenous PLANT-BASED EXPRESSION
Tiemann. “Significant progress has glycoprofiles, highly homogenous Ve nt r i a B i o s c i e n c e ’s p r o p r i -
been made, but a lot has yet to be cell lines that exhibit reduced host- etary ExpressTec technology is a
discovered,” she asserts. cell protein secretion, and cell lines plant-based expression system.
Adds Voldborg: “Cellular expres- resistant to certain virus infections. Recombinant proteins, peptides,
sion systems are highly complex, At Sanofi, establishing differen- multi-subunit molecules, mono-
and we still lack knowledge of the tiating CHO expression systems is clonal antibodies, fusion proteins,
cellular machinery that is used to a clear goal for the company, says and enzymes are manufactured
transcribe, translate, fold, modulate, Mueller-Tiemann. Sanofi is also within a growing plant using sun-
and finally secrete desired protein pursuing process intensification for light, soil, water, and air as raw
products.” He does note, however, high-throughput, semi-continuous materials, according to Deeter. He
that the use of computer-based mod- manufacturing in the short term. adds that products manufactured
els and big data analysis are being using this expression platform
used to improve this knowledge. PLASMID-BASED EXPRESSION are cost-effective and free of ani-
For Havenga, continuing issues Batavia Biosciences’ plasmid-based mal, human, and bacterial con-
with the stability of expression cell STEP technology increases protein taminants, which is an important
lines and clonality associated with expression in CHO cells by at least safety factor.
gene amplification technologies, 10-fold, taking just 12 weeks to gen- “ExpressTec also delivers mean-
such as dihydrofolate reductase erate stable cell clones, according to i ng f u l adva ntages by ma k i ng
(DHFR) selection, remain a con- Havenga. A cytomegalovirus (CMV) molecules that would be diffi-
cern. “The problem here is loss of promoter drives the transcription of cult to produce in other systems,
expression, and [the use of] tech- one mRNA from which two proteins enabling new product opportuni-
nologies that do not involve gene are translated (i.e., the protein of ties that were not previously avail-
amplification, such as the STEP interest [product] and a functionally able. Ventria is in the process of
technology developed by Batavia impaired Zeocin selection marker). doubling our production capacity
Biosciences, is one approach to As the impaired Zeocin selection with the platform to meet grow-
addressing this problem,” he says. marker needs to be expressed in a ing needs in developing new bio-
CHO cell to high levels for the cell therapeutics, cell-culture media
ENGINEERING CHO CELLS to survive the antibiotic pressure, reagents for biomanufacturing,
The platform technology developed that cell per definition also makes and industrial and animal nutri-
at The Novo Nordisk Foundation high levels of the desired product. tion enzymes,” says Deeter. ◆

The Next Evolution
For 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.
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not contain supplements. It is optimized for extended growth and enhanced recombinant
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Downstream Processing
Connector Integrity in Single-Use

Biomanufacturing Systems
Feliza Mirasol
Connectors
are a critical
element in
the process
optimization
of single-use
bioprocessing
viktor_kov/Shutterstock.com
systems.
S
ingle-use technology has become therapies being developed are valuable,
more widely adopted in bio- so any failure in the system will lead to
pha r maceut ica l ma nu fac t u r- an expensive loss, notes Scott Herskovitz,
ing, shifting from acceptance of vice-president of sales and marketing at
the technology to standardization (1). Qosina, a Ronkonkoma, NY-based pro-
Optimizing single-use systems and main- vider of stock components for medical
taining quality are as much functions of devices.
the types and configuration of the con- Connection types vary depending on
nector components as they are a func- the classification of the manufacturing
tion of overall process design. environment in which the connection is
A single-use system is at the mercy of being made, says Todd Andrews, global
its weakest link, which centers around sales and business development manager,
the connectors used to unify the manu- Bioprocessing, Colder Products Company
facturing assembly, such as valves, joint (CPC), a provider of quick disconnect
connectors, and blockers, among others. couplings, fittings, and connectors for
plastic tubing based in St. Paul, MN.
CRITICAL CONNECTORS “Any connection where product ste-
In single-use systems, criticality exists rility could be compromised is impor-
wherever a connection is made so that tant. Critical connections can be located
product can flow through. The drugs and upstream where the end user is trying to

protect the cell line, or downstream and accelerates the adoption of sin- use system by shut-off valves or
where patient health could be gle-use manufacturing technologies clamps (2).
affected. The best defense against used in the production of pharma- The management of these connec-
a potential breach in sterility is ceuticals and vaccines. Connectors tor elements is an important aspect
employing connectors that are well and tubing should be assessed in of process optimization because the
validated, robust, easy to use, and qualification studies to determine development of new drugs and ther-
highly reliable,” Andrews says. their impact on the system, the apies in single-use systems requires
The importance of sterile connec- BPSA said in a report (2). components that are made to a
tors in the single-use bioprocessing For example, the diameter, wall, higher standard than those used in
system revolves around their ability thickness, length, and material other industries, Herskovitz says. In
to help maintain volume and prod- type of the tubing used should particular, the materials with which
uct flow. all be taken into account because various connectors are made must be
Their impact, as well the impact these properties can affect the able to withstand exposure to chemi-
of other attachments such as tub- stiffness of the tubing under pres- cals without introducing bioburden
ing, to the system must be assessed sure. This can have an effect on or other chemicals into the final
as they may significantly change pressure measurements, said the product.
the system volume. This in turn BPSA in its report. In addition, the Furthermore, connections should
can potentially lead to erroneous organization recommends that reflect the manufacturing environ-
results when testing the system for any permeable membranes, such ment in which they are used as well
sterility (2), according to the Bio- as vent filters or hydrophobic peel as the risk associated with those
Process Systems Alliance (BPSA), an strips, on connectors should be connection. In a highly classified
industry association that promotes isolated from the tested single- environment, such as ISO Class 5,
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for example, open connectors, such the traditional “male” and “female” SKUs needed at the component and
as quick connects, are acceptable. connections where each side is finished-system levels. Fewer SKUs
In this case, the environment unique, adds Andrews. simplify ordering and reduce the
has less inherent risk than a lower- Genderless connectors avoid issues burden on inventory control, which
class environment, according to associated with male/female connec- contributes to lower overhead costs
Andrews. More and more, how- tions, such as accidentally specifying and shorter lead times for single-use
ever, drug manufacturers are seek- the same gender on each half and systems, Andrews says.
ing connections outside of highly requiring more stock keeping units
classified environments to improve (SKUs), to ensure sufficient inventory CONNECTOR CRITERIA
flexibility and reduce overhead. In of male and female components for AND COST CONSIDERATIONS
these situations, manufacturers are proper matching, he says. There are certain key criteria for the
moving toward sterile connectors, An example of the former situa- types and quantity of connectors to
Andrews notes. tion would be having male connec- use in a single-use system, includ-
The particular configuration of tors on both the bag assembly and ing the quality of material from
connectors in the bioprocessing the tube manifold, which would which the connectors are made, the
network depends on the applica- not allow a proper connection. This manufacturing environment, and
tion, quantity, and price, Herskovitz is typically discovered at the point testing data, to ensure the compo-
says. “Molded connections give a of use, to the detriment of the oper- nents will not introduce bioburden
higher level of confidence than ator. To remedy the situation, an or leachables/extractables into the
zip ties, but there is a higher cost operator might then need to create product, says Herskovitz.
involved and a lengthier develop- a makeshift tube assembly—assum- Andrews highlights other criteria
ment time to configure and pro- ing that components are readily that should be considered in select-
duce,” he remarks. available—sterilize it, and attempt ing the right connectors. One of
“Genderless” connectors simplify a connection, all of which delay them is ease of use: in an industry
use and the inventory management manufacturing and affect produc- where the primary cause of failure is
of system components. In a gen- tion efficiency, Andrews explains. operator error, well-designed connec-
derless connector, each connector In the latter situation, genderless tors are important for reducing the
half is the same design, eliminating connectors reduce the number of opportunities for operator mistakes.
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.

To test a connector’s ease-of-use, operators should The saving of time and money on cleaning and vali-
be allowed to attempt installing the connections with dation is important, but this means rapid changeover
minimal training. The operators who are putting between batches, he notes. Using disposable connec-
together the connections on the floor are the best gauge tors also reduces water and waste and eliminates cross-
of ease-of-use in real-life manufacturing conditions, contamination.
Andrews asserts. “Manufacturers also have greater flexibility when
Durability is another key criterion; do the connectors using mobile single-use designs over pre-existing stain-
still function properly when used in less-than-perfect less-steel facilities. Single-use equipment can be dupli-
conditions? “Some connectors, for example, function cated with less effort and cost and can help you keep
adequately if there is zero side-load or tension in the manufacturing closer to end-users. Stainless-steel facili-
line. However, these conditions are hard to achieve in ties can take time to build; single-use is cheaper and
real-world applications. Robust connectors will work quicker,” Herskovitz states.
well in a variety of circumstances,” says Andrews.
Other key connector criteria are integrated function- REFERENCES
ality and availability. For example, biomanufacturers 1. T. Andrews, “The Standardization of Single-Use Components
for Bioprocessing,” CPC White Paper 7003, https://content.
should seek out connectors that deliver the required cpcworldwide.com/Portals/0/Library/Resources/Literature/
functionality and performance without the need for WhitePapers/Documents/CPC_WhitePaper_standardization_
extra equipment or processes. of_single-use_components.pdf, accessed Oct. 18, 2017.
2. Bio-Process Systems Alliance, “Design, Control,
Secondary equipment such as welders, sanitary and Monitoring of Single-Use Systems for Integrity
clamps, or machined fixtures add complexity and Assurance,” http://bpsalliance.org/wp-content/
become potential sources of problems or mistakes, uploads/2017/07/Integrity-assurance-of-single-use-
systems-FINAL-7.7.17.pdf, accessed Oct. 20, 2017. ◆
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.
In-line Sensors to Meet Your Single Use
“For cost and process efficiencies, obtain connectors
from connector specialists dedicated to delivering the
Process Monitoring Requirements
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 Pressure Conductivity Temperature UV Absorbance
clean and sterilize reusable equipment between usages.
“With disposables, manufacturing can be up and In-line Sensors:
NEW!
running immediately after replacing the disposable • USP Class VI materials 1/8 inch
assembly,” remarks Andrews. • May be gamma irradiated pressure
sensor
“This is a classic question addressing the entire sin- • No calibration required
gle-use movement,” says Herskovitz. “The consideration • Available in a variety of sizes
is volume. If you are manufacturing a billion doses, it is • Sensors connect to monitors that
more cost effective to go the traditional route. However, can be integrated to a control
system or PC
the trends have been toward small batches of targeted
therapies that serve a much smaller population. This ,62&HUWL¿HG ZZZSHQGRWHFKFRP
has been where single-use systems have shined.”

Manufacturing
ADC Development Robust

Despite Lackluster Performance
Feliza Mirasol
Despite the
disappointing
therapeutic
performance of
ADCs thus far,
the pipeline
molekuul_be/Shutterstock.com
still boasts
promising
prospects.
F
oc us on the development of the cytotoxic agents that are used in
a nt ib o dy d r ug conjugates ADCs are typically more potent than
(ADCs) remains robust as drug currently used anti-cancer drugs (1).
companies continue to invest T he A DC const r uc t combi nes a
resources in this area of therapeutics. targeted monoclonal antibody (mAb)
The road to market has been diffi- with a cytotoxic agent, linked together
cult, however, with only three ADC with a stable linker technology. An
products approved for sale by FDA in ADC enables the specific delivery of
the United States as of October 2017. chemotherapeutics to tumors while
This has not stopped ADC develop- avoiding systemic exposure to the
ers, though, and the biopharmaceutical cytotoxic compound (1).
pipeline is populated with ADC candi- Because the stable linkers conju-
dates under development. gate cytotoxic molecules to the mAb,
ADCs can remain inactive while in
THE PROMISE OF CONJUGATION circulation within the patient’s body.
ADCs are part of a relatively new class The agent is internalized by the tumor
of targeted cell immunotherapeutics cell after it is bound to the cell by the
that represent a major step in develop- mAb end of the ADC molecule. Inside
ing precision drugs (1). The target for the tumor cell, the ADC breaks down
ADCs has primarily been cancer, and into its components, which releases

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Manufacturing
the cytotoxic agent inside the cell, cers, response rates to these drugs Seattle Genetics has the
thereby killing it (1). in clinical trials have been typ- commercialization rights in the
“The potential of ADCs has been ically low, and in addition, tox- US a nd Ca nada while Ta keda
enhanced by a greatly expanded icity issues have been common. ha s com me rc ia l i z at ion r ig ht s
knowledge of ADC technolog y, This has led to an unfavorable in the rest of the world. Joint
cancer biology, and pharmacology. attitude toward ADCs for some worldwide development costs are
It is projected that the global industr y participants. Overall, funded equally between the two
market for ADCs will reach $2.8 however, the industry continues companies, except in Japan where
billion by 2018,” said Mirella to believe in the clinical benefits Takeda has full responsibility for
Zulueta, business development of these drugs (1). Some examples development costs (6).
director at Oncomatryx, a Spain- of ADCs in clinical development Seattle Genetics has an ADC
based biopharmaceutical company include candidates from Seattle candidate in Phase II development
focused on tumor stroma, in a Genetics, Immunomedics, and as well: denintuzumab mafodotin.
company blog (1). Roche. In addition, companies This candidate is in two Phase
such as Mersana Therapeutics and II trials for relapsed/refractory
ADCS ON THE MARKET NOW Oncomatryx are using different and frontline diffuse large B-cell
Currently, there are only three approaches to ADC development. lymphoma (7). Also approaching
ADCs approved by FDA for the US Phase II development is enfortumab
market. These three, from Pfizer,
Roche, and Seattle Genetics, are all
The industry continues vedotin, an ADC that the company
is co-developing with Japanese
indicated for treating cancers. pha r mace ut ic a l f i r m A ste l la s
P f i z e r ’s p r o d u c t , My lo t a r g to believe in the Pharma. This ADC is expected
(gemtuzumab ozogamicin), was to go into a Phase II tr ial in
approved in 2017, nearly a decade
after an initial approval in 2000 (2).
clinical benefits of metastatic urothelial cancer in
the second half of 2017 and has
Soon after its first approval by FDA been undergoing a Phase I trial
in 2000, Pfizer voluntarily with- these drugs. evaluating its safety and antitumor
drew Mylotarg from the market activity in escalating doses for
because the company was unable Seattle Genetics. S e at t l e metastatic urothelial cancer (8).
to verify a clinical benefit and Genetics is among the companies Seattle Genetics also has several
because of safety concerns. The developi ng a pipel i ne t hat other ADC programs in early-stage
more recent approval authorizes highlights ADCs (5). In addition clinical development, including
the use of the drug for treating to having Adcetris on the market candidates for cervical cancer,
acute myeloid leukemia (AML). for cHL and ALCL, the company metastatic breast cancer, metastatic
Roche’s product, Kadcyla (trastu- is also further developing the ADC u r o t h e l i a l c a n c e r, r e l a p s e d /
zumab emtansine), was approved for other indications, including refractory aggressive B-cell non-
by FDA in 2013. It is indicated for in three Phase III clinical studies Hodgk in ly mphoma, relapsed/
treating HER2-positive, metastatic to evaluate its potential in earlier refractor y AML, and relapsed/
breast cancer. The drug is among l i nes of t reat ment w it h i n its refractory multiple myeloma (5).
Roche’s top-10 selling products, already approved indications (6). Immunomedics. Immunomedics,
earning 2016 sales of CHF 831 mil- In addition, the company is a clinical-stage biopharmaceu-
lion (US$844 million) (3). developing brentuximab vedotin, tical company based in Morris
S e at t l e G e n e t i c s ’ p r o d u c t , the active ingredient in Adcetris, Plains, N J, specializes in anti-
Adcetris (brentuximab vedotin), in many additional types of CD30- body-based therapeutics and has
was approved in 2011. It is indi- expressing lymphomas, including t wo A DCs in clinical develop -
cated for treating classical Hodgkin c ut a ne o u s T- c e l l l y mpho m a , ment. Sacituzumab govitecan is a
lymphoma (cHL) and systemic m a t u r e T- c e l l l y m p h o m a s — Phase II ADC candidate in devel-
anaplastic large cell lymphoma commonly referred to as opment for metastatic triple-neg-
(ALCL). Adcetris had 2016 sales of peripheral T-cell lymphoma—and ative breast cancer (TNBC) and
approximately $266 million (4). B-cell lymphomas (6). metastatic solid cancers, includ-
Seattle Genetics is developing ing lung, urothelial, and esopha-
OPTIMISM IN THE PIPELINE brent uximab vedotin in geal (9). Labetuzumab govitecan
Despite the promise of ADCs as c o l l a b o r a t i o n w i t h Ta k e d a is the second ADC, also in Phase
an alternative therapeutic for can- Pha r maceut ica l, u nder wh ic h I I c l i n ic a l deve lopme nt. It is

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Manufacturing
being developed for metastatic the ADC conundrum to come up cytotoxic payload and compensate
colorectal cancer (9). with different approaches on how for the payload’s poor solubility,
In February 2016, FDA granted an ADC can be made and what it thus minimizing aggregation and
breakthrough therapy designation should do. Two examples include maintaining the ADC’s stability
to sacituzumab govitecan for the a company that developed a water- while in circulation (13). Multiple
TNBC indication. The agency also soluble polymer that can enhance molecules of this polymer-payload
awarded the ADC a fast-track des- the effectiveness of an ADC and construction (Dolaflexin) can then
ignation. If approved, the ADC will another company that chooses a be attached to the chosen mAb,
join Eisai’s eribulin, for treating target outside of, but significantly which results in an ADC with a sig-
metastic liosarcoma, and Novartis’ associated with, tumor cells. nificantly increased payload capac-
ofatumumab, for treating recur- Mersana Therapeutics. Cambridge, ity, according to the company.
rent or progressive chronic lym- MA-based Mersana Therapeutics, a Me r s a n a’s appro ac h d i f fe r s
phocytic leukemia, both of which clinical-stage company, is develop- from other ADC technologies in
were approved in 2016 (10). ing an ADC pipeline across mul- which the cytotoxic payload is
Roche. Although it is not cur- tiple tumor types. Its lead ADC directly conjugated to the mAb
rently conducting clinical develop- candidate, XMT-1522, is in Phase using a linker. With the compa-
ment of new ADCs in its pipeline, I clinical development for tumors ny’s Dolaflexin platform, ADCs
Roche is further developing its expressing the HER2 antigen (12). can be produced that carry a drug-
already-approved ADC, Kadcyla, by to-antibody (DAR) ratio between
pairing it up in clinical trials with
other anti-cancer agents.
Due to past failures in 12 to 15 — a three to four-fold
increase in DAR compared to tra-
In one Phase III clinical trial, d it ional A DC const r uc ts — and
the company is studying Kadcyla
in combination with its anti-breast
efficacy, safety, and still maintain pharmacokinetics
and drug-like properties within an
cancer biologic Perjeta (pertu-
zumab) as an adjuvant treatment
tolerability, other ADC acceptable range, as demonstrated
in animal models (13).
for early-stage HER2-positive breast In addition to its XM T-1522
cancer. In a Phase II trial, the com- developers are looking le ad c a nd id ate, t he compa ny
pany is evaluating the combined is a lso developi ng X M T-1536,
use of Kadcyla with its anti-cancer
biologic Tecentriq (atezolizumab)
deeper into the ADC a no t he r A D C c r e at e d o n it s
Dola f lex in plat for m, which is
as a second-line treatment for in the pre-clinical phase and for
HER2-positive metastatic breast conundrum. which an investigation new drug
cancer. The company plans to application was f iled. T he lat-
submit regulatory filings for these The candidate is built on the ter is targeting tumors express-
indications in 2020 or later (11). company’s lead ADC platform, ing the NaPi2b antigen, which is
In addition to these combina- Dolaflexin, which consists of a highly expressed in 75% to 90%
tion-use clinical trials, Roche is also biodeg radable, biocompat ible, of non-squamous non-small cell
conducting two Phase III clinical and water-soluble polymer, called lung cancer and epithelial ovar-
trials for Kadcyla in the third-line Fleximer, and multiple molecules ian cancer cells (12).
and adjuvant treatment of HER2- of the company’s proprietary drug T he Na P i 2b a nt igen was
positive metastatic breast cancer. payload, aur istatin, which are e v a lu ate d a s a t a r ge t for a n
The company plans to file a regula- attached to Fleximer by a linker ADC (lifastuzumab vedotin) by
tory submission for the adjuvant specifically designed to work with G enentech, a Roche compa ny
treatment indication in 2020 or this polymer (13). Takeda has the (12). Mersana expects to enter
later, but has not specified a time- rights to XMT-1522 outside the into clinical trials for XMT-1536
line for regulatory filing of the US and Canada under a strate- in early 2018.
third-line treatment indication (11). gic partnership it entered with In addition to these two ADC
Mersana in February 2013 (14). prog ra m s i n deve lopme nt, a s
DIFFERENT APPROACHES Mersana’s technology aims to we l l a s t wo ot he r ea rly d r ug
TO BUILDING AN ADC enhance the efficacy, safety, and discovery-stage ADC programs,
Due to past failures in efficacy, tolerability of ADCs. Because its Mersana partnered with
safety, and tolerability, other ADC polymer is highly water soluble, EM D Serono, t he life-sc iences
developers are looking deeper into it can be used to surround the b u s i ne s s o f M e r c k KG a A , i n

Manufacturing
2014 to develop next-generation specifically target two stromal- 5. Seattle Genetics, “Strong Development
Pipeline,” www.seattlegenetics.com/
A D C s u s i n g M e r s a n a’s A D C cell membrane proteins, MTX5 pipeline, accessed Oct. 23, 2017.
te c h nolo g y (15). Me r s a n a i s and MTX3 (17,18). 6. Seattle Genetics, “Brentuximab
generating Fleximer-ADCs using The first of these targets, MTX5, Vedotin,” www.seattlegenetics.
com/pipeline/brentuximab-vedotin,
mAbs provided by EMD Serono. is a membrane glycoprotein found accessed Oct. 23, 2017.
Mersana will also conduct drug in f ibroblasts associated w it h 7. Seattle Genetics, “Denintuzumab
discover y and preclinical cancer. However, Oncomatryx’s Mafodotin,” www.seattlegenetics.
com/pipeline/denintuzumab-
development ac t iv it ies, wh i le approach is not to block MTX5, mafodotin, accessed Oct. 23, 2017.
EMD Serono will be responsible because blocking this protein was 8. Seattle Genetics, “Enfortumab
for c l i n ica l development a nd shown to be ineffectual in previ- Vedotin,” www.seattlegenetics.
com/pipeline/enfortumab-vedotin,
commercialization of any products ous Phase II studies. Instead, the accessed on Oct. 23, 2017.
that result, as per an exclusive company’s approach is to use the 9. Immunomedics, “Pipeline,” www.
immunomedics.com/pipeline-demo.
license granted by Mersana (15). protein as a cancer-associated-fibro- shtml, accessed Oct. 24, 2017.
S i m i l a r l y, M e r s a n a h a s a blast-specific vehicle to internalize 10. BioPharm International,
col lab orat ion w it h Ta ke d a to cytotoxic molecules because MTX5 “Immunomedics Receives
Breakthrough Therapy
develop ADCs. In February 2016, is naturally capable of internalizing Designation for Breast Cancer
t he c o mp a n ie s e x p a nd e d a n molecules (16). Similarly, the other Antibody-Drug Conjugate,”
a l ready e x ist i ng col laborat ion target, MTX3, is a membrane pro- www.biopharminternational.
com/immunomedics-receives-
bet ween t hem. T he e xpa nded tein found in endothelial cells that breakthrough-therapy-
d e a l p r o v i d e s Ta k e d a w i t h also possesses a natural ability to designation-breast-cancer-
additional access to Mersana’s internalize molecules (17). antibody-drug-conjugate-0,
accessed Oct. 24, 2017.
F l e x i m e r t e c h n o l o g y ( 14 ) . The cy totoxic payloads that 11. Roche, “Product Development
Mersana has an option to Oncomatr yx is developing are Portfolio,” www.roche.com/
co-develop and co-commercialize cytolysin and nigrin. The com- research_and_development/
who_we_are_how_we_work/pipeline.
prog rams f rom its par tnership pany has designed three cytolysin htm, accessed Oct. 24, 2017.
w i t h Ta k e d a w h e n P h a s e molecules that will be conjugated 12. Mersana Therapeutics, “Pipeline,”
I clin ica l development is to mAbs. With nigrin, the com- www.mersana.com/pipeline,
completed. The companies will pany has developed two payloads: 13. Mersana Theraputics, “Our
also co - develop new c y totox ic a nigrin b–A chain molecule and a Technology,” www.mersana.
com/our-technology#dolaflexin,
payloads to use in ADCs (14). recombinant version of the nigrin accessed Oct. 23, 2017.
Oncomatryx. The Spanish ADC- b –A chain. Nigrin b is a plant 14. Takeda Pharmaceutical, “Mersana
focused company, Oncomatryx, toxin derived from the bark of an Therapeutics and Takeda
Expand Partnership to Advance
specializes in precision drugs that elder plant (Sambucus nigra) (19). Development of Fleximer Antibody-
target the tumor stroma, that is, The company’s first ADC clini- Drug Conjugates and XMT-1522,”
the supportive microenvironment cal candidate, OMTX705, is being Press Release (Feb. 3, 2016).
15. BioPharm International, “EMD Serono
that surrounds tumor cells. developed for pancreatic cancer and and Mersana to Develop Next-
Oncomatryx’s approach is to invasive lung and breast cancer. Generation Antibody-Drug Conjugates,”
develop precision drugs that tar- The company has already run pre- www.biopharminternational.com/
emd-serono-and-mersana-develop-
get proteins located in the tumor clinical trials on the candidate (20). next-generation-antibody-drug-
m ic r o e nv i r o n me nt , w h ic h it conjugates, accessed Oct. 24, 2017.
believes is a novel route to cancer REFERENCES 16. Oncomatryx, “Our Battlefield,
the Stroma,” http://oncomatryx.
treatment because it is directed at 1. M. Zulueta, “Antibody Drug Conjugates
Against Tumor Stroma: The Beginning com/targeting-tumor-stroma/,
stromal cells that propagate the of the End?,” http://oncomatryx.
invasiveness, immune suppression, 17. Oncomatryx, “Targets: MTX5 &
com/antibody-drug-conjugates-
MTX3,” http://oncomatryx.com/
and drug resistance of tumor cells, beginning/, accessed Oct. 23, 2017.
antibody-drug-conjugates/targets-
2. Pfizer, “Pfizer Receives FDA Approval
rather than directed at the epithe- for Mylotarg (gemtuzumab ozogamicin),”
mtx5-mtx3/, accessed Oct. 24, 2017.
18. Oncomatryx, “Antibodies: MTX5 &
lial cells of the tumor (16). Press Release (Sep. 1, 2017). MTX3,” http://oncomatryx.com/
T he company has developed 3. Roche, “Annual Report 2016,” www. antibody-drug-conjugates/antibodies-
roche.com/dam/jcr:ee2f197f-5487- mtx5-mtx3/, accessed Oct. 24, 2017.
a pipeline of A DCs, as well as
4629-9e28-66b77c9cbbab/en/ 19. Oncomatryx, “Payloads: Cytolysin &
antibodies and human- derived ar16e.pdf, accessed Oct. 20, 2017. Nigrin,” http://oncomatryx.com/antibody-
proteins, that target the tumor- 4. SEC, “Seattle Genetics Form drug-conjugates/payloads-cytolysin-
associated stroma. For its ADC 10-K,” http://services.corporate-ir. nigrin/, accessed Oct. 24, 2017.
net/SEC.Enhanced/SecCapsule. 20. Oncomatryx, “Pipeline,” http://
development, t he compa ny aspx?c=124860&fid=14839381, oncomatryx.com/pipeline/,
is developi ng a nt ibod ies t hat accessed Oct. 20, 2017. accessed Oct. 24, 2017. ◆

An Executive
Cell Culture Media Lot-To-Lot
Summary Variability: Can We Control It?
The importance of taking into account
variability in cell culture media.
iopharmaceutical manufacturers are constantly seeking to gain more control over protein
Graziella Piras, PhD

Scientific Application Manager
BD Life Sciences
B 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 amount of protein from the cell line and ensure
about variability in cell culture media. the efficacy and safety of the biological drug
How does this variability affect the being produced. This is at the center of pro-
bioprocessing industry? cess control: making sure we always produce
Piras: This is a critical question in our industry. a consistent amount of protein and with an
A bioprocess will depend on several factors. appropriate quality profile.
The cell line from which a biological drug is
produced is very important, particularly how it BioPharm International: Are peptones
is derived and generated as well as its stability. the major source of variability in com-
In addition, there is also the process itself, plete media formulations?
how it is controlled through all parameters, Piras: Peptones are certainly a potential
and the cell culture media, which has many source of variability. But what we have found
components. Some chemically defined media is that the chemical components of the media
have more than 80 components, which can itself can also be a major source of variability.
be sources of variability. Therefore, defining For instance, if we are using a peptone-
the concentration of each component is very containing media, we will have the peptone
important as well as controlling what goes in addition to the base medium that contains
into the medium to ensure no impurities are numerous chemically defined components.
present that could derail the process. Some impurities, like trace metals (e.g.,
Medium can be supplemented with manganese), in chemically defined compo-
peptones, which are derived from natural nents can have a drastic effect on protein
products such as plants or yeast, and can quality. Therefore, whether the variability
introduce some inherent variability. We want stems from peptones or chemically defined
to make sure we can control that and define medium components, it’s very important to
the parameters to always produce the same control it.
SPONSORED BY
CELL CULTURE MEDIA LOT-TO-LOT VARIABILITY: CAN WE CONTROL IT?
BioPharm International: Understanding what is driving the process and may affect variability, the model will assign
your cell culture process is important. What exactly are that component a high coefficient. If the component is not
these key drivers and how do you identify them? driving the process, the model will eliminate that component.
Piras: This is key to the approach we have developed at BD. If Finally, the model will eliminate all the components that do not
we focus on a process where we are using peptones that are correlate with the performance and variability.
composed of over 50 components, to really understand what The next important step is to assess the causative nature
is driving the process, we want to nail down the key, specific of those key drivers. This is done by generating peptones
components that will positively or negatively affect the process. in which those potential key drivers are modulated beyond
In our experience, we have found that not everything is impor- the natural variation. By modulating the amount of a potential
tant and that every process is unique and will depend on the driver, we can demonstrate its causative nature. If the compo-
presence and proper concentration of just a few components. nent further positively or negatively affects the variability, then
We analyze each component within the peptones and that is a good indication that this is a key driver of variability.
generate a statistical model to establish a statistical correla- The last step is then to lock in the model and demonstrate
tion between each analyte and the performance. We then that this is a predictive tool to identify lots of peptones with
reduce the system to just those few components that show a a very high likelihood of working in the customer’s process.
statistical correlation with key performance parameters. At the
center of this approach is defining which components cause BioPharm International: Can you apply this method-
the variability versus the ones that just correlate with vari- ology to reduce variability in chemically defined media
ability. We see some components, for example, that fluctuate as well as complete media?
slightly but are not correlating with the variability. By using Piras: Any cell culture medium has impurities and this meth-
a statistical model, we can establish which ones cause the odology can be applied to a peptone-containing medium or
variability. We also find that key drivers have a narrow range a chemically defined medium where, even though the com-
of optimal performance and that is what we need to define. ponents are defined, each component may bring in impurities.
We have examples where copper needs to be between 1 and Our methodology can identify the variability in both.
2.5 ppm in a very tight range of lower order ppm. We don’t
just accumulate analytical data, but apply a statistical model BioPharm International: And once you have defined the
and develop a predictive tool to identify which parameter is key drivers, how does BD help to manage the variability?
causing the variability. Piras: Once we have the key drivers, we can screen lots of
chemically defined media or peptones and make sure that
BioPharm International: How do you get to this statis- they fit the model for that specific process. In this way, we
tical model that you mentioned? can provide material that works very well early on rather than
Piras: We use an iterative process in which the model will having to go through extensive screening using a complex
analyze the statistical significance of the impact of each biological process. The idea is to prescreen the material
component that is present in a chemically defined medium or before it is used in large- or small-scale models to save time
a peptone and establish a correlation. If a component drives and resources.
Cleaning Validation and Monitoring
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
TRAIMAK/Shutterstock.com
replace surface
sampling.
R
egulated companies that use ing cleaning qualification and continu-
automated cleaning applications ous monitoring stages without impacting
have always struggled with cor- quality. Laboratory results from total
relating rinse sample quality or organic carbon (TOC) and conductivity
visual inspection to surface cleanliness. rinse sample for an alkaline detergent
The process typically involves perform- along with determining visible residue
ing 100% spray coverage testing, rinse limits using multiple concentrations,
recovery testing, specific or non-specific light intensity, viewing angles, inspec-
analytical method qualification, surface tors, and distances have been used by
sampling and recovery testing of the multiple biopharmaceutical companies.
sampling technique, and visual inspec- This approach has helped correlate rinse
tion performed during the cleaning vali- sample quality or visual inspection and
dation. Each element of the justification justify a lean approach to continuously
needs to be reviewed and evaluated dur- monitoring surface cleanliness.
ing the cleaning process design stage
to defend a lean approach in continu- CLEANING VALIDATION
Paul Lopolito is a senior technical ously monitoring the cleaning process. A REGULATORY GUIDANCE
services manager and Elizabeth risk-based approach, supplemented with FDA’s 1998 cleaning validation guidance
Rivera is a technical services manager, laboratory studies and information from document focuses on general aspects
both at the Life Sciences Division of published literature, can be leveraged in and qualification of the cleaning pro-
STERIS Corporation in Mentor, Ohio. the justification to reduce testing dur- cess (1). The design and post-validation

monitoring aspects are factored Figure 1. Example of cleaning validation activities in a lifecycle model.
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 DESIGN VALIDATION MONITOR
or traditional approach to valida-
tion. Other countries used a simi-
lar approach to provide guidance Process equipment Readiness check: Periodic review
– Process equipment Process controls
to the industry of the regulatory Utilities
Continuous monitoring
Cleaning methods – Utilities system
expectations regarding cleaning Cleaning parameters – Analytical method
Residue detection Cleaning documentation
and cleaning validation (2–3). Personnel training
Acceptance criteria
In 2011, FDA issued a revised pro-
cess validation guidance document
that introduced a concept known
today as the product lifecycle model Figure 2. Correlation between the lifecycle model, International Council
(4). This model separates the various for Harmonization (ICH), and process analytical technology (PAT) guidance
steps and activities of validation into documents.
three stages: process design, process
qualification, and continuous pro-
Roadmap to the cleaning validation
cess verification. Since then, the life-
Lifecycle approach
cycle model has become the “gold
standard” for all types of processes ICH
including cleaning validation; it pro- Q8
vides a better understanding of the Stage 1:
design and monitoring of the clean- ICH ICH Cleaning process
Design
ing process (see Figure 1) and, con- Q9 Q2
Confirm
sequently, it ensures a more robust

cleaning validation program. ICH ge
s
an
Along with the process lifecycle Q10 Ch
approach, other guides have been Stage 2:

Cleaning process
issued by FDA and the International Performance
Qualification
Council for Harmonization (ICH),
Confirm
which include the concepts of

quality by design (QbD), risk man-
agement, and process analytical ICH
technology (PAT) (5, 6). The pur- Q10 Stage 3:
Continued cleaning
pose of these guidance documents PAT Process verification
is to promote enhanced under-

ges
Chan
standing of products and processes,
to build quality into manufactur-
ing, and to provide the basis for
continuous improvement of prod- Cleaning in the GMP industry is to ensure that surface cleanliness not
ucts and processes. Figure 2 shows a critical process intended to prevent only is feasible and consistent but
the correlation between these doc- or, in more modern terms, reduce also relates to patient safety. Figure 3
ALL FIGURES ARE COURTESY OF THE AUTHORS
uments and the lifecycle model. risk of contaminating the subsequent depicts a workflow that helps bridge
Consequently, the lifecycle model product with undesirable residues the gap between sampling to surface
places more attention on under- that may impact patient safety. For cleanliness, which will be discussed
standing the process and its design, that reason, it is important to make in more detail.
and continued monitoring of the the right connection between rinse
operation to ensure the expected sampling and/or visual inspection to REVIEW ENGINEERING DESIGN
results. By comparison, the old vali- surface cleanliness. Reducing the risk AND COVERAGE TESTING
dation approach placed most efforts requires good understanding of the The design of the process equip-
on qualifying the process rather cleaning process. Some aspects of the ment must be considered to ensure
than understanding it. lifecycle model must be considered that the cleaning recommendations

Figure 3. Workflow to bridge the gap between sampling and surface cleanliness. should be included in the laboratory
studies to ensure that such levels do
Roadmap to the cleaning validation not adversely impact cleanability
Lifecycle approach and recovery of residues.
Review Cleaning
engineering parameters CLEANING AGENT AND
Stage 1:
design and
coverage
and analytical
method
ANALYTICAL METHOD SELECTION
Cleaning process
Design testing selection Cleaning agents should be selected
based on laboratory studies that sim-
Confirm
ulate the process soil, soil condition,

Ch
an
ge
s
and cleaning method used, as well
Stage 2: as performing a supplier qualifica-
Cleaning process Surface
Performance
Qualification sampling
tion and technical support review.
selection and Further consideration should be
Confirm
swab
given to formulation, toxicity, ana-
recovery
lytical method for residuals, rinsabil-
Stage 3: ity of components, stability of closed
Continued cleaning Rinse Visual
Process verification sampling inspection and open containers, and assurance
and rinse and visible that the product will be made con-
ges recovery residue limit
Chan
sistently over the life of the prod-
uct, which is often in decades for
cleaning agents intended for GMP
can be successfully scaled-up from to prevent air entrapment at vertical applications. Several cleaning agent
laboratory-scale experiments. For elbows. Dead legs should be mini- options are available, including
automated clean-out-of-place (COP) mized, and the length-to-diameter water, solvents, commodity chemi-
and clean-in-place (CIP) applica- ratio of less than or equal to 1.5 is cals, and formulated cleaning agents
tions, it is important to review cov- preferred. Dead legs should also be (11). Formulated cleaning agents are
erage and flow velocity in vessels oriented at an angle to allow for full blends of the latter components that
and piping, drainability of the wash coverage and drainage during wash- help improve cleaning performance
and rinse solutions, surface finish, ing and rinsing. by incorporating several cleaning
and materials of construction (7–9). The drainage of wash and rinse mechanisms in solution. Table I
Spray devices should cover all the solution is also important. Pooling in lists different components used in
surfaces that they are intended to vessels and piping may lead to micro- designing cleaning agents (12).
clean. These types of devices can bial blooms, biofilm, and carryover of A variety of analytical methods
be fixed or dynamic. Riboflavin process and cleaning agent residues. are used to detect active ingredients,
(vitamin B2) testing using 0.2 g/L The mixing of the drain solution degradation or byproducts, biobur-
vitamin B2 and an ultraviolet (UV) (heel) can reduce residue deposition den, endotoxin level, and cleaning
light ensures that the spray device on the side walls. Horizontal tanks, agent residues. The selection may be
gives full coverage during the wash equipment surfaces, and piping based on multiple factors including
and rinse steps. For vertical tanks, should be sloped at 1/8–1/16 inches the analyte of interest, analytical
the flow rate of a static spray device per square foot (3.6 –1.8 cm per resources available, rinsability, and
should be about 2.5–3 gallons per square meter) to allow full drainage. carry-over risk.
minute per feet of internal tank The preferred materials of con- The rinsability of a cleaning
diameter (10). Vessel inserts such as struction in the pharmaceutical agent is crucial in demonstrating
agitators, probes, and baffles may industry are 304 and 316L stain- that the components within the
be challenging to clean in place and less steel. Other materials of con- formulation rinse freely from the
hence, coverage testing becomes struction are used throughout the surface with water. If the compo-
more crucial to designing for a suc- industry. The selection of materials nents within the formulation rinse
cessful cleaning. should be based on both the manu- at similar rates, then either non-
Flow rates in piping are important facturing process and on the clean- specific methods, such as conduc-
for proper coverage of solutions, as is ing procedure required for reducing tivity or TOC, or specific methods,
providing turbulent flow. The flow the amount of residue to safe levels. such as ultra high-performance liq-
velocity in piping should be five feet Surface roughness as well as other uid chromatography (UHPLC), can
per second (approximately 1.5 m/s) materials of constructions in use be used (13, 14). If the components

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do not rinse at similar rates, then Table I. Components in formulated cleaners.

it is important to identify and set
Component Function
residual limits based on the last-to-
Water Solvent for salts, polar materials; carrier for additives
rinse component. Refer to Figure 4
to compare rinsing results with Wet, solubilize, emulsify, disperse, lubricate, soften, release, detergent,
Surfactant
level, corrosion inhibitor, couple, foam, foam stabilizer, disinfectant
various analytical methods for
monitoring components within a Chelants Tie up calcium, iron, and other metals
formulated cleaning agent (13). Solvent Solubilize
Cleaning agents used for product Bases Alkalinity source, hydrolysis
contact surfaces must have toxic- Acids Acidity source, hydrolysis
ity information available, which is
Builders Assist in detergency; multifunctional
important in determining safe lev-
els of cleaning agent residues. The Dispersants Suspend solids
toxicity of components is important, Antimicrobials Kill, reduce microbes
especially if they are the last to rinse Oxidant Oxidize, kill microbes
from the surface or if they display
mutagenic, reproductive, carcino- Figure 4. Monitoring of cleaning agent residues on surface.
genic, developmental, or chronic tox- TOC is total organic carbon.
icity. In the case of cleaning agents,
Percent residue removal
the sum of components may have 100.0
95.0
increased or decreased toxicity com- 90.0
85.0
pared to individual components, and 80.0
75.0
toxicity of the cleaning agent should 70.0
TOC
Sodium (IC)
65.0
be available from the suppliers. 60.0 Potassium (IC)
% Removed
55.0 Titration
50.0 Organic Acid
SURFACE CLEANLINESS 45.0
40.0
Chelant
The ability to sample the surface for 35.0
30.0
cleanliness is the preferred technique 25.0
to demonstrate the equipment is 20.0
15.0
ready to manufacture the next batch 10.0
5.0
of product, a new product, or to pro- 0.0
15
30
45
ceed with the next manufacturing Rinse Time, Seconds
process step. Surface testing, however,
requires a significant amount of time
to: prepare the equipment for sam- Selection of sampling sites site selection. Figure 5, for example,
pling; prepare and source sampling The European Union GMP guideline, shows the interior of a vessel with
tools; sample the surfaces; transport Annex 15 section 10.11, cites that multiple accessories that reduce
samples for testing; test samples; and cleaning validation protocols should the coverage provided through the
review results of testing. specify or reference the locations to spray device (top circumference)
In addition to the amount of time be sampled, specify the rationale for in a CIP system. The shaded area
required for sampling and testing, the selection of these locations, and in the vessel represents the nor-
there is allocation of labor for sam- define the acceptance criteria (15). A mal process air-to-liquid interface,
pling and testing, often scheduling documented sampling and testing which is often an area where solids
between multiple departments, and plan must be prepared describing: settle onto the surface and form a
more importantly lost time that location of samples (and rationale), scum-like ring on the walls.
could be used for manufacturing or number of samples per location, Sampling sites should be defined
sampling and testing critical steps sampling test methods used, wetting based upon the geometr y and
within the manufacturing process. agent, and surface area sampled. design of the equipment, materi-
The selection of sampling sites and The use of diagrams, such as the als of construction, hard-to-clean
test methods and performing sur- one illustrated in Figure 5, provides areas, and locations that may have
face sampling recovery will help in the operator with a better picture a higher risk to product contamina-
significantly reducing or even elimi- of the sampling areas to focus on tion (i.e., risk assessment), or they
nating routine surface sampling to (16). They also aid in understanding may be based on historical refer-
demonstrate surface cleanliness. the rationale behind the sampling ence from similar equipment on

Visible residue limit case study
A large biopharmaceutical manufacturer was designing a new viewing endcap on the final formulation compounding tank, so
facility for the final compounding and filling of their product. the higher VRL observed was not critical.
This standard parenteral facility consists of an automated
parts washer, steam sterilizer, automated vial washer, Visual inspection training
depyrogenation tunnel, filling machine, closure machine The visual inspection procedure as well as the inspector
to insert stoppers, capping machine, and product labeler. qualification study consisted of precleaning and visual
This product was being filled by a contract manufacturing inspection of the coupons before spiking. An analyst
organization (CMO), which was using only water for cleaning. receives a yearly eye exam with 20/20 vision (glasses
During the design phase of the cleaning program, coupon or contact lenses are acceptable), wears safety glasses
testing was performed by coating the finished product onto during visual inspection, and is informed that some coupons
stainless-steel coupons and evaluating the cleaning with water may not contain a sample. This procedure is used to try to
and a formulated alkaline cleaning agent to remove the finished eliminate phantom residues or false positives.
product. Water-only cleaning at ambient to 80 oC was not The coupons were placed flat on a table in front of a
sufficient to yield a visual clean and water-break free surface. fume hood in groups of three, and the inspector stood back
Cleaning the coupons with water was successful in meeting approximately 0.85 m and inspected the coupons at a 50o
the gravimetric testing of around 1–2 mcg/cm2. In support of angle. The groups of three coupons were mixed in order
a visual inspection program of the items being washed in the as seen in Sidebar Table I. The lighting in the room was
parts washer, a visible residue limit (VRL) study was performed between 500 and 1000 lux.
on the final drug product as well as on a formulated alkaline An acceptable result is that the inspector identifies all
cleaning agent on stainless-steel and glass surfaces. coupons with a loading of 10 mcg/cm2 and 12 out of 15 of
The VRL study procedure consisted of precleaning and the remaining coupons.
drying 304 stainless-steel coupons with a 2B finish as well Figure 1. Visible residue limit (VRL) results for the
as borosilicate-glass coupons. The roughness of the 304 formulated alkaline cleaning agent.
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
Increase in light to 1000 lux no issues, VRL at 1:600
applied over a 1-cm2 area. The sample was then allowed to Increased distance resulted in difficulty using mirror and operator variability
air-dry at ambient temperature for at least 16 hours. Adjustment in angle improved VRL but increased difficulty in using mirror
An angle of 90 degrees without mirror had a VRL at 1:600
After drying, the coupons were inspected by two analysts, Glass substrate was difficult and displayed variability even at lower
concentrations (1:10, 1:20 and 1:50)
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 Table I. Visual inspection training test matrix example.
without a viewing mirror. A light meter (Cooke Corporation Coupon set 1 7 mcg/cm 2 10 mcg/cm 2 Blank
Cal-Light 400 lux), digital protractor, and 1–5 mcl syringe Coupon set 2 10 mcg/cm 2
5 mcg/cm 2
10 mcg/cm 2
(Hamilton) were used in the study. The acceptable results
Coupon set 3 Blank 7 mcg/cm 2 5 mcg/cm 2
for both analysts on two coupons per set for the formulated
Coupon set 4 5 mcg/cm 2
Blank 7 mcg/cm 2
alkaline cleaning agent are noted in Sidebar Figure 1. The
borosilicate glass surface was used in the construction of the Coupon set 5 10 mcg/cm 2 7 mcg/cm 2 10 mcg/cm 2
site (i.e., benchmark). The ribofla- Risk-based sur face sampling ple of a list of sampling sites and
vin testing used for spray device locations and testing performed assigned risk factors.
qualification in CIP systems also A risk assessment should be per- A risk assessment should also be
helps in identifying areas that must formed to minimize the number of performed to minimize the number
be sampled due to limited coverage. sampling sites. Table II is an exam- of tests performed, such as micro-

Table II. Risk assessment of surface sampling locations. MOC is material of construction.
Cleanability
Critical Site: Hot Spot Affinity to Role in process
Sampling of location/
Potential large (historically MOC or likely to lead to Ranking
Location coverage and
contaminant area hard to clean) surface finish difficult residue
access
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
bial, detergent, or active ingredient Figure 5. Sampling site selections.

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 ents as well as cleaning agent residues analytical testing. There are limita-
sampled, material of construction from a single site using various materi- tions, similar to surface sampling,
of the surface, number and condi- als of constructions (including metals, with routine visual inspections, such
tion of the swab(s) or wipe(s), sam- plastics, and elastomers) supported as large equipment or lengths of pip-
ple storage and stability conditions, that stainless steel could be used as a ing, as well as the time and resources
swab or wipe diluent, and sam- representative surface for swab recov- required for proper visual inspection.
pling accessories; qualified analysts ery (18). Forsyth, et. al. pooled recov- Visual inspection can be defined
should perform the testing. The ery factors from 16 sites, 29 different as the process of using the unaided
surface sampling recovery study materials, and hundreds of samples. eye as the sensing mechanism from
should also consider, if applicable, The reported recovery factor from a which judgments can be made
the swab or wipe wetting solu- formulated alkaline cleaning agent, about the condition of a unit to be
tion and various spiked amounts CIP 100 detergent, from 316 stainless inspected. A visual non-uniformity
on the surface. The spiked amount steel was 93% (18). on equipment surfaces may present
and design of the surface sampling as an interruption of the normal pat-
recovery test should challenge the VISUAL INSPECTION tern or grain either by residue or dis-
sampling and analytical procedure. Visual inspection is important to coloration in amount as perceived by
The analysis of swab recovery from ensure that the equipment looks the unaided eye. This non-unifor-
various active pharmaceutical ingredi- sufficiently clean to proceed with mity could be on the surface, such

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
EVENT OVERVIEW Key Learning Objectives

In mAb purification, viral clearance is a requirement of ■ Learn about resin selection for viral
clearance in mAb purification
downstream processing of biologics, especially those
■ Learn about the effectiveness of
derived from microbial expression systems that contain
different resins for viral clearance in mAb
endogenous host cell endotoxin. Viral clearance studies, purification
which verify virus removal, do not have a set standard ■ Learn about viral clearance methods
method. Depending on the potential viral contaminant without jeopardizing the yield or purity of
mAb
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 Presenters
interaction chromatography (HIC), ion exchange Bill Evans
chromatography (IEX) and mixed mode—are studied and Process Chromatography
Technical Specialist
compared to verify the effectiveness of viral removal in Tosoh Bioscience LLC
mAb purification.
Moderator:
Who Should Attend Rita Peters
■ Chief Medical Officer Editorial Director
BioPharm International
■ Downstream process development scientists for mAb
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■ Downstream process development managers for mAb
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■ Supply chain managers for downstream process
manufacturing Sponsored by
Presented by
For questions, contact Ethan Castillo at ethan.castillo@ubm.com

Figure 6. First rinse recovery study; linearity between conductivity to terion will require a justifiable, sci-
concentration of a formulated alkaline cleaning agent. 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/cm 2 (19), and this article
was referenced in the FDA guide
to cleaning validation (1) as well
as Parenteral Dr ug 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
Figure 7. Second rinse recovery study; linearity between total organic carbon studies. The case studies include
(TOC) and concentration of a formulated alkaline cleaning agent. spiking a 1 cm 2 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 SAMPLING
Rinse sampling is commonly used
to evaluate surface cleanliness of
as visible residue, particulate matter, that a visual inspection or rinse closed production equipment, hoses,
pooling of liquid, or rouge (oxides) or sample can be scientifically justified and piping commonly cleaned by
within the surface, such as scratches, to determine that the equipment, CIP systems (23–25). The advan-
corrosion, or etching. piping, or parts are cleaned. Visual tages of rinse sampling are that the
During the design and qualifica- inspection as the method to assess entire surface can be sampled, with
tion stages of the lifecycle model, a for cleanliness is ideal for small parts no disassembly of equipment and
correlation between visual inspec- or open process equipment that are no direct sampling of the surface,
tion, surface sampling, and rinse easy to inspect. However, “visually and that rinse sample analysis via
sampling should be performed, so clean” as the only acceptance cri- conductivity, TOC, UV, and other

methods in-line or on-line can be The selection of the residue, condi- ery case study includes a linearity
adapted to PAT technologies. The tioning of the residue, surface mate- between concentration and TOC of
disadvantages of rinse sampling are rial, roughness of the surface, rinse a formulated alkaline cleaning agent
that the analyte measured may not solution, volume of rinse solution (Figure 7) as well as the recovery fac-
be soluble in the rinse solution, rins- per surface area, rinse solution tem- tor from stainless steel, PTFE, rub-
ing may not pick up the residue due perature, and flow rate should all be ber, and glass surfaces (Table IV).
to poor coverage during rinsing, and considered in setting up a rinse solu- Three lots of the formulated alka-
the analyte may be too diluted in tion recovery study. line cleaning agent were diluted at
the rinse solution volume. Two rinse recovery studies are dis- various concentrations between 1
cussed as examples. The first rinse and 100 ppm by volume using DI
Rinse recovery studies recovery case study includes a lin- water and tested at ambient tem-
Rinse recovery studies can be used earity between concentration and perature. A conductivity meter
in addition to assessing the solubil- conductivity of a formulated alka- (Radiometer/Copenhagen CDM83)
ity of the active ingredient in the line cleaning agent (Figure 6) as well was used, and the conductivity
rinse solution. The studies are per- as the recovery factor from stain- probe was standardized following
formed by adding a specified con- less steel, polytetrafluoroethylene the manufacturer’s recommenda-
centration, around the acceptable (PTFE), rubber, and glass surfaces tions with 50 and 100 mcS/cm stan-
limit, of the residue on the surface. (Table III). The second rinse recov- dards prior to testing. Temperature
Table III. Conductivity and pH results, 24-hour air-dried samples; SS is stainless steel.
Average Percent Relative Standard
Sample Identification Conductivity mS / cm pH
Recovery, % Deviation, %
SS 5.608 8.05
SS 5.360 66.1 0.1 8.11
SS 5.387 8.08
Teflon 5.276 8.43
Teflon 5.361 66.5 0.3 8.55
Teflon 5.804 8.30
Rubber 4.915 8.44
Rubber 5.460 63.6 0.3 7.80
Rubber 5.362 7.93
Glass 5.081 6.85
Glass 5.378 63.0 0.2 7.44
Glass 5.121 7.29
Table IV. Total organic carbon (TOC) results, 24-hour air-dried samples. SS is stainless steel.
TOC
TOC Average Relative
Sample theoretical Percent
experimental, Net TOC, ppb C Percent Standard
Identification (at 100 % Recovery, %
ppb C Recovery, % Deviation, %
Recovery), ppb C
SS 463 355 327 92.2
SS 475 353 339 96.1 95.2 2.6
SS 488 362 352 97.2
Teflon 708 341 370 108.6
Teflon 762 342 424 124.1 98.7 31.5
Teflon 564 356 226 63.5
Rubber 505 358 263 73.4
Rubber 595 350 353 100.8 95.5 20.0
Rubber 525 356 400 112.3
Glass 452 354 290 82.0
Glass 512 352 350 99.5 92.7 9.4
Glass 503 353 341 96.5

compensation was not used for this drug manufactured. Surface clean- 8. G. Verghese and P. Lopolito,
“Cleaning Engineering and Equipment
testing. The conductivity to concen- liness can be determined through Design,” in Cleaning and Cleaning
tration curve is reported in Figure 6. surface sampling, rinse sampling, Validation Volume I, P. Pluta Ed. (DHI
Three lots of the formulated and visual inspection. The pre- Publishing and the Parenteral Drug
Association, 2009) pp 123-150.
a l k a l i ne c lea n i ng agent were ferred method is surface sampling
9. J. Voss, Cleaning and Cleaning
diluted at various concentrations through swabbing, w iping, or Validation: A Biotechnology Perspective
between 0.1 and 5 ppm C by vol- direct measurement. Surface sam- pp 1-39 (PDA, Bethesda, MD, 1996).
ume using DI water and tested at pling can add production delays, 10. ASME, Bioprocessing Equipment
(BPE) p. 52 (2012).
ambient temperature. A laboratory increased sampling costs, and 11. G. Verghese and N. Kaiser,
TOC analyzer (Sievers 900) was often increased safety risk to the “Cleaning Agents and Cleaning
used for testing, and the TOC ana- analyst. If the engineering of the Chemistry, Chapter 7” in Cleaning
and Cleaning Validation Volume
lyzer was standardized following equipment, coverage testing of the I, P. Pluta Ed. (Davis Healthcare
the manufacturer’s recommenda- equipment, and cleaning agent International and Parenteral Drug
tions with reference standards for and analytical method selection Association, 2009) pp 103-121.
12. P. Lopolito, “Critical Cleaning for
sucrose and benzoquinone. The have been well vetted during the
Pharmaceutical Applications, Chapter
TOC to concentration curve is design and qualification stages of 17” in Handbook for Critical Cleaning
reported in Figure 7. the lifecycle approach, then rinse Applications, Processes and Controls,
Rinse recovery testing was per- sampling or visual inspection can Second Edition, B. Kanesgsberg and
E. Kanesgsberg, Eds. (CRC Press,
formed by applying 1 +/-0.1 g of be successfully used to demon- Taylor & Francis Group, 2011).
the prepared 0.24% w/w formu- strate surface cleanliness. Attention 13. H.J. Kaiser, J.F. Tirey, and D.A.LeBlanc,
lated alkaline cleaning agent to to detail and application of a risk- J. Val. Tech. 6 (1) 424-436 (1999).
14. H. J. Kaiser and B. Ritts,
about 100 cm2 area of one side of based approach during the design “Validation of Analytical Methods
the stainless steel, PTFE, glass, and stage can provide justification for Used in Cleaning Validation,” J.
rubber coupons using an analyti- using either rinse sampling or Val. Tech. 10 (3) (May 2004).
15. European Commission, Good
cal balance (Mettler Toledo XS). visual inspection in determining
Manufacturing Practice Medicinal
Solution was applied in drops surface cleanliness. Products for Human and Veterinary
to provide a uniform coverage. Use—Annex 15, Qualification
Samples were air-dried on the ACKNOWLEDGEMENT and Validation (2015).
16. P. Lopolito and E. Rivera, “Cleaning
coupons in a horizontal position. T he aut ho r s a r e g r ate f u l to Validation: Process Lifecycle Approach,”
After drying, 300 mL of DI water at Amanda Deal for excellent techni- in Contamination Control in Healthcare
ambient temperature was poured cal assistance in performing the Product Manufacturing, Vol 3. R.
Madsen and J. Moldenhauer, Eds.
from a squeeze bottle over the cou- VRL study as well as the first and (DHI Publishing, PDA Books, 2014).
pon so that the flow cascades down second rinse recovery case studies. 17. M. Gietl, B. Meadows, and P. Lopolito,
the face of the coupon for approxi- “Cleaning Agent Residue Detection with
mately 30 seconds. The collected REFERENCES UHPLC” Pharm. Manufacturing (April,
2013) www.pharmamanufacturing.
rinse water was agitated for 30 sec- 1. FDA, Guide to Inspections Validation
of Cleaning Processes (July 1993). com/articles/2013/1304_
onds to ensure uniformity, then 39 2. Health Canada, Guide-0028 Cleaning SolutionsTroubleshooting/,
mL was poured into a labeled TOC Validation Guidelines (Jan. 2008). accessed Oct. 10, 2017.
3. PIC/S, PE-006-3 Validation Master Plan 18. R. L. Forsyth, J.C. O’Neill, and
vial, sealed, and measured for TOC J.L. Hartman, Pharm. Tech. 31
Installation and Operational Qualification
(Sievers 900 laboratory TOC ana- Non-Sterile Process Validation (10) 103-116 (2007).
lyzer). The TOC recovery results are Cleaning Validation (Sept. 2009). 19. G. L. Fourman and M.V. Mullen,
4. FDA, Process Validation: General Pharm. Tech. 17 (4) 54-60 (1993).
reported in Table IV. The remain- 20. PDA, Technical Report No. 29 (Revised
Principles and Practices (Jan. 2011).
ing sample (39 mL) was measured 5. FDA, Guide for Industry. PAT—A 2012) Points to consider for cleaning
for conductivity (Fisher Scientific Framework for innovative pharmaceutical validation. (Bethesda, MD, 2012).
development, manufacturing, and 21. R.J.Forsyth, V. Van Nostrand,
AB30 conductivity meter). The
quality assurance (Sept. 2004). and G.P. Martin, Pharm. Tech.
conductivity recovery results are 6. ICH, Harmonised Tripartite 28 (10) 58-72 (2004).
reported in Table III. Guideline—Q9 Quality Risk 22. D. A. LeBlanc, J. Pharm. Sci.
Management (Nov. 2005). Tech. 56 (1) 31-36 (2002).
23. D. A. LeBlanc, Rinse sampling for
CONCLUSION 7. E. Rivera, “Basic equipment-
design concepts to enable cleaning cleaning validation studies, Pharm.
Surface cleanliness is crucial in in place: Part I,” Pharm. Tech. Tech. 12 (5) 66-74 (1988).
ensuring that process residue, Equipment and Processing Report 24. B. Bunimovich, P. Lopolito,
(June 15, 2011), www.pharmtech. and B. Meadows, J. Val. Tech.,
cleaning agent residue, and biocom/basic-equipment-design- p. 62-69 (Winter 2011).
burden do not adversely affect the concepts-enable-cleaning-place- 25. K. Bader, et al., Pharm. Eng.,
safety, quality, and potency of the part-i, accessed Oct. 10, 2017. 29 (1) 8-20 (2009).◆

Clinical Trial Logistics
Moving Toward
Direct-to-Patient Models
Agnes Shanley
Despite GxP
and data-
management
challenges,
pharma is
moving toward
new models
A and N photography/Shutterstock.com
for clinical
trial logistics.
C
linical trials pose major man- manufacturing, packaging, and distri-
ufacturing and distribution bution for clinical trials.
challenges, which have been
magnified by the trend to out-
source more operations. The success of A growing number of CRLs
any clinical trial demands strong adher-
ence to GxPs—required good current
practices in manufacturing, clinical,
reflects dosage complexity
distribution, and documentation. The
end goal, says Matthew Caponi, senior and a clinical-to-cGMP
director of North American depot and
production services at PAREXEL, is pro-
viding assurance that the rights, safety,
disconnect at some
and wellbeing of patients are protected,
and that the results of the trial will be companies.
unbiased and credible.
A nu mber of fac tor s, i nclud i ng In addition, a growing number of
increasing complexity of drug forms manufacturers are moving from tradi-
and increased reliance on outsourcing, tional to direct-to-patient clinical trial
has made it more difficult to optimize designs, a shift that will change basic

communication, logistics, and the New Drugs in FDA’s Center for new APIs require a difficult syn-
way that manufacturing, patient Dr ug Evaluation and Research thesis, and the resulting drug prod-
compliance, and logistics data are (CDER), the agency issued 14 CRLs ucts can require special storage and
exchanged. This article examines for new drugs (1) in 2016, and five cold-chain handling.
some current trends and changes involved cGMP issues at contract
that can be expected in clinical development and manufact ur- PATIENT-CENTERED PACKAGING
trial logistics in the near future. ing organization (CDMO) or con- Not all that long ago, many oral,
tract manufacturing organization solid-dose products were shipped
MANUFACTURING DELAYS (CMO) partner facilities (2). in corr ugate, and temperat ure
On the manufacturing side, fail- Some of these cGMP deficiencies monitoring was not even needed,
ure to maintain GMP standards are due to tight timelines and the says Vyas. “Today, a biologic must
at the clinical stage is resulting in fact that formulations are becom- be moved in shippers using phase-
an increased number of new drug ing more complex, especially as change material of far more robust
approval delays. In 2016, for exam- drug development shifts from an and technical design, with temper-
ple, FDA issued a record number of emphasis on small molecules to ature monitoring devices to ensure
complete response letters (CRLs) one on biologics, says Sanjay Vyas, and demonstrate environmental
for new drugs under development. corporate vice-president, global control,” he says. “All of these spe-
CRLs detail problems found at pre- head of clinical trial supplies and cific requirements must be sup-
approval facility inspections for new logistics at PAREXEL.“Clinicians ported by a supply logistics chain
drug applications (NDAs) and require want a simple dose to adminis- that can ensure that the material
that manufacturers or contract part- ter the most robust and efficient is maintained exactly as required
ners fix these issues before the NDA drug formulation, but some dos- as it moves a long t he supply
approval process can continue. age forms must be administered chain—the chain of custody must
Accord i ng to Joh n Jen k i ns, intravenously instead of orally.” be unbroken and documented as
retired director of the Office of In addition, he says, a number of such,” he adds.
Seventeenth Annual
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Packaging for clinical trials must selection of kits is completely ran- st rateg y. “T he end resu lt is a
not only support the required stor- dom,” he says. dosing regimen that is easier for
age conditions but also enhance Street suggests using a hidden the patient to maintain and less
patient compliance and ease of use, sequence number that will not expensive to produce,” he says.
as well as efficient logistics, says be visible on the kit, which will For oral solid-dosage forms, the
Vyas. “A blister card that clearly allow depot and warehouse staff to best solution for blinding may
shows the morning and evening know the order in which kits will be as simple as over encapsulat-
dose as part of its design will work be requested, so that packing can ing the product comparator with
better than a series of bottles pre- be done most efficiently. “When the same size capsule, Caponi says.
sented to the patient, each with selecting your RTSM/IRT vendor, “Injectables present another whole
different dosing instructions,” he it is essential that you work with spectrum of issues—questions to
says, adding that smaller, less com- a team that fully understands the ask include: Does your syringe
plicated packs will help support process at study sites and the GMP/ look the same or can it be some-
logistics efforts. GCP implications of system set up. how blinded to the comparator?
Something as small as the sequen- Is the actual product visually the
BLINDING CHALLENGES tial numbers utilized on a patient same color?” he says.
Beyond basic manufacturing, the kit can jeopardize the credibility It’s especially important to be
most challenging part of any clini- of an entire clinical trial program,” aware of issues that can result
cal trial is maintaining the practice says Street. when blinded drugs for clinical tri-
of double blinding, which helps als are manufactured on existing
to ensure unbiased trial results by commercial lines, a practice that
preventing patients, healthcare pro- Early planning can is becoming more common, and
viders, and those who collect and will become to be widespread in
analyze trial data from knowing
whether each individual subject
reduce the clinical the future.
Caponi recalls a case in which
in the trial has received the actual
drug being studied or a placebo. trial complexity and transdermal pouches were pro-
duced at various clinical strengths
The challenges posed by blinding on a single commercial produc-
requirements run from manufac-
turing to dosage-form selection,
the need for double- tion line. Each of the pouches was
marked so that it could be traced
packaging, and distribution. “The
range of potential unblinding or at dummy designs. back to the production line, a use-
ful practice for commercial opera-
least complicating factors is enor- tions. However, when the material
mous, and as varied as the products AVOIDING THE NEED FOR was received by the clinical sup-
themselves,” says Caponi. DOUBLE DUMMY TRIAL DESIGN plies packager, something had
Even numbering the kits to be In trials where two compounds to be done to blind these marks,
used by each individual patient in are being compared, a double because each mark indicated a dif-
a clinical trial requires strategy. If dummy approach may be required, ference in strength for each pouch
the randomization and trial supply in which each of the drugs and manufactured on that line.
management (RTSM) or interac- its placebo are given distinctive
tive response technology (IRT) sys- forms, for example, different col- DIRECT-TO-PATIENT TRIALS
tem being used is not configured ors for oral solid-dosage forms and T he move f rom traditional to
with blinding in mind, it will be their placebos. direct-to-patient clinical trials (in
possible for sites to see trends in Howeve r, c a re f u l a nd ea rly which patients take the medica-
the dispensation of kit numbers planning can eliminate the need tion independently in their own
and identify kits that are different for this approach, says Caponi. homes) is gaining ground, and
from another, explains Tony Street, “An early decision on dosage form is likely to result in fundamen-
PAREXEL’s head of global portfolio may prevent the need to resort to tal changes in the way products
leadership for clinical trial supplies double dummy designs, in turn, are packaged and distributed and
and logistics. “The use of scram- reducing the total number of dos- how product data are transferred.
bled rather than sequential num- age forms manufactured, as well “Distribution and medical adher-
bers eliminates this risk, but this as the labels produced, packag- ence will now be more closely
approach can present operational ing components used, and sim- intertwined with the design of the
challenges at the warehouse if the plifying overall packaging design clinical trial itself and the loca-

tions of the distribution of the that will involve direct contact form and packaging appear iden-
drugs,” says James Streeter, global with patients. Third-party vendors tical will be crucial. Individual
vice-president of life-sciences prod- will interact with patients who will dosage forms and their packaging
uct strategy at Oracle. get supplies either directly at home will require unique identifiers, and
In formulation and drug deliv- or at their local pharmacies, says each will need to be monitored
ery, ease of use and safety will Oracle’s Streeter. closely, he says.
become even more important, Sponsors will have to have the
because patients themselves, rather technology required for tracking
than healthcare providers, will be As patient ease-of-use and monitoring as part of each
administering dosing, says Vyas. clinical trial design and as part
As a result, products such as infu-
sions or those that need to be
becomes paramount, of their overall data-management
toolkit, Streeter says. “We won’t
reconstituted at the point of use be tracking data at the individual
will need to be reformulated, he drugs that must be patient’s kit level, but at the level
says, while packaging design will of the individual pill, and data will
have to become even more stream-
lined. Biologics manufacturers will
reconstituted at the become part of overall operations
data, so a much more coordinated
also be under greater pressure to approach to data management will
develop products that remain sta- point of use will need to be needed,” he says.
ble under a wider range of tem-
peratures and conditions, he adds. be reformulated. A ROLE FOR BLOCKCHAIN?
Data lineage and even blockchain
LAST-MILE PLANNING IS CRUCIAL methodologies will be required so
Instead of sending large shipments Tracking and controlling who that manufacturers will be able
to investigator sites, manufactur- gets these drugs will shift from to trace each drug, its packaging,
ers will now be sending multiple, one central operation to individ- and shipments precisely, Oracle’s
smaller shipments to patients, Vyas ual operations, and regulators will Streeter says. As a result, he says,
says, and logistics planning and require that patient adherence data data requirements will explode,
patient monitoring data will need be aligned with distribution con- requiring large amounts of storage
to be linked. Planning the last mile trol, Streeter predicts. In fact, he space, analytics and machine learn-
of drug delivery to the patient’s says, distribution, patient adher- ing software to manage and mine.
home from either the manufactur- ence, and overall clinical trial data “Evidence-based medicine has
ing plant or the storage depot will will no longer be managed sepa- become the norm in the medical
become more challenging, he says, rately, but together, because opera- field today, and, as the need grows
because each country has its own tions teams running the clinical for real-world evidence in clinical
different product stability require- trials will need all three types of trials, so will the need to break
ments as well as different geogra- data to optimize trial control. In down the silos that still separate
phies and climates. addition, although investigators manufacturing, patient compli-
“For the clinical supply pro- will still be responsible for patient ance, and logistics data. Together,
vider, orchestrating an integrated safety, their operations will also these forms of data will provide
technology and data sharing capa- need to be monitored. better overall control, and promise
bility becomes highly important to reduce the overall costs of clini-
to ensure that not only the right FROM THE PACKAGE TO THE DOSE cal trials in the future,” he says.
drugs reach the right patient safely Blinding and packing the phar-
and on time, but also that patient maceuticals used in clinical trials REFERENCES
information remains blinded from will no longer be controlled at the 1. J. Jenkins, “A Review of CDER’s Novel
Drug Approvals for 2016,” FDAVoice,
the sponsor to support regulatory package level, but at the level of
January 4, 2017, www.blogs.fda.gov/
requirements,” says Vyas. Proactive the individual dose, says Streeter, fdavoice/index.php/2017/01/a-review-
supply chain planning, agility, and who adds that social media will of-cders-novel-drug-approvals-for-2016/
integrated technology will be key make blinding more challenging, 2. A. Thayer, “The Complete
to success. because patients may inadvertently Response Letter: The Mail No
One Wants to Receive,” cen.acs.
In the direct-to-patient world, share information with each other org, May 15, 2017, www.cen.acs.
shipping controls and tracking will about drugs and their packaging. org/articles/95/i20/complete-
be handled through new methods The need to ensure that dosage response-letter-mail-one.html ◆

PRODUCT SPOTLIGHT
Pump Head for Analytical Data System Update

Shear-Sensitive Pumping An updated version of
Shimadzu’s LabSolutions
The Masterflex L/S analytical data system
Cytoflow pump head from incorporates additional
Cole Parmer is suited functions to comply with data
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and microbiology support development and
applications. The quality inspection procedures.
pump was developed The software features an
for pumping live operating environment for complete data management
cells and shear- and security in networked laboratories and can be used
sensitive fluids, and with traditional peak integration methods. Users can switch
is compatible with all Masterflex L/S drives between traditional and new peak integration methods
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The pump head has a large-diameter rotor peak integration method for the circumstance. This includes
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is available in two- and three-roller configurations. A peak integration algorithm in the software can quantify
Two-roller heads offer higher flow rates, and three- overlapping peaks more accurately, the company reports.
roller heads deliver less pulsation. In addition to the The intelligent peak deconvolution analysis (i-PDeA II),
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has a convex roller for cell viability. According to the PDA detector, has been improved and can be used to
the company, performance in live-cell applications show data traces for single components more accurately
has been verified by independent test data. than with the conventional peak purity method, enabling
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Dip-Molded Plastisol Y Temperature-Controlled

Connectors Shipping Solution
Qosina has added a Almac Group has expanded
variety of Y connectors availability of the Almac Pod,
manufactured from a temperature-controlled
plastisol, also known shipping solution service
as liquid polyvinyl for biologics and other
chloride (PVC), a temperature-sensitive
material used to make products, to the United States
flexible components. as part of the company’s
According to the end-to-end, global supply
company, plastisol chain management
is Class VI approved solution. Originally released in Europe, the service is
and BPA and latex compliant with good distribution practices and comes
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are produced through a dip-molding process The protected model is qualified for up to 96 hours
rather than traditional injection molding. against thermal challenges by the International Safe Transit
The company offers standard and universal plastisol Association and is available in -15 °C to -25 °C, +2 °C to +8
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There are 15 different Y connector configurations, eliminates temperature excursions, is suited for reuse
sample assortment kits, and custom design services with no shippers left at the clinical site, and requires no
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Qosina change material to offer increased thermal protection. It can
www.Qosina.com 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.
Almac Group
www.almacgroup.com

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System scales to your drug annealing temperature). This allows you to take your PCR to the next level, as the
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identifying the lead candidate yield of a PCR. Coming with a highly intuitive touchscreen and the capabilities to
to optimizing scale-up conditions. Explore our platform and see how connect up to 10 units to a network, it puts a lot of PCR power in your hands.
to get on the path to better protein purification. www.bio-rad.com Eppendorf, www.eppendorf.com/pcr
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Ad Index
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Ask the Expert
Change Control for

Standard Operating Procedures
Siegfried Schmitt is
The level of formality in change control may be principal consultant
holding back your SOP progress, according to at PAREXEL.
Siegfried Schmitt, principal consultant at PAREXEL.
Q
: We have one established change control Your example of preparing a line-by-line
process, and this process is applied to all description of the rationales for each individ-
planned changes, including changing ual change in the text of the SOP gives a good
standard operating procedures (SOPs). On aver- idea of the level of formality you apply at
age, it takes far too long to complete the pro- present. A change to a SOP will be requested
cess. For example, just preparing a line-by-line by the owner of the procedure covered by the
description of the rationales for each individual SOP. So this person needs this change and
change in the text of the SOP can take sev- is thus in a position to assess the technical
eral weeks. The result is that we often have to and operational feasibility of the change very
operate according to draft versions of SOPs, as well. More importantly, the requester is per-
changes must be implemented faster for opera- fectly well aware of the reasons (i.e., the ratio-
tional or safety reasons. How can we expedite nale for each change in the document). For
this process? these reasons, it is standard industry practice
A: You have correctly interpreted the regu-

lations, which require you to establish
change control, or as International Council
to provide a summary rationale, not a line-
by-line explanation in the revised document
(e.g., change due to revision in the applicable
for Harmonization (ICH) Q10 calls it, change regulations).
management (1), and to have documented pro- It is also easy for reviewers to see changes to
cedures, most likely in the form of SOPs (2). The the revised draft document as these are created
issue seems to lie in the way change control is with word processors in ‘track changes’ mode.
applied (i.e., the level of formality). This normally provides sufficient information
A formal change control process, which as you for the reviewers and approvers. One issue often
describe can take weeks or months to complete encountered at this step in the change process is
(e.g., for the replacement of a filling line), typically the number of reviewers and approvers that have
consists of these steps: to sign off on the document. In effective organi-
• Change request zations, this is kept to a minimum (i.e., two or
• Feasibility assessment three signatures).
• Technical review The solution to your problem is to review the
• Input by regulatory affairs level of formality applied, especially in the docu-
• Review by quality assurance (QA) mentation of the change and the reasons for the
• Approval of change change. There is no reason why a change to a
• Implementation of change SOP cannot be completed in a compliant, con-
• Verification of change effectiveness trolled, and formal manner in as short a time as
Damian Palus/shutterstock.com
• Close-out of the change request. one working day.

Notwithstanding the formality of the process,
a change control process should be effective (1), REFERENCES
meaning it is user-friendly, simple, and with 1. ICH, Q10 Pharmaceutical Quality System (ICH, June 2008),
www.ich.org.
minimal cycle time for decisions. This is aligned 2. European Commission, EudraLex Volume 4, Part I,
with the concept in ICH Q10 that the level of Chapter 4 Documentation, https://ec.europa.eu/health/
effort and formality should be commensurate documents/eudralex/vol-4_en ◆
with the level of risk.

Sent 4:35 PM
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info@wuxibiologics.com
www.wuxibiologics.com

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November 2017 The Science & Business of Biopharmaceuticals

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