VOLUME 14, ISSUE 9

WWW.PHARMAMANUFACTURING.COM

Bio Pharma in 2015 Overview P.10

Continuous SHM P.14
Downstream Efficiencies P.20
Antibody Facility Design P.24

Leveraging Audits P.26

Biomagnetic Separation P.30
Single-Use Integrity P.33
Endotoxin Testing P.36

BIOPHARMACEUTICAL

NOVEMBER 2015

TECHNICAL RESOURCE GUIDE

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inside
7. 
Getting to Know Biosimilars

Although generic style competition is unlikely,

biosimilars cost-savings potential remains
By Steven E. Kuehn, Editor-in-Chief

10. 
Soaring to New Heights: Bio Pharma 2015

Bio Pharmas ascendancy continues as the

industry matures
By Steven E. Kuehn, Editor-in-Chief

14. 
Continuous SHM Assures Pfizers
Automation System Performance

Automation system health needs to be continuously

transparent; fortunately Emerson has an app for that
By Richard Dedzins, Pfizer Biotech,
Matt James, Emerson Process Management

26. 
Leveraging Supplier Audits in Pharma/
Biotech Industries

Finding ways to reduce complexities eliminates

redundancies and streamlines operations while
staying compliant
By Daniel Fishman, Complya Consulting

30. 
Biomagnetic Separation:
Thinking Bigger, Part I

Contrary to popular belief, biomagnetic separation is

ready for large-scale processing
By Lluis M. Martinez, Ph.D., CSO at SEPMAG

33. 
Single-Use Integrity Testing Goes Mobile

Manufacturers adopting point-of-use testing with

flexibility and mobility
By Amber Sherrick, ASI

20. 
New Technologies for
Downstream Efficiencies

Industry sees promise in continuous purification

By Eric S. Langer, BioPlan Associates Inc.

23. 
Process and Facility Design for a
Monoclonal Antibody Facility

Single-use technology delivers strategic flexibility

to EMD Millipore

36. 
Inside 2015 Endotoxin TestinG

Why LER is here to stay, the need to safeguard test

supply, revisiting the definition of alternative assays and
moving towards automation
By Lakiya Wimbish, Lonza

41. 
classifieds

By Christian Cattaruzza & Sebastien Ribault, Millipore SAS, France

Pharmaceutical Manufacturing (USPS number 023-188) is published monthly by Putman Media Inc. (also publishers of Food Processing, Chemical Processing, Control, Control Design, and Plant Services), 1501 E. Woodfield Road, Suite 400N, Schaumburg, IL 60173 (Phone: 630-467-1300 Fax: 630-467-1179). Periodicals Postage Paid at Schaumburg, IL and additional mailing Offices. POSTMASTER: send change of address to Pharmaceutical Manufacturing, Post Office Box 3431, Northbrook, IL 600653431. SUBSCRIPTIONS: To receive a complimentary subscription go to www.pharmamanufacturing.com. Subscription rate for non-qualified U.S. subscribers is $68/yr. Single copy rate is $15.00. Other international is $200/yr (airmail only). Canada Post
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Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

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EDITORIAL TEAM

Getting to Know Biosimilars

Although generic style competition is unlikely, biosimilars cost-savings
potential remains
by SteveN E. kuehn, Editor in Chief

Steven E. Kuehn EDITOR IN CHIEF

[email protected]
katie Weiler

managing EDITOR

[email protected]
KAREN langhauser

Digital Content
Manager

[email protected]

KEITH LARSONV.p., CONTENT

[email protected]

EDITORIAL ADVISORY BOARD

Ali Afnan, Step Change Pharma
Jim Agalloco, Agalloco & Associates
Carl Anderson, Duquesne University
James Blackwell, Bioprocess Technology Consultants
John Blanchard, ARC Advisory Group
Tom Cambron, P&G Pharma
James Cheney, Celgene
Bikash Chatterjee, Pharmatech Associates
Emil Ciurczak, Doramaxx Consulting
Robert Dream, HDR Company
ERIC Langer, BioPlan Associates
Robbe C. Lyon, FDA
Ivan Lugo, INDUNIV, Puerto Rico
Girish Malhotra, Epcot International
Fernando Portes, Stevens Institute of Technology
Gary Ritchie, Consultant

DESIGN & PRODUCTION TEAM

STEPHEN C. HERNERV.P., Creative &
production

[email protected]
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SENIOR art director

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Rita fitzgeraldPRODUCTION MANAGER
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ADMINISTRATIVE TEAM
JOHN M. CAPPELLETTIPRESIDENT/CEO
JACK JONES

CIRCULATION DIRECTOR

In Memory of Julie Cappelletti-Lange,

Vice President 1984-2012
USPS number (023-188)

In March 2015 the U.S. FDA approved Zarxio (filgrastim-sndz), the United
States first biosimilar product to earn the distinction. According to the FDA,
Sandoz Inc.s Zarxio is biosimilar to Amgen Inc.s Neupogen (filgrastim), originally
licensed in 1991. At the time FDA Commissioner Margaret A. Hamburg, M.D.,
explained Biosimilars will provide access to important therapies for patients who
need them. Patients and the health care community can be confident that biosimilar products approved by the FDA meet the agencys rigorous safety, efficacy and
quality standards.
Zarxios approval, said the FDA, is based on review of evidence that included
structural and functional characterization, animal study data, pharmacokinetic
and pharmacodynamics data plus clinical immunogenicity data and other clinical
safety and effectiveness data. Under the BPCI Act, a biological product that has been
approved as an interchangeable may be substituted for the reference product without
the intervention of the health care provider who prescribed the reference product.
Rand Corp.s study, The Cost Savings Potential of Biosimilar Drugs in the
United States, notes the introduction of biosimilars is expected to reduce prices,
albeit to a lesser degree than small-molecule generics. Rands analysts explain this
perspective combines prior research and recent data to estimated U.S. market cost
savings. We predict that biosimilars will lead to a $44.2 billion reduction in direct
spending on biologic drugs from 2014 to 2024, or about 4 percent of total biologic
spending over the same period, with a range of $13 billion to $66 billion. At the
time of the studys release Rand added this caveat: Actual savings will hinge on the
specifics of the final FDA regulations and on the level of competition.
Forbes magazine contributor David Kroll succinctly reported a bit of truth last
March: its fair to say that manufacturing a biologic agent that acts similarly to
the original branded drug is an order of magnitude more difficult and has more
places where it can go wrong. No kidding. It takes a highly competent, experienced
player to succeed, and thats why Seeking Alphas analysts singled Amgen out as one
biopharmaceutical company well-poised to be an early biosimilars champion.
Amgen has three Phase III candidates right now, including ABP 215, its answer
to bevacizumab (Avastin), developed and currently marketed by the Genentech arm
of Roche; ABP 980, Amgens biosimilar answer to Herceptin, another Genentech/
Roche blockbuster; and ABP 501 currently under trial for moderate to severe
rheumatoid arthritis, targeting the replacement of AbbVies Humira. Seeking
Alpha says Amgens IPR petition against Humira patents could set a precedent for
biosimilars in patent law going forward.
Seeking Alpha says when Amgen reported its second-quarter 2015 results in
its earnings call, the company reiterated its focus on biosimilars. According
to a 2014 analysis, it costs Amgen somewhere in the region of $200 million
to develop a biosimilar, compared to the average cost-to-market of a new
pharmaceutical treatment of $2.6 billion. The point being that companies with
experience innovating and processing biologics have a real leg up when it comes to
manufacturing economics, but also the ability to price competitively, and to some
minds that might mean more fairly as well.

November 2015

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soaring to new heights

Bio Pharma 2015

Bio Pharmas ascendancy continues as the industry matureS

Whats the future of Bio Pharma? While no ones

crystal ball is clear enough to exactly predict where the
industry is headed, it remains perfectly clear Bio Pharma
is soaring, climbing to a new cruising altitude, flying
higher than ever as it becomes the carrier of choice for the
future of the pharmaceutical industry.
John J. Castellani, president and CEO of Pharmaceutical
Research and Manufacturers of America (PhRMA)
offered this in his letter introducing the associations 2015
Biopharmaceutical Research Industry Profile: Massive
change continues across the United States and global
health care systems driven by new health care policies,
demographic shifts, changes in lifestyle, but most of all
evolving, accelerating science. His final remark, evolving,
accelerating science succinctly describes the force from
which Bio Pharma has and will continue to derive its lift.
Research and development spending by its members,
according to PhRMA, grew from $2 billion in 1980 to an
estimated $51.6 billion in 2013. The percentage of sales that
went to R&D in 2013 reached 23.4 percent of domestic sales.
Apparently a lot of that R&D money was spent by
the Bio Pharma sector. The U.S. biopharmaceutical
industry is one of the most research-intensive industries
in the country, says PhRMAs report, investing more
than 13 times the amount of R&D per employee than
manufacturing industries overall. According to the
National Science Foundation, the U.S. biopharmaceutical
sector accounts for the single largest share of all U.S.
business R&D, representing about 1 in every 5 dollars
spent on domestic R&D by U.S. businesses.

10

November 2015

Of the billions of dollars spent on R&D each year by

the biopharmaceutical industry, the vast majority is spent
on clinical research, says PhRMAs report, accounting
for roughly 90 percent of all spending on clinical trials
of medicines and devices in the United States. In 2013,
PhRMA says the biopharmaceutical industry sponsored
an impressive 6,199 clinical trials.
Everyone knows developing biopharmaceutical drugs
is expensive. Average time to develop a new drug is more
than 10 years, and the percentage of drugs entering
clinical trials resulting in an approved medicine equal
less than 12 percent. Current estimates peg the cost to
successfully develop and bring to market a new drug at
more than $2.6 billion. PhRMA notes rapid changes in
molecular science have ushered in a new era of innovative
biopharmaceuticals and their rise has been spectacular,
especially over the last 10 years. From the first angiogenic
medicine for Cancer in 2004 to oral treatments for
Hepatitis, 17 new drugs for rare diseases and 7,000
medicines in development in 2014, Bio Pharma has truly
ascended to a new level.
Money Well Spent

Forbes Magazine contributor Bernard Munos notes in a

recent article that 2014 was a great year for pharmaceutical
innovation for both New Chemical Entities (NCEs) and
New Biological Entities (NBEs): The best, in fact, since the
industrys all-time record of 1996. Munos says in 2014 the
FDA approved a total of 44 drugs, 39 by CDER, and 5 by
CBER. Explaining that the total excludes imaging agents

Pharmaceutical Manufacturing www.pharmamanufacturing.com

and includes only the biologicals drugs

that are of rDNA origin, Munos reported that biologicals captured a total of 16 approvals (35 percent) a big
hike from 2013 when they garnered
22 percent. Seventeen of these drugs
(39 percent) featured novel modes of
action, as in 2013 (37 percent).
Munos says that compared to
innovation during the pre-2010
decade that was dominated by
mediocre, overpriced drugs, we
are now seeing cure rates (hepatitis)
or remission rates (cancer) that
are nothing short of stunning.
Regarding biopharmaceutical
innovation, Munos says the
industry is witnessing rapid
progress with a range of new
technologies such as CAR T-cell,
gene editing, synthetic biology,
biochips, bioprinting, and tissue
engineering that promise to
transform treatments for entire
therapeutic areas such as rare
diseases as well as produce tools
that will speed drug R&D and
lower its costs.

An Evolution, Underway, Deloittes

analysts find the past 10 years have
seen a significant shift in the nature of
the products being manufactured and
sold by the Bio Pharma industry. The
global biopharmaceutical portfolio of
today reflects increased therapeutic
competition, a greater prevalence of
large molecule drugs, expansion in the
number of personalized or targeted
products, and a rise of treatments for
many orphan diseases. These trends,
says the report, have driven a rise in
biopharmaceuticals with extremely
limited production runs, highly
specific manufacturing requirements,
and genotype-specific products.
This fundamental shift in the overall
product mix, says Deloitte, and a
focus on improving the efficiency
and effectiveness of production
is spurring an evolution in the
technologies and processes needed to
support advanced biopharmaceutical
manufacturing.
According to Deloitte, innovation
in manufacturing technology will
drive better economics, flexibility
and quality while benefiting patients

both directly and indirectly.

Where will Bio Pharmas players
be investing their capital dollar?
Deloitte identifies the following as
targets for improving the operational
excellence of biopharmaceutical
manufacturing assets:
Continuous manufacturing to improve scalability and facilitate time
to market, while lowering capital
and operating costs and enhancing
quality.
New process analytical tools to improve process robustness, accelerate
scale-up to commercial production and drive more efficient use of
resources.
Single-use systems to increase flexibility and reduce production lead
times, while lowering capital investment and energy requirements.
A lternative downstream processing techniques to improve
yields while lowering costs, green
chemistry to reduce waste, and
new vaccine and therapy production methods to increase capacity,
scalability and flexibility.

To Come: Hyper Innovation

Future facilities will allow for greater

productivity in a smaller footprint

Courtesy of Amgen

Munos notes that far from running

out of innovation, we are actually on
the cusp of a hyper-innovation age
that will see treatment options expand
from small molecules, monoclonals
and peptides to a whole range of new
and more effective therapies. But
this innovation wont be free from
challenges or a fair measure of risk,
and companies that will emerge as
leaders will need to be more aggressive, less conservative and push past
their comfort zones to succeed. These
innovation champions, says Munos,
include Novartis, J&J, GlaxoSmithKline, as well as recent converts such
as AstraZeneca that are working hard
at restoring a vibrant culture of innovation to their R&D operations.
In its report Advanced
Biopharmaceutical Manufacturing:

figure 1
Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

11

BIOPHARMACEUTICAL
technical resource guide

Amgens Take

Amgens vice president for Process &

Product Development Jim Thomas,
offered Amgens take on how to
achieve operational excellence in the
presentation Biopharmaceutical
Manufacturing Technology: Vision
for the Future. Thomas explains that
only the highest quality manufacturing environments will answer the demands of a rapidly changing industry
earmarked by a more competitive
business environment, a more challenging reimbursement environment,
and a more conservative regulatory
environment.
Thomas and his team at Amgen
describe their strategy in a holistic
way using the mantra Design
the molecule. Design the process.
Design the Plant, and that molecule
heterogeneity can be influenced
by the manufacturing process.
Compared to current methodologies,
there are both upstream and
downstream opportunities to reduce
variation and improve yields.
Trends in analytical tools,
notes Thomas, will support
operational excellence and quality

goals in biopharmaceutical
process by measuring host cell
proteins, measuring molecule
fragmentation, and measuring
protein microheterogeneity. Thomas
and Amgen point out that the tools
for analysis (a key element to their
corporate manufacturing strategy)
have come a long way since the 90s
and that by 2020 mass spectroscopybased analysis will provide host
protein fingertips, top-down
analysis and routine analysis of
CQAs to support biopharmaceutical
development and manufacturing.
How will biotherapeutics be
manufactured in the future, Amgen
wonders? To Thomas and his
colleagues the most likely scenario
wont involve transgenic animals,
transgenic plants or cell-free systems,
but center on cell-based systems. That
makes correctly mapping the design
space of critical unit operations
all the more a priority and will be
important for building quality into
the manufacturing process. What is
called for, says Thomas, is two-fold:
High throughput processes and high
throughput purification.

Courtesy of Amgen

streamlined processes result in increased felxibility

figure 2

12

November 2015

Holistic approach
to optimization

To achieve higher yielding processes,

greater plant flexibility, and better
utilization of capital, as well as a significant reduction in operating costs,
Thomas and Amgen are pursuing
a holistic approach to optimization
that encompasses process design,
plant design and process control.
In keeping with its history of
manufacturing innovation and
excellence, Amgen launched its
Transforming Biotechnology
Manufacturing initiative, which
the company touts as leading the
way in the development and use of
manufacturing technologies that
will set the standard for the future.
Amgen says future facilities will
allow for greater productivity within
a smaller footprint. According to
Amgens infographic, cost and
footprint make geographic expansion
difficult and that its new facility
concept allows for expansion
almost anywhere in the world to
support local market needs. Indeed,
especially when Amgen is projecting
60-70 percent square foot reductions
at 1/5 the cost of existing plant
designs, which Amgen puts at more
than $1 billion. (See Figure 1: Future
Facilities Will Allow for Greater
Productivity in a Smaller Footprint.)
Flexibility within this advanced
biomanufacturing environment is
another goal; Amgen says this will
come from streamlining processes
moving from complex, varied
processes at different stages of drug
development to standardized processes
across all stages of development
something many will recognize as a
direct path to operational excellence
and cost efficiency. (See Figure 2
left.)
Putting its capital where its mouth
is in 2013, Amgen announced plans
to build a new manufacturing facility
in the Tuas Biomedical Park area

Pharmaceutical Manufacturing www.pharmamanufacturing.com

of Singapore. At the time, Amgen anticipated investing

approximately $200 million to build its innovative new
facility, based on its professed strategy and, according to
the press release, will initially focus on expanding Amgens
manufacturing capability for monoclonal antibodies.
PAT and Control

Deloittes analysts agree with Amgen explaining that

new process analytical tools can help improve process
robustness, accelerate scale-up to commercial production and drive more efficient use of resources. The FDA
defines process analytical technology (PAT) as a system
for designing, analyzing and controlling manufacturing
through timely measurements (i.e., during processing)
of critical quality and performance attributes of raw and
in-process materials and processes.
Deloittes analysts explain that when it comes to
biopharmaceutical process monitoring, PAT equipment is
helpful in understanding biological, chemical and physical
attributes, as well as univariate factors. In manufacturing
with PAT, says Deloitte, continuous monitoring
determines if the process is operating as expected and
allows correction of errors at the time of their occurrence.
This is fortunate, because most understand the
overarching goal of PAT is to ensure final product quality.
Process analytical technology, say Deloitte analysts, is based
on the FDAs perspective that quality cannot be tested into
products; it should be built-in or should be by design.
Similarly, PAT is well aligned with the R&D process,
says Deloitte, as companies can begin using it in clinical
manufacturing and then continue to use it during scaleup in an effort to ensure consistent quality and reduce
time to market. Deloittes report affirmed PATs role in
operational efficiency and excellence in that it enables
both real-time release testing and parametric batch
release to further quality assurance goals.
From a cost-control perspective, Deloitte finds PAT
can promote fewer recalls and less scrap inventory,
more efficient equipment deployment and capacity
utilization, as well as an organizations ability to manage
raw material variability, for instance, all of which can
potentially reduce the overall price tag associated with
manufacturing biologics of all types. Finally, notes
Deloitte, the advancement of continuous manufacturing
is largely connected to PAT, as continuous processes by
definition do not have stoppages or support traditional
product quality testing, PAT addresses the need to
monitor product continuously, raise any specification
exceptions immediately, or adjust the process through
advanced process controls based on predictive
manufacturing process models.

A Continuous Future?

Some companies have developed continuous technology

for certain parts of their manufacturing process, say Deloittes analysts, but few, if any, have announced the use
of a fully continuous bioprocessing system in commercial
production. Bayer and Genzyme, cites Deloitte, have
been using continuous perfusion technology for large
molecules in the initial phase of upstream processing for
the past two decades and have manufactured at least 12
products via these methods.
The industry is well aware of continuous processings
potential for the manufacture of small molecule drugs,
but for large molecule drugs not so much. According
to Deloitte it can improve quality by constantly
maintaining media nutrients and avoiding lags that
reduce cell viability.

flexibility comes from Streamlining processes

moving from complex, varied processes at different stages of drug development to standardized
processes across all stages of development.

The FDA, says Deloittes study, views continuous

manufacturing as consistent with the FDAs quality
by design efforts, as it has resulted in a more modern
manufacturing approach, enables quality to be directly
built into process design, and has the potential to
improve assurance of quality and consistency of drugs.
Regardless, continuous manufacturing has its challenges
and biopharmaceutical manufacturers arent likely to
adopt the operational doctrine wholesale anytime soon.
Amgen, as outlined, is committed to optimizing batch
operations for its processing future and this kind of longterm investment, notes Deloitte, is just one headwind
continuous process faces within the Bio Pharma segment.
Deloitte points out that for the purposes of
biopharmaceutical process quality control, manufacturers
are challenged, among other things, on how to define a
batch in cases of product recall, for example. As a result,
continuous manufacturing requires new methods of
measuring quality and gathering metrics. Continuous
manufacturing is not necessarily the most economical
method for low-volume, high-value products and would
not offer any production gains as opposed to the efficient,
well-planned and engineered facilities Amgen and other
Bio Pharma innovators are instituting to attain their own
vision of biopharmaceutical manufacturings future.

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

13

BIOPHARMACEUTICAL
technical resource guide

BY RICHARD DEDZINS, PFIZER BIOTECH, & MATT JAMES, EMERSON PROCESS MANAGEMENT

Continuous SHM Assures

Pfizers Automation System

Performance
Automation system health needs to be continuously transparent;
fortunately Emerson has an app for that
Over the past 20 years, it has become an essential business requirement for process manufacturing plants to use
digital automation systems to compete in a global economy. During this time period, the reliability of electronic
equipment has also significantly improved. As a result,
management has often redirected limited plant resources
to perform higher value-added continuous improvement
projects, with less time being allocated to manage the automation system. Todays lean manufacturing environment
provides limited technical expertise and reduced staffing
levels. In turn, some plant sites awareness and processes
are not fully optimized for reacting to disruptive events
or unexpected failure(s) in their automation system. Even
when a plant is in full regulatory compliance, any loss in
monitoring and control functionality while diagnosing
a problem increases risk to the plants overall site health,
safety, product and the environment (HSE).
To address these challenges, many plant sites are
investing in an affordable system health monitoring
(SHM) solution that continuously monitors the health and
fitness of the automation system, detects trends and uses
diagnostic best practices to proactively notify plant staff
to take corrective action and avoid unexpected failure(s).
As a result, scarce plant resources can be directed to work
on higher priority projects without having to worry about
handling an unexpected system failure.
Why is Monitoring a Challenge?

Retaining experienced automation professionals to work

at plant sites is often challenging for many reasons. Consistently finding the appropriate level of expertise in all
plant locations around the world can be equally difficult.
The task of managing an automation system is often delegated to a system administrator, who is responsible for
the operation and maintenance of the system.

14

November 2015

With continuous improvements in automation

technology, its often technically difficult and
administratively challenging for a systems administrator to
keep the hardware and software revision levels up to date
and within allowable budget and production schedules.
Obtaining around-the-clock, continuous coverage to
monitor the automation system is not only tough, its often
cost prohibitive. Thus, with limited expertise and available
time, the amount of resources available for monitoring the
automation system are scarce and must be used wisely.
All automation systems offer maintenance and
diagnostic displays to indicate operational status of the
system and generate alarms in case of failures. However,
the type of information provided by the automation
system is typically after the fact, that is, after the failure
event. Visibility to information leading up to the event(s)
that caused the system failure is often not readily
available. The response time to react to the system failure
may be longer than desired since engineering staff must
conduct an investigation to determine root cause and
implement the necessary corrective action.

DEVELOPING SHM REQUIREMENTS

While there are many commercially available IT-related

network health monitoring systems on the market, the SHM
solution Pfizer adopted was tailored to specifically monitor
a DeltaV distributed control system infrastructure. Requirements for the SHM solution included automatically checking health information of all automation system components
including controllers, servers, workstations and safety
controllers. Firewalls, cyber security protection devices,
uninterruptible power systems and other non-automation
system servers and workstations connected to the automation network were also included. The SHM solution had to
provide trending and automated diagnostics to help leverage
best practices and shift maintenance practices from a reactive to proactive stance. Pfizer expected the SHM solution to
deliver a centralized, consolidated monitoring service for the
entire plant. The SHM service also needed to integrate and
be complementary to existing remote monitoring services.
IMPLEMENTATION TIME

Within a year of addressing the challenge and exploring

options, the plant staff partnered with the digital automation systems supplier and its local service provider to
implement the SHM solution at the site. Figure 1 reveals
an architecture diagram of the SHM system. The SHM
monitoring device is coupled to the control network and
to the plant-wide information network behind a corpo-

rate firewall. An SHM monitoring device automatically

checks health information of any network device connected to the control network.
Figure 2 illustrates the SHM monitoring device based
centralized health monitoring of network devices. The
SHM health monitoring solution centralizes the data
collection function by monitoring network devices or
nodes including DCS controllers, application servers
and workstations, safety instrumented system (SIS)
controllers, switches, firewalls, UPSs, and non-DCS PCs,
servers and workstations (e.g., data historians, batch
servers, operator stations, and similar devices).
Referring to Figures 1 and 2, the SHM monitoring
device is configured to monitor detailed parameters
indicative of the health, integrity and performance
of the automation system. Server health checks may
include monitoring of availability status, hard disk space
utilization and performance, CPU and memory usage.
Network switch health monitoring may include availability
status, redundant power supply status, temperature,
communications status, network communication error
rates, and number of packets/second sent and received
(See Figure 3). Controller health checks may include
monitoring of availability status, CPU usage, availability of
free memory, and controller redundancy status. Additional
details of the device level parameters that offer a quick
overview of the system health are shown in Figures 4 and 5.

Mail
Server
Remote Monitoing Center
Plant LAN

Increasing System Reliability, Reliably

Plant staff at Pfizers Biopharma facility located in

Sanford, North Carolina, faced a challenge of increasing
automation system reliability, availability and production
uptime, while reducing infrastructure support costs. To
address these issues, the plant staff explored industry best
practices for shifting monitoring activities from afterthe-fact or reactive to implementing proactive processes
that improve automation system availability and avoid
unscheduled downtime. Secondly, the plant staff explored
options for an affordable 24x7x365 system health monitoring solution that would centralize the data collection
while providing maximum value for the investment.

Pharmaceutical Manufacturing www.pharmamanufacturing.com

Application
Station

SHM Monitoring Device

DCS network

SHM SYSTEM ARCHITECTURE

FIGURE 1

PHARMACEUTICAL MANUFACTURING WWW.PHARMAMANUFACTURING.COM

NOVEMBER 2015

15

A PROACTIVE FUTURE

Parameters being monitored by SHM are typically useful

in performing proactive analysis of future events. For
example, repeated ping failures may indicate an insecure
connection and may require re-termination of a cable to
avoid a network failure. Since the SHM device is continuously monitoring health of the automated system on a
continuous non-stop basis, it eliminates the need for site
maintenance staff to perform periodic, manual health
checks via internal system diagnostic tools. Any deviation
conditions are automatically detected and reported.
An increased level of system security is also a feature
of Pfizers SHM. Continuous monitoring of control
system servers, smart firewalls and smart switches
supports effective cybersecurity protection measures
by assuring these devices are online and operational.
SHM is integrated with Emersons Guardian Support
service to improve decision making. The support
service requires up-to-date system information in
order to provide the site staff with current systemspecific actionable information. The SHM enables
frequent and automatic collection of automation
system related profile data and securely emails it to
Guardian. Any changes made to the system content are
automatically checked against previously published
critical KBAs for potential conflicts. The integration
between SHM and support service ensures the latest

safety and security updates for the automation system,

and applicable operating systems are always readily
available to the site staff for download.
Figure 3 illustrates a SHM solution workflow from an
initial health alert detection, to analysis and diagnosis
of root cause, to resolution of the problem. The SHM
solution sends notifications and alerts via email to
the automation system suppliers Remote Monitoring
Center (RMC) that operates continuously. The
notifi
Mailcations are automatically sent by the SHM device
Server any observed health parameter exceeds expected
when
or normal operating values. The automation supplier
Remote Monitoing Center
provides pre-defi ned templates with recommended
limits rooted in best practices.
Plant LAN These limits can also be
configured as needed for site-specific conditions. The
SHM device sends a periodic heartbeat message to the
RMC to indicate that it is operating normally. The RMC
staff includes dedicated resources and subject matter
SHM Monitoring Device
experts thatApplication
use soft ware tools to monitor and analyze
Stationfrom the plant.
real-time alerts
Diagnostic data related to the initial alert message is
DCS network
analyzed by the experts at the RMC
to determine the root
cause(s) of the problem and identify a potential solution.
After that, RMC staff collaborates with local service
experts and site engineering personnel to recommend an
action plan and ensure any required corrective actions
are taken. Thus, SHM proactively notifies plant staff to

CENTRALIZED, CONTINUOUS SYSTEM HEALTH MONITORING

FIGURE 2

Remote Monitoing Center

x365

SHM Monitoring Device

Computers

Automation System Infastructure

Switches
16

NOVEMBER 2015

Firewalls
PHARMACEUTICAL MANUFACTURING WWW.PHARMAMANUFACTURING.COM

make corrective changes well before

the initial alert notification escalates
into a system failure. The RMC staff
can monitor multiple plant sites from
a central location on a continuous
and concurrent basis.
Figures 4 and 5 are illustrative
display screens available at the
monitored site for real-time
monitoring of current health,
integrity and performance of the
automation system. SHM displays
can provide information about the
automation system at an overview
level, an individual network device
level, or at an individual parameter
level within each device.
With a simple observation of the
colors displayed on a screen, any
authorized user can intuitively and
instantly ascertain the operational
status of the automation system. A
green indicates normal operation, a
yellow implies caution or warning,
a blue indicates a communication
link problem that may require
reconfiguration between a sender
and receiver device, and a red
indicates a critical alert condition.
All displays contain hyperlinks that
may be used to call up other displays
for further detail.
Figure 6 illustrates trend data
collected on any analog variable in
the system. Historical data related
to performance of each network
device and analog parameters
within each device connected to the
control network may be collected
and trended without utilizing
data historian tags and incurring
additional data historian license fees.
The site engineering staff and/or the
local service provider often use the
trend data to perform root cause
analysis that can link an alert event
with a root cause, such as a controller
running on low memory.

System Health Monitoring Service Workflow

figure 3

4. Local Service Provider

and/or Site Personnel
Resolve Condition

3. Additional Analysis
and Diagnosis

Local
Service
Provider
Customer

Challenges Encountered
at the Sanford Site during
Implementation

Similar to configuring an automation system, a first step in configuring the SHM system is to identify all
network devices connected to the
control network. The SHM solution
provides a utility to read configuration files of the automation system
and convert them to text. The text
file is then modified by the system
administrator and imported into the
SHM device. The SHM device can
monitor any device or node on the
control network that has an IP address and has a communication protocol supported by the SHM device.
Initial challenges at the Sanford
site included limited SHM device
installation and configuration
documentation, along with limited
local expertise on technical issues
related to the SHM solution. This
partially stemmed from early
Pfizer adoption of the initial
SHM release. The most recent
SHM release now addresses these
challenges, and installation manuals
and overall guidance documents
have significantly streamlined the
deployment process. The SHM

Site

1. Health Alert Detected

and Communicated

Remote
Monitoring
Center

2. Alert Monitored,
Analyzed,
and Tracked

monitoring appliance is configured

to send SMTP messages to the mail
server (through the control system
layer firewall) at the plant site. The
plant site mail server then sends out
health alerts by exception via email
to the Remote Monitoring Center.
Once the initial SHM system was
up and running, the next challenge
was to better manage the large
quantity of email alerts originally
being generated. Similar to the
need for better management of the
operator alarming function in an
automation system, a tuning effort
is needed to focus on allowable
tolerance levels for each SHM
measurement and eliminate nuisance
alarms. Today, assessing the health
of the automation system is very
simple no email alerts received
from SHM means there is a high
degree of confidence that everything
is functioning normally. This allows
plant staff to focus on more value
added activities that have a direct
impact on the business.
SHM Solution Delivers Results

The system health monitoring

service adds value by continuously
monitoring performance data used

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

17

System Overview Display

figure 4

network device detail display

figure 5

trend display

figure 6

18

November 2015

as an indicator of the health of the

automation system. The SHM solution includes a proactive monitoring service that alerts plant and
local service provider staff to take
corrective action that preempts the
occurrence of a potential failure and
avoids unexpected downtime. For
example, since initial installation,
the SHM monitoring device has
already identified several significant
conditions at Pfizer including ping
failure(s) due to a loose connector,
low controller memory during specific production operations, network
time protocol offset drifts during
backup operations and an unsecured primary switch fiber connection. SHMs proactive monitoring
and alert notifications enabled site
personnel to address these conditions before they became major
issues, which resulted in optimal
system availability.
The SHM service supports
centralized operations as well
as the affordable monitoring
and managing of all automation
systems at the Sanford site without
a large upfront investment
in capital and staff resources
necessary to build and maintain
a site-specific operations
monitoring center. Thus, the
remote monitoring centers
centralized operations increased
control system availability while
reducing plant staff resources for
continuously monitoring the health
and performance of all automation
systems at the site. SHMs early
detection of events and proactive
alert notifications also resulted in
an overall process improvement
and personnel efficiency gain at
Sanford, which were two of the
primary objectives for Pfizer for
deploying SHM.

Pharmaceutical Manufacturing www.pharmamanufacturing.com

Superhuman team for superhero clients.

Powerful Separately,
Unstoppable Together.

Thats Nice is a research-driven marketing agency with

20 years dedicated to life sciences. Nobody understands
your industry better and can help you to refine your strategy
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For more information, call +1 212 366 4455 or visit www.thatsnice.com

BIOPHARMACEUTICAL
technical resource guide

By Eric S. Langer, president and managing partner, BioPlan Associates Inc.

Industry sees promise in continuous purification

The biopharmaceutical industry has seen

dramatic improvements in upstream manufacturing
yields over the past 30 years[1]. However, increased
efficiencies in upstream operations have contributed
to downstream bottlenecks, as these filtration and
purification operations have failed to keep pace with
upstream developments.
Indeed, according to preliminary results from
our industry study, 12th Annual Report and Survey
of Biopharmaceutical Manufacturing Capacity and
Production, a majority of biotherapeutic developers
continue to suffer capacity constraints as a result
of downstream processing. More than seven in 10
respondents (biomanufacturers, excluding CMOs)
report experiencing at least minor problems attributed to
downstream processing, including more than four in 10
experiencing more serious bottlenecks today.
This is certainly not a new problem: Downstream
processing has impacted capacity and overall production
for upwards of six in 10 biomanufacturers and contract
manufacturing organizations (CMOs) surveyed.
Theres obviously a lot to be gained from improving
downstream operations. Separate results from our
survey indicate that the impact of improved downstream
production operations on biomanufacturing performance
at respondents facilities over the past year has been on
par with the impact of respondents use of disposable/
single-use devices. In past years, improved downstream
production operations have also been in the top half of
factors creating improvements at respondents facilities.
How to Improve Downstream Operations

As part of our study, we measure the ways in which organizations tackle the problems associated with downstream processing, asking them which of 19 specific actions they have implemented in the past year to improve
downstream purification operations.

20

November 2015

Year

Serious Bottleneck Today

2015

12.5%

2014

7.7%

2013

6.8%

2012

8.5%

2011

11.8%

2010

9.0%

2009

8.1%

2008

4.6%

Fig. 1: Impact of Downstream Processing on Overall Capacity, 2008-2015 [2]

Source: 12th Annual Report and Survey of Biopharmaceutical Manufacturing, April
2015, www.bioplanassociates.com/11th Preliminary Data

So far this year, the top five reported activities are:

Optimizing running conditions (62 percent)
Used ion exchange membrane technologies (45 percent)
Used membrane-based filtration technologies (44 percent)
Cycled columns more frequently (41 percent)
Developed downstream processes with fewer steps (41
percent)
These are similar to biomanufacturers responses last year,
although results to date this year suggest that companies
have been more likely to optimize running conditions.
New Downstream Technologies
in Consideration

Aside from tracking the activities implemented by

the industry to improve downstream operations, we
also measure the new downstream purification (DSP)
technologies that respondents are actively considering to
address production issues or problems. Its worth noting
that this question only asks about active consideration,
indicative of potential future adoption, and as a result

Pharmaceutical Manufacturing www.pharmamanufacturing.com

While these top technologies in active consideration

are similar to those seen in last years study, survey
results to-date suggest a greater interest in continuous
purification systems, which were actively considered

by only 30 percent of biomanufacturers last year. Its

also notable that roughly one in five biomanufacturing
respondents in this years study said that they worked
with continuous chromatography purification (e.g.
simulated moving SMB) within the prior 12 months
to improve downstream purification operations, a
figure which would represent a step up from 15 percent
in last years study.
The apparent increase in active consideration of
continuous purification technologies this year is
interesting, as development of these technologies tends
to have lagged behind advances in upstream continuous
bioprocessing, with new bioprocessing methods
typically pairing continuous upstream processing with
conventional batch purification. The lag in adoption of
continuous purification potentially relates to its more
complex nature, as many more smaller aliquots requires
processing. Adoption of continuous purification may also
depend on newer chromatography technologies, which
are yet to be ready for mass-market adoption.
Were likely to see a focus on this area in coming
years, though, as new technologies appear that allow
for continuous and semi-continuous operation. The
excitement generated by these technologies owes to their
potential to enable a jump in the titers processed by
downstream operations. Should this come to pass, we
could expect to see smaller, more modular and disposable
downstream facilities be constructed, ultimately
leading to fully disposable facilities, which are currently
constrained by the lack of downstream options. Despite
their promise, though, we do not foresee continuous
purification technologies reaching widespread use at
commercial scale this decade.
E

Dow
Downstream
s ream Efficiencies
fficie cies

does not include those respondents already using these

technologies or those considering them but not actively
pursuing them as an interest.
In our results, respondents actively considering at least
one of the 22 new DSP technologies we identified were led
by Continuous purification systems (60 percent); Disposable
UF systems (48 percent); and Single-use filters (48 percent).
This years preliminary list of Most Innovative
Downstream Systems from the 12th Annual Report
include:
Continuous purification systems
Disposable UF systems
Single use filters
Use of high capacity resins
Single use disposable TFF membranes
Membrane technology
In-line buffer dilution systems
Buffer dilution systems/skids
Single use-prepacked columns
A lternatives to chromatography
On-line analytical and control devices
Use of filters instead of resin chromatography
Centrifugation
Moving beds
Precipitation
2-phase systems
Countercurrent
Development of MAb Fragments
n

New
NewTech
Technologies
ologies for
for

Survey Methodology
The 2015 Twelfth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields
a composite view and trend analysis from over 200 responsible individuals at biopharmaceutical manufacturers
and contract manufacturing organizations (CMOs) in 30 countries. The methodology also included over 150 direct
suppliers of materials, services and equipment to this industry. This years study covers such issues as: new product
needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, trends
and budgets in disposables, trends in downstream purification, quality management and control, hiring issues, and
employment. The quantitative trend analysis provides details and comparisons of production by biotherapeutic
developers and CMOs. It also evaluates trends over time, and assesses differences in the worlds major markets in
the U.S. and Europe.

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

21

Alternatives to Protein A

An interesting trend that seems to be continuing this year

relates to alternatives to Protein A: Although a significant
portion of biomanufacturers are investigating alternatives to
protein A, few have actively switched to alternatives. Specifically, early data from our study suggests that almost one in
five (17 percent) of biomanufacturers investigated Protein A
alternatives during the past year, but just 7 percent switched.
Still, if those figures were to hold true, they would
represent a shift from last years ratio: That year, 33
percent of biomanufacturers had investigated Protein A
alternatives, compared to just 59 percent switching. So
the percentage evaluating these new chromatography
technologies appears to be on the decline.
The high mAb purification efficacy of Protein A resins
is one of the attractive qualities of Protein A compared
to many proposed alternatives. Protein A resins now
estimated to represent a $400 million per year market
have become increasingly robust and reliable, becoming
a dominant downstream mAb purification platform
technology. This success and consistent popularity causes
difficulties for any improved and/or cheaper alternatives
to gain market adoption, although for the time being
there remain few cost-effective alternatives. Indeed, while
Protein A affinity chromatography has been targeted
for replacement from the start due to high acquisition
costs and limited recycling, few alternative options have
emerged to pose a real challenge to conventional resins.
Thats not to say that alternative approaches dont
resolve problems (e.g., the high costs, leaching and
recyclability). But for them to be successful and gain
more rapid adoption, it appears that Protein A resin
alternatives will need to display radical rather than
incremental improvements.
Putting It All Together

Early results from our 12th annual biopharmaceutical

manufacturing survey indicate that biomanufacturers are
taking active steps to improve downstream operations,
such as optimizing running conditions and evaluating an
assortment of technologies. There remain few who have
switched to alternatives to Protein A, and recent studies indicate that fewer industry suppliers are working on
such alternatives. In fact, the percentage of suppliers last
year who indicated that they are working on chromatography alternatives to protein A (12.7 percent) was almost
half the share from 2011 (23.4 percent).

22

November 2015

Technological innovations in downstream

purification have yet to lead to the same
productivity improvements experienced
in upstream operations as most
respondents report at least some
bottlenecks at their facilities.
Last year, technology innovators and suppliers were
more likely to report new product development on
continuous chromatography. This may be in response to
increasing demand, as continuous purification appears to
be a notable area of interest for biomanufacturers. Other
new DSP technologies of interest to biomanufacturers
include a range of disposable applications such as
disposable UF systems and single-use filtration devices.
For now, though, technological innovations in
downstream purification have yet to lead to the same
productivity improvements experienced in upstream
operations, as the majority of survey respondents report
at least some bottlenecks at their facilities owing to
downstream purification issues. It remains to be seen when
downstream innovation will make up that deficit.
References
[1] White Paper: Analysis of Biopharmaceutical Manufacturing:
Historical and Future Trends in Titers, Yields and Efficiency in
Commercial-Scale Bioprocessing, BioPlan Associates, Inc. July 2014,
Rader, RA, Langer, ES
[2] 11th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, April 2014, Rockville, MD www.
bioplanassociates.com/11th
About the Author
Eric S. Langer is president and managing partner at BioPlan Associates, Inc., a biotechnology and life sciences marketing research and
publishing firm established in Rockville, MD in 1989. He is editor
of numerous studies, including Biopharmaceutical Technology in
China, Advances in Large-scale Biopharmaceutical Manufacturing, and many other industry reports. elanger@bioplanassociates.
com 301-921-5979. www.bioplanassociates.com.

Pharmaceutical Manufacturing www.pharmamanufacturing.com

By Christian Cattaruzza & Sebastien Ribault, Millipore S.A.S., France

BIOPHARMACEUTICAL
technical resource guide

Process and Facility Design for a

Monoclonal Antibody Facility

Single-use technology delivers strategic flexibility to EMD Millipore

The biological drug products market is expanding, especially in emerging economies. With the improvement of living standards in those countries, the number
of patients accessing drug treatments is growing rapidly.
In Brazil alone, an estimated 40 million people joined
the middle class between 2000 and 2010. In China rapid
economic growth and the emergence of a middle class
with growing disposable income in the last decade have
contributed to an increased demand for high-quality
healthcare services. In India the number of middle-class
households (earning between $4,413 and $22,065 a year)
is estimated to increase more than four-fold, from $32
million in 2010 to $148 million by 2030.
Countries that are growing in size and wealth are
looking to establish more domestic industries to
support a growing population that can afford to buy
more goods and services. In particular, governmentdriven incentive programs are multiplying to
encourage local investments in biologics production
facilities. For example, if a company in Brazil decides
to build a modern manufacturing plant to produce a
product for the local market, the government will buy
this product from the company. Companies that do
not have plants in Brazil will eventually be eliminated
from the market for a particular product. In India
the government has been proactive and supportive
in driving the growth of the biotechnology sector by
offering grants and tax incentives, and implementing
investment-friendly regulations.
Since the mid-1980s, South Korea is by far the best
example of government support for the biotechnology
industry. One of the fastest-aging countries
demographically in the Organization for Economic
Co-operation and Development (OECD), South Korea
needs to prepare for and deal with the rising incidence
of chronic diseases such as diabetes, Alzheimers and
Parkinsons. The government provides various incentives

such as tax reductions or cash grants to companies

targeting treatment of those specific diseases.
In other cases, governments apply a protectionism
strategy favoring a model where drugs must be
produced locally to be eligible for local healthcare
system reimbursement or to be available for patients. In
Russia, for example, local pharmaceutical companies
are able to meet only a small percentage of the countrys
requirements and 80 percent of drugs are imported.
To change this situation, Russia is implementing
extreme protectionist policies such as a law that allows
discriminatory procurement practices by giving the
government the right to enforce a ban on foreign goods in
public procurement tenders.
At the same time, some biologics blockbuster patents
going to public domain lead to development of multiple
biosimilar programs, benefiting the broader population
with lower treatment costs. With more than 200 biosimilar
drug development programs spanning from research
to Phase III in China, Brazil, India, Turkey and Russia
alone, biosimilars are becoming a public health challenge
and a large business opportunity in many countries.
This overall situation is leading to a new for country
in country strategic trend in biopharmaceutical industry
supply chains where biopharmaceutical companies are
considering localizing small scale production facilities to
serve specific countries or regions.
However, there is a high level of risk related to
investments in emerging countries. Political instability
can be of great concern in some countries, turning a
winning market environment into a real no-go in a matter
of months. Economical fragility and a governments
inability to fund existing incentive programs often limit
attractiveness of those markets. Also, the limitation or
absence, in some cases of healthcare systems, as well as
relative complexity of drug reimbursement processes may
limit populations access to drug treatments.

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

23

Figure 1. The design of Flexware assemblies assures

correct installation every time.

Companies interested in investing in biologics in

emerging countries such as Brazil, Russia, India, China
and in middle-eastern and Asian-Pacific countries must
solve an equation which consists of investing quickly
to be the first to enter, lowering the financial risks and
ensuring drug products cost of goods sold (COGS)are
competitive and affordable. The key to this equation is
the flexible factory concept.
The flexible factory concept is a single-use facility
designed with ease of use, minimized contamination
risk and flexibility in mind. A wise implementation of
single-use technologies allows drug manufacturers to
get the best possible outcome from those technologies:
easy and fast re-purposeability for a variety of processes,
increased capacity with rapid changeovers between
batches, minimization of SIP/CIP steps with associated
time and costs savings. The ability to run some of
the process steps closed and continuously also allows
fewer cleanroom classifications and reduced capital
expenditures while increasing facility flexibility and
adaptability to meet local market demand.

24

November 2015

Despite the introduction of single-use new

technologies, the majority of biotech processes and
facilities still contain a number of stainless-steel and
multi-use equipment. At EMD Millipore, a subsidiary of
Merck KGaA, Darmstadt, Germany, the company made
the decision to move away from this traditional setup and
implement full single-use processes at both the laboratory
and manufacturing scale. This change from multi-use to
single-use was developed in parallel with the revamping
of EMD Millipores Biodevelopment Center in Martillac,
France, as well as part of the companys global strategic
development of flexible facilities concepts.
ALL STEPS UP, AND DOWN STREAM

With the adoption of single-use equipment, all steps

from upstream to downstream and fill and finish can
be completed in a single-use manner. This is not only
true for small and medium scale; large scale disposable
systems are now available on the market and routine
manufacturing can be done using disposables as well.
EMD Millipores implementation of disposables is go-

Pharmaceutical Manufacturing www.pharmamanufacturing.com

ing from development scale to routine manufacturing

at the 2,000 liter scale.
EMD Millipore has seen a number of advantages to
implementing single-use equipment including reduced
risk of contamination, ease of use and enhanced
flexibility. The risk of contamination is reduced at all
steps as the disposable systems arrive sterile with no need
to clean or sanitize, and are set up for the run without
opening. As an example, bioreactor bags are connected to
media bags through sterile connectors so there is no open
phase and the harvest is completed the same way. Welders
can be used as well, depending on the scale.
Ease of use is threefold. First, operators require
less training than with stainless-steel equipment (less
piping, no spare parts, no cleaning or sanitization,
etc.). Second, the assemblies used on the hardware
part are typically preconfigured for simplified
installation (connectors with two clicks confirm good
connections, asymmetric pieces avoid bad orientation,
etc., Figure 1). Finally, operations are mostly automatic
and the recipes used are virtually foolproof.
In terms of enhanced flexibility, EMD Millipore has
found implementing single-use equipment to yield a
range of advantages. For one, bioreactors are no longer
fixed; they can be moved from one room to another
depending on needs. Downtime is reduced to a few hours
rather than several days, as is the case with stainless
steel. When running a single-use upstream suite, drug A
can move from one bioreactor to three in parallel for the
validation runs of drug B in less than a day. The ability to
reconfigure in a day or less provides superior flexibility
and allows quick changes in production plans.
Buffers are prepared in single-use mixers and then
pushed into the suite for use. As nothing is fixed, there
is no need for hard piping and maximum flexibility in
the options. A new buffer can be brought in or taken out
without impacting the suite and the rest of the process.
New generations of equipment, such as the Mobius
FlexReady System, make it possible to have one piece of
equipment for several operations. The tubing has been
replaced by a new type of consumable that prevents
operator errors (Figure 2). These systems enable
either chromatography or TFF with a single piece of
equipment. The additional cart will contain pumps for
chromatography or a tank for TFF. This new concept not
only reduces footprint, but also investment and operator
training. Flexibility is embedded in the equipment

The flexible factory concept is a single-use facility designed with

minimized contamination risk and flexibility in mind.

design. All of this equipment can be connected using

sterile connectors or welders, making running a closed
process now feasible.
IN THE BAG

Instead of using a vial, cells can be stored in a bag at

-80C or in Nitrogen. This bag is connected by welding
to the first seeding bioreactor and cells are transferred
by gravity. Cells are grown to the desired concentration
and transferred again by sterile connection to the next
bioreactor and so on until the production unit. The next
steps through clarification are similar and the resulting
clarified harvest is collected into a closed bag.
Purification can also be performed in a closed and
continuous manner using several columns consecutively
loaded, washed, eluted, cleaned and regenerated. Virus
inactivation happens in a closed bag between protein
capture and a series of membrane absorbers. The process
ends with virus filtration and aliquoting.
This closed process has several advantages, including
reduced risk of contamination and the ability to
run a multiproduct facility with ballroom suites for
upstream and downstream or several products in
the same area. These benefits are creating a clear
global trend toward single-use equipment and flexible
facilities concepts.

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

25

BIOPHARMACEUTICAL
technical resource guide

By Daniel Fishman, Senior Consultant, Complya Consulting

Leveraging Supplier Audits in

Pharma/Biotech Industries
Finding ways to reduce complexities eliminates redundancies and
streamlines operations while staying compliant

Those of us in the competitive and highly regulated pharmaceutical, biotechnology and medical device
industries understand the need to balance operational
efficiency with regulatory compliance. We must find
ways to reduce complexities, eliminate redundancies and
streamline operations while staying compliant with an
array of regulations, guidance documents and regulatory expectations (some explicit, others less so). Making
changes to our processes requires overcoming challenges
arising from these often competing interests.
When publishing guidance documents, the FDA
includes language implying that industry can use an
alternative approach if it satisfies the requirements
of the applicable statutes and regulations. Using this
language as a stick by which to measure well-intentioned
process optimization proposals, this article will explore
considerations for creating desired efficiencies while
maintaining compliant processes.
For illustrative purposes, lets look at a common
process optimization example of streamlining a supplier
audit program.
Optimizing the Supplier Audits Program

Onsite audits are an important and well established tool

for assessing suppliers. Still, there are ways to optimize
supplier audit programs.
At this point, you have already sliced and diced your
list of suppliers by establishing risk-based categorizations
of the types of services and/or goods they provide. While
retaining other supplier oversight mechanisms, you have
eliminated onsite audit requirements for suppliers with
no potential impact to your products. You have also
reduced onsite auditing frequencies for the suppliers with
a lower potential for product impact.
Nonetheless, the list of annual required audits remains
daunting. Many have dwelled for the millionth time on the

26

November 2015

fact that they are not the only one auditing each supplier.
The dozens of times each year that other entities audit a
supplier can make you wonder: Is there a way to leverage
those activities to reduce onsite auditing requirements?
A process optimization idea is born. Fewer onsite
audits mean:
Spending less time on scheduling and audit preparation
Reduced execution and reporting activities
Decreased travel time and costs
Fewer findings to track to resolution
Simplified metrics and management reporting
Purchase an Audit Report?

Various industry proposals for leveraging common audit

reports have been circulating for years. Typically a third
party audits a supplier, prepares a report and sells it to
companies that want to avoid conducting their own audit.
There may be a place for common audit reports,
particularly with regard to low-risk suppliers. Before taking
such an approach, though, consider the following factors:
The report may not adequately address the scope
needed, but one likely wont realize that until after it has
been purchased. You alone know the importance of the
services and/or goods that the supplier is providing; the
auditor might not have placed sufficient emphasis on
what is critical to you.
Even if it does satisfy the scope required, the report
may grow stale. The supplier may experience impactful
regulatory inspections and/or changes to procedures,
personnel, facilities, equipment, etc. Will a window
into the past suffice?
Perhaps a proprietary process is involved, and the third
party would not have had access to audit those processes. And if the third party did have access, it would not
be prudent to share those details with other companies.

Pharmaceutical Manufacturing www.pharmamanufacturing.com

Assessment: Purchasing common

audit reports can fulfill some of ones
needs. Lets call this option a Maybe.
Leverage Quality System
Certifications?

Leveraging your suppliers quality system certifications to certain

standards such as ISO 13485 (applicable for medical devices) may be
an option. To gain and maintain that
certification, quality system experts
must audit the suppliers routinely.
Whether your organization makes
medical devices, pharmaceuticals
or biologics, many may potentially
benefit from this approach.
However, be sure to consider the
following questions:
Who issued the certificate? There
are vast differences in the weight
that certificate-issuing organizations
carry. For the harmonized European
version (EN ISO 13485), the certificate should be issued by a group with
rigorous standards called an authorized notified body. Organizations
with similarly rigorous qualification requirements exist to audit and
issue quality system certificates to
ISO 13485 for other regions, such as
Canada (recognized registrars).
Is the certificate relevant? If, in
addition to medical devices, the
suppliers scope includes pharmaceutical and/or biotechnology (and
one is only interested in these two
areas) and if the quality systems are
independent of each other, then the
medical device ISO 13485 quality system certificate may not be
relevant enough.
If there are common quality
system elements, then the
certification may provide some level
of assurance that your needs are
being met. The FDA combination

products regulation 21CFR Part

4 is intended for the development
of a combination product quality
system. That regulation gives a
view into why a pharmaceutical or
biotechnology company might find
it acceptable to leverage at least part
of the elements present within a
medical device quality system for a
supplier audit program.
W hich certificate should be accepted? One complication is that
a supplier can have both a notified
body and a registrar, each of which
issues a certificate to ISO 13485.
Furthermore, the notified body and
registrar can be different organizations. Or the supplier can have
more than one notified body or
registrar, each of which may issue
their own certification for the scope
of activities that they are covering.
The question of which certificate
to accept is even harder to answer
if the supplier is not manufacturing
a medical device or component
for you (in which case, you can at
least pinpoint which organization
has oversight of the type of device
or component that you will be

procuring). Just picking one is not

the best strategy, so its important
to discuss this with the supplier to
understand which certificate will best
cover services and/or goods.
Is the certificate alone enough?
No. The quality system certificate
must encompass the scope of your
services and/or goods. The only way
to really know if a quality system
certificate is meaningful and can be
leveraged is to review the underlying audit reports associated with
the certificate.
W hich audit reports should one
review? Some notified bodies or
registrars may break up the areas
they are evaluating into small
pieces and do multiple audits
each year before gaining the full
picture of the quality systems
performance. In those instances,
multiple reports may need to be
reviewed before the scope relevant
to you has been covered.
W hat if the supplier wont release
their audit reports? This can happen. Citing client confidentiality
or proprietary technology reasons,
your supplier may not be willing

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

27

to share their most recent notified body or registrar

reports. And they may or may not be willing to share
redacted reports.
Assessment: Leveraging quality system certificates
and associated audit reports must be a thoroughly vetted
process to understand exactly what scope they cover
and thus how to best use them as part of a supplier audit
management process. This may be an acceptable strategy
to reduce the frequency of onsite audits. Conversely,
with all of the considerations mentioned here, one may
conclude it is easier and less time-consuming to perform
onsite audits yourself.
Lets call this option another Maybe, but note that it
will require careful implementation.
LEVERAGE REGULATOR AUDITS AND INSPECTIONS?

If suppliers are willing to share regulator audit/inspection

reports (e.g., FDA Establishment Inspection Reports),
that option might be worth exploring. Considerations
with this approach include:
What is the scope of the report? The same concerns

apply here as with the previously discussed reports. For

you to leverage it, the report must cover the scope of
your services and/or goods. Each time a regulator audits
or inspects a supplier, it is just a snapshot and unlikely
to be inclusive of the full scope of a suppliers activities.
Was the audit relevant? How can you leverage a regulators report if it was focused on a different governments
regulations? While eorts have been ongoing to harmonize as many of the regulations as possible, there are
still differences, and it will require an understanding of
what you are trying to leverage. If the regulations mapping methodology described within the aforementioned
21 CFR Part 4 is extended through a comparison of the
other global regulations performed, then one can make
a legitimate argument for leveraging those reports.
Assessment: This scenario is not very different from
leveraging quality system certificates. But it is advised
to restrict which regulator reports one is willing to
leverage; otherwise, it may require a good deal of work
unless someone is already mapping the various global
regulations. This option, then, is yet one more Maybe.

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REGULATOR PERCEPTION

What would regulators think about

industry leveraging third-party audit
reports? It is important to first put
into perspective that, like anyone in
this industry, regulators are under
a tremendous burden to fulfi ll their
audit obligations within mandated
timeframes. And they, too, have been
evaluating options to leverage the
work of third parties.
One pilot program for the
regulators is already underway.
The International Medical Devices
Regulators Forum (which includes,
but is not limited to regulators from
the United States, Canada, Brazil
and Australia) is leveraging thirdparty audits using the Medical
Device Single Audit Program
(MDSAP). An extensive framework
surrounding the MDSAP governs
the qualifications for authorizing
a third party to perform the audits
and defines the required audit report
content (among the establishment of
many other criteria).
Suppose this program reduces for
regulators the number of required
audits for medical devices while
maintaining the integrity of the
regulators respective missions. In
that case, you can bet that pharma
and biotech regulators will also want
to participate in such programs. If
the regulators have seen the benefit of
leveraging third-party audit reports
and have begun implementing those
processes, they would likely have no
issues with industry taking a similar
approach (as long as appropriate
controls are employed in doing so).

to help strike the balance of creating

efficiencies while also maintaining
regulatory compliance.

of industry experience and global regulatory compliance/quality systems consulting

that spans the broad range of the medical
device, pharmaceutical and biotechnology
industries. He received his BA in biochemistry from Brandeis University. Fishman can
be reached [email protected].

ABOUT THE AUTHOR

Daniel Fishman is a senior consultant at
Complya Consulting. He has over 23 years

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The example provided in this article

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BIOPHARMACEUTICAL
technical resource guide

By Lluis M. Martinez, Ph.D., CSO at SEPMAG

Biomagnetic Separation

Thinking Bigger, Part I

Contrary to popular belief, biomagnetic separation is ready
for large-scale processing

Separation is a key process used in life science.

Cells, proteins and genetic material of interest for medical
and pharmaceutical use are rarely obtained in a purified
form. The molecules that the industry usually is interested in are found in a matrix that contains numerous other
biological substances. Therefore, its critical to extract/
isolate these molecules from the supernatant before work
can start. Even high-value pharma processes such as protein purification, the downstream process (i.e. purification) can lead to losses of 50-80 percent of the product.

When working on a small scale, using magnetic beads

or particles as solid support for separation has become
increasingly popular, particularly when it involves
immunocapture. Coated with the right antibody,
magnetic carriers can capture the molecule of interest in
seconds and retain this by magnetic force while washing
out the supernatant. When the magnetic field is removed,
the beads can then be re-suspended in a clean buffer.
With such obvious benefits, it makes sense to use this
technology on a larger scale. It is commonly believed
that biomagnetic separation is not suitable for large
volumes, which may explain why people are so doggedly
attached to centrifugation, filtration and packaged
columns even though the methodology is slow,
complex, requires extremely expensive equipment and
can be a cleaning nightmare.
CLIAs Success Transferable

One life science industry has already tackled these questions. Efficiency, rapidity and simplicity of biomagnetic
separation are among the reasons behind the success
of chemiluminescent immunoassays (CLIA). The rapid
growth of this market has prompted In-Vitro Diagnostics
(IVD) manufacturers to scale up magnetic-bead processes
to cope with demand. The lessons learned by this industry can be very helpful in other life science companies
and cell capture or protein purification may be of benefit
to processes in the IVD industry for coping with volumes
up to tens of liters.
At the beginning of the current century, the IVD
industry had similar challenges to those now facing
other life science companies. Attempts made to scale up
biomagnetic separation processes beyond a few milliliters
proved unsuccessful. The paradox was that the main
cause of failure lay in its success with small volumes. Easy

30

November 2015

Pharmaceutical Manufacturing www.pharmamanufacturing.com

Coated with the right antibody,

magnetic carriers can capture the
molecule of interest in seconds and
retain this by magnetic force while
washing out supernatants.

implementation of biomagnetic separation at milliliter

scale had allowed researchers to focus on selecting the right
magnetic beads and how to coat them with the antibody
or biomolecule. Given that almost any magnetic separator
(or even a simple magnet) would capture the beads in
few seconds, little emphasis is placed on the workings of
the process. Descriptions of the biomagnetic separation
conditions were limited to a description of the magnet and,
at most, the separation time. When the volume was scaled
up, the initial attempts used a larger magnet, usually
with no more specification than the material (NdFeB
magnet) or the required magnetic field on the surface.
However, with this approach, the scaled-up biomagnetic
separation process did not work as expected. Separation
time increased exponentially, magnetic beads losses were

significant and the beads became irreversibly aggregated.

The process is no longer fast, reliable or consistent
technology when the working volume is increased.
Around 2000, when the SEPMAG team and I were
approaching the problem, IVD manufacturers were
considering several options. One was to replicate the
small volume process. To increase production by a
factor of 10 it was necessary to build 10 production
lines. This option involved large-scale investment and
proportionally increased labor costs with virtually no
economy of scale. Worse still, a new problem arose: The
need to guarantee batch-to-batch consistency between
the different lines. As one of our customers said, It is far
simpler to validate one ten-liter batch than to guarantee
that 10, one-liter batches are the same.

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

31

The problem was so significant that some IVD

manufacturers considered using tangential fi ltration to
separate the coated beads from the incubation buffer.
Th is investment may have made economic sense despite
the complex process (flow, pressure and temperature,
etc., all of which need to be controlled ...) and running
costs were relatively high.
Our discussions with IVD production managers focused
on finding the ideal solutions from both technical and
economical standpoints. The result of these discussions
was clear. These operations-centered managers wanted
a large-volume permanent magnet-based system with
100 percent magnetic bead recovery, a separation time
of few minutes and perfect in-batch and batch-to-batch
consistency. Permanent magnet-based systems would
mean no maintenance and no running costs.
High recovery meant high magnetic force, even on the
beads, which are farther away from the retention area
and a high-enough magnetic retention force to prevent
aspiration of magnetic beads when the supernatant was
pumped out. In-batch consistency would mean that all
the magnetic beads in the vessel would be subjected to

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the same force, avoiding crushed beads and forming

clumps due to high forces while other are gently attracted.
Finally, batch-to-batch consistency would require a wellvalidated process and, if possible, a means of monitoring
the process for traceability of every single batch.
This list of requirements seems to pose a big
challenge, as many of them are, and at first sight, often
contradictory. Then, theres the temptation to look
for trade-offs. What is the acceptable loss rate? Could
the separation time be increased to one hour? Should
we find more aggressive re-suspension techniques to
disaggregate the clumps?
However, closer analysis of the requirements reveal
that no trade-offs were necessary. All we needed to do
was the homework that was neglected when working on
a small scale to understand how magnetic beads move
under the influence of magnetic fields. This would enable
us to correctly parameterize the biomagnetic separation
process, validate the right conditions and then define the
characteristics of the separation systems, regardless the
working volume.
Editors note: Because downstream biopharmaceutical
processing efficiency is so critical the topic merits further
examination. To learn how and why biomagnetic
separation is so effective, please look for Part II online and
in print in the very near future.

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BIOPHARMACEUTICAL
technical resource guide

By Amber Sherrick, ASI

Single-Use Integrity testing

Goes Mobile

Manufacturers adopting point-of-use testing

with flexibility and mobility

There is little debate single-use systems have found a

permanent place in bioproduction facilities. Once revolutionary, now commonplace, the acceptance and adoption
of single-use technologies continues to grow. In addition,
incorporating single-use technology in processes that are
further and further downstream means that single-use
bags are now closer to final product delivery, something
that is changing how the industry views quality testing
for single-use systems.

Downstream protein purification (where the protein is

isolated and purified) is one of the final steps in biopharmaceutical manufacturing. With such high value
relative to the rest of the process, and no way to recover
or decontaminate materials as there is
upstream, sterility and leak detection
of single-use bags becomes a QSMoriented operational imperative.

To a great extent, concerns

involving bag integrity issues
associated with poor manufacturing
quality control are a thing of the past.
Single-use technology manufacturers,
including ASI, have instituted well
defined and documented quality
procedures that assure performance
and reliability. As a result, bag quality
and integrity inspection routines as
well as operator handling have now
become more of a focus, particularly
for single-use systems used in
downstream production.

Focus on Downstream Quality

In upstream processes, most of the liquids

are media or buffer solutions, which are of
comparatively lower value and recoverable
by sterile filtration in the event of a problem.
However, for downstream process equipment,
and for containers used to store product further downstream, quality concerns magnify.

Figure 2: Operators initializing a validated fine leak test.

Care in Handling and

Other Issues

Even when single-use bags integrity

is verified and in perfect shape coming off the delivery truck, there are
multiple opportunities for flaws to be
introduced between the truck and installation on the process floor. Flaws
can be introduced by such things as
improper loading of the bag into the
equipment, connecting tubes and
hoses, or simple inadvertent mishandling that goes unnoticed. Handling
errors can cause microscopic tears or

worse, and the further downstream

this occurs in the process the more it
can impact final product quality.
Get As Close as You Can

Most operational staff understands

the best time to test single-use bags is
just prior to use, when the bags are in
place and ready to use. Called pointof-use testing, the procedure is usually part of a thorough QSM regime
to detecting flaws that in practice
can be introduced through handling
errors or installation mistakes. This
type of test can lower the risk of
lost time, loss of product, and even
improve operator safety.
Point-of-use testing systems can
mitigate the risk of flaws being
introduced and unnoticed during
operations such as shipping,
unloading and installation. Such
testing systems give manufacturers
the ability to test every bag and
produce reports that document the
testing procedure and results.
Flaws from a bag already installed
in the tank, mixer or bioreactor can
happen a few ways. A large, obvious
leak, usually called a gross leak
can occur from an unattached hose.
There are many tubing elements that
require connection during media
prep, bioreactor setup, or transfer
of inoculum or other transfers. On
the other hand, a fine leak test needs
to be able to spot a flaw so tiny that
it could elude the naked eye. Both
types of leaks threaten production
time and supply, and pose significant
financial risk for the manufacturer.
In addition, in the case of vaccine
production, leaks can pose a threat to
operator safety.
Figure 1: Operators preparing a 3,000 L bag
for a point-of-use integrity test.

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

33

34

November 2015

Pharmaceutical Manufacturing www.pharmamanufacturing.com

Integrity Testing
Methods Vary

ASIs inSITE Pressure Decay System

There are two integrity testing methods

on the market today: helium integrity
testing and pressure decay testing.
Helium integrity testing takes the
entire bag assembly and places it
inside a sealed chamber, evacuates
the air and introduces a measured
quantity of helium into the bag. The
vacuum pulled inside the chamber
ensures that helium will escape
through holes in the bag, and a mass
spectrometer is then used to detect
and quantify the helium.
Pressure decay testing is a triedand-true industry standard [ASTM
F2095-01] for testing flexible bags.
The term pressure decay testing
refers to a change of pressure inside
a pressurized containment during a
leak test. The test is an inflation test
in which the bag is pressurized to a
preset level. After the bag system has
been stabilized, the decay in pressure
over time is evaluated to determine
if a leak is present. If the pressure
is lost, then air has escaped from
inside the bag, and a drop in pressure
correlates to the size of the defect.
The advantage of pressure decay
testing is that it ensures that no
alternative gasses are introduced into
the cleanroom, by using in-room air,
and can detect leakage problems with
a high degree of accuracy. Innovations
in the flexibility and mobility of such
technology have occurred recently,
where mobile units are available that
can be wheeled to the exact container
for testing.

According to ASI, its inSITE system has some special and useful characteristics. The system, explains ASI, walks users through a validation set-up, which
then becomes unique to each bag and tank combination and is stored in
memory for later access. A wireless PC Operating system allows the user to
save, store and email testing results. Recorded results are available as PDFs,
and files can be emailed, printed and saved for future use. These documents
become part of the audit trail that accompanies the product being manufactured, a feature that is highly valued by the manufacturers.
ASI says its system inflates to a specified pressure allowing the user to load
the bag more easily. For gross leak detection, users simply select the gross
leak test to find large defects and visible leaks. A gross leak detection test
will also indicate a loose tube or nozzle. Fine leak selection is similar. Users
can select the fine leak test to detect pinholes, small tears and leaks. Lastly,
inSITE testing can be applied to bags of virtually any tank size, although the
current maximum size is 3,000 Liters.
A consistent environment is required for each setup and test because any
variance in these conditions can affect the test results. The test is a pressure
test which makes it ultra-sensitive to changes in external pressure, tank size
and room temperature.
Another aspect to ask about when looking for pressure-decay integrity
systems for point-of-use is automatic inflation, which can assist operators in
loading bags with minimal human intervention, reducing operator handling
errors that can cause tears in the first place.
A liquid filling monitor is also available, which moderates internal pressure
within the bag for the purpose of monitoring over-fill. It works by regulating
the open/close position of the coaxial valve.
Single-use technology in biopharmaceutical production continues to grow,
and its move into downstream processing has pushed the focus on quality
testing of the technology in the same direction: downstream. In many ways,
it is heartening to see the partnerships taking place between manufacturer
and single-use suppliers to improve usability, flexibility and accuracy of
integrity testing. As the application of single-use technology continues to
move from upstream to downstream, the focus of testing will move in parallel, and has put a spotlight on doing everything possible to ensure and document quality in products that are so much closer to final production batch.
Pressure decay testing is up to the challenge.

Documentation and
Flexibility Key

Pressure Decay Detection tests should

quickly be able to locate small leaks
(between 100 microns and 1,000

microns) and confirm connection

and setup of the bag system; fine leak
detection tests will uniquely validate
each tank and bag assembly. Very fine
leak detection is possible and is dependent on the environment and the
time allotted for the testing to occur.

The initial pressure decay approach

should always include the purposeful
comparison of intentionally flawed
bags and non-flawed bags during
the validation set-up procedure. A
comparison of these tests measures
the changes in pressure that occur.

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

35

BIOPHARMACEUTICAL
technical resource guide

By Lakiya Wimbish, manager, Endotoxin Detection, Lonza

Inside 2015

Endotoxin TestinG

Figure 1: The supply of LAL and TAL is

reliant on several horseshoe crab species including Limulus polyphemus
(shown here) on Pickering Beach,
Delaware.

Why LER is here to stay, the need to safeguard test

supply, revisiting the definition of alternative assays,
and moving toward automation
It is currently a very interesting and dynamic time for
the endotoxin testing community, as highlighted at Lonzas
recent Global Endotoxin Testing Summit during which
vendors, regulatory bodies, pharmaceutical manufacturers,
and conservationists came together to share their thoughts
and perspectives on some of the industrys key issues.
Some of the challenges being addressed at the summit and
discussed in detail here include methods to overcome the
issue of low endotoxin recovery (LER), the need for alternative tests in order to safeguard lysate supply and conserve
the horseshoe crab, a guide to validating these alternative
assays and the move toward automated systems.
Overcoming low endotoxin recovery

LER is widely regarded as a real challenge for the endotoxin testing community and a problem that must be
overcome. As Ingo Spreitzer, deputy head of the Microbial Safety Department of the Paul-Ehrlich-Institute (PEI)
and European Directorate for the Quality of Medicines
and Healthcare (EDQM), whose group published the new
European Pharmacopoeial (EP) Chapter 5.1.10, Bacterial
Endotoxins Ph. Eur. Policy for Substances for Pharmaceutical Use, proposed, LER is the most important issue in
endotoxin testing today because it is affecting the testing
of current products that are already on the market.
LER occurs when various combinations of excipients
used in biopharmaceutical production mask known
amounts of endotoxin in undiluted samples. This
can result in false negatives if added endotoxin is not
adequately recovered and ultimately challenges the
validity of these results.
While regulators, pharmaceutical manufacturers and
test vendors are aware of the issue, there is still much
debate concerning the mechanisms behind LER and how
endotoxin masking might be overcome. Allen Burgenson,

36

November 2015

U.S. Regulatory Affairs manager at Lonza, thinks, LER

is a new type of inhibition. Weve seen inhibition before
and we solved it. There are a number of methods by which
LER can be overcome before you have to go into the
chemistry of demasking. The issue of LER is manageable,
and while I think it is an important technical problem, we
do not necessarily have a public health problem.
Alan Baines, UK Strategic Projects head at Lonza,
suggested that, when considering new biological license
applications, manufacturers should be aware of the potential
issues with LER when using polysorbate in combination
with citrate or phosphate buffers. Finding the right
combination could side-step potential problems. For existing
products, it is likely that additional sample treatment steps
will be needed to overcome the masking effect, as changes to
formulations are usually a much less attractive option.
To overcome the masking effect, Johannes Reich,
PhD student at the University of Regensburg, has been
working in conjunction with Hyglos GmbH to gain a
better understanding of the aggregation and interaction
of lipopolysaccharides in endotoxin testing. His theory
assumes that LER is the result of endotoxin aggregate
breakdown into monomers, which are subsequently
embedded in surfactant micelles. He proposes that this
process is reversible and as such, endotoxin demasking
will require adjustments in magnesium and calcium, pH
and/or the addition of polyanionic dispersants such as
Pyrosperse, in order to reassemble the aggregates to allow
for sufficient endotoxin recovery.
However, demasking is still an active area of
contention among some industry members as Kevin
Williams, senior scientist for Endotoxin Detection at
Lonza, believes, many people are resisting using
the demasking protocol as they want to maintain
the simplicity of the test. I can certainly understand.

Pharmaceutical Manufacturing www.pharmamanufacturing.com

However, you cant maintain simplicity by denying that

complexity exists. So what we hope to do is to inform
and educate at least the manufacturers of biologics
such as monoclonal antibodies about the importance of
addressing LER, as these are life-saving drugs and its a
significant and growing market area.
This reluctance is understandable, as carrying out
an investigation into LER could delay the release of
new products and cause significant financial issues
if a product cannot be released within a reasonable
timeframe. This is a particular problem for biological
products, as they often have a very short shelf-life and
require a fast turnaround time.
Regulators can also add additional time pressures; if a
product is tested and shown to display LER, manufacturers
will need to overcome the issue within a given timeframe,
as stipulated by the FDA (typically one year but this can
vary). The manufacturing delays introduced by the need to
overcome the issue will likely be significant. In addition,
biological products for which no defined hold-time has
been established will need to be tested as soon as possible.
This may cause a back-up in QC testing, as products that

exhibit the signs of early or somewhat instantaneous LER

will need to be pushed ahead of other products where a
longer hold-time has been established. If no clear hold-time
can be established during the development stage due to
LER, significant time and money may need to be invested
to uncover better formulations that exclude the excipients
known to be associated with LER.
The threat of LER can also influence manufacturing
efficiency and cost in other ways. For example, in some
cases, manufacturers may feel the need to implement
alternative testing strategies, such as the introduction
of additional in-process analysis steps during the
manufacturing stage, or even at different points in the
process where LER is not yet a factor. Such changes to
existing workflows can have significant operational and
financial impacts. Lastly, the FDA requires extensive
evaluation of the drug product regardless of whether LER
is present, which could be time-consuming and costly.
Evidently, further investigation in this area will ensure
a better understanding of the LER and the means by
which this issue can be overcome in a timely and costeffective manner.

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

37

Figure 2: Lonzas Global Endotoxin Summit delegates taking

part in the Just Flip em program to help save stranded
crabs on Pickering Beach, Delaware, one of ERDGs community horseshoe crab sanctuaries.

THREATS TO NATURAL AMEBOCYTE LYSATE

The Limulus or Tachypleus Amebocyte Lysate (L/T-AL)

assays are currently the most widely used bacterial endotoxin testing (BET) methods. The need for these tests is
on the rise due to an increase in the demand for medicinal products, including biopharmaceuticals, particularly
as more countries become economically developed. All
parenterally administered pharmaceuticals will inevitably need to be tested for bacterial endotoxins and as such
arise in vaccine production could place strain on lysate
resources if current habits remain unaltered.
The supply of LAL and TAL is reliant on several
horseshoe crab species namely, Limulus polyphemus
(Figure 1) and Tachypleus gigas or Tachypleus
tridentatus, respectively. Th is is because when
endotoxins come into contact with the blood of
these crabs, a clotting cascade is activated. It is this
mechanism that has been used for endotoxin testing
since its commercialization in the 1970s.

38

NOVEMBER 2015

As the need for the amebocyte lysate increases, so

too does the need to protect the crab populations.
In North America, this has meant that the Atlantic
States Marine Fisheries Commission has implemented
a state-by-state fishing quota and the conservation
efforts of the Ecological Research and Development
Group (ERDG) such as Just Flip em and Backyard
Stewardship community horseshoe crab sanctuary
(Figure 2) have been put in place to safeguard the
native L. polyphemus populations.
However, in Asia a lack of regulation has meant
a considerable reduction in indigenous T.gigas and
T. tridentatus numbers. A collaborative effort from
regulatory bodies, pharmaceutical industry, vendors,
end-users and conservationists will aid in ensuring
horseshoe crab populations are preserved. In addition,
the development and adoption of alternative testing
methods that do not rely on a potentially finite animal
resource could also help to achieve this.

PHARMACEUTICAL MANUFACTURING WWW.PHARMAMANUFACTURING.COM

Alternative endotoxin
testing methods

Alternative methods, such as Lonzas

PyroGene recombinant Factor C (rFC)
assay, use a synthetic form of Factor C, the essential component of the
endotoxin-activated clotting cascade
(Figure 3). Not only do such alternatives
negate the need for an animal resource,
but also they offer several other benefits
over the natural assays. These may include ease-of-use, lot-to-lot consistency,
statistically robust spike recovery and
enhanced endotoxin specificity.
Despite these benefits, many are
reluctant to use these alternatives.
This is due to the fact that both
the FDA USP <1225> and EP
Chapter 5.1.10 stipulate additional
validation steps to be conducted
when using these methods. However,
pharmacopeial members, like Ingo
Spreitzerare keen to discuss how
rFC-based tests are defined. I hope to
see increased usage of rFC in the field
of endotoxin testing. This shouldnt
be too challenging in my opinion,
as I dont see a significant difference
between the LAL assay prepared from
crab and industry prepared rFC
both depend on Factor C.
Furthermore, the validation
procedure can be accomplished in
1-3 days and doesnt require much
additional effort compared to
compendial methods. The process
is simplified by the availability of
documentation and well-structured
protocols from test manufacturers that
can help users generate sufficient data
to meet the regulatory requirements.
Allen Burgenson thinks, Well need
big players to adopt rFC so that others
will follow and this will increase
the chance of it being accepted by
regulatory bodies, if alternatives are to
become common practice.

LAL

Recombinant Factor C

Endotoxin
Endotoxin
Glucan

FC

FC

rFC

rFC
FC

FC

FG

FG
Substrate

Proclotting
Enzyme

Detectable
Signal

Clotting
Enzyme

Substrate

Detectable
Signal

Figure 3: Endotoxin-activated clotting cascade comparing LAL assays and Pyrogene recombinant
Factor C Assay (Lonza).

Moving toward
automated testing

Automating the endotoxin testing

process could help improve efficiency
and manage the increase in demand.
Alan Baines believes, Automation
of the preparation steps will be possible. In fact, for large-scale users
this has already been successful, but
this is expensive for the application
and out-of-scale with the need of the
assay. Testing is moving from the
QC laboratory to the manufacturing floor, with the hope that this will
allow problems to be detected sooner
and prevented at an earlier stage. This
has had some limited success so far,
but this could become much more
prevalent over the next 10 years.
Wolfgang Mutter, general manager
of Hyglos GmBH, concurred saying,
If we have the technology I think
we can manage this. However, if
the regulators do not account for the
technological advances, this could
mean that rather than using the

latest biochemistry, such as rFC,

new automation processes will be
designed using LAL reagents, even
though they could soon become
obsolete. For this reason, it is
imperative that the pharmacopeias
be kept up-to-date on developments
in endotoxin testing in order to
ensure the guidelines for use are
acknowledged in the compendia.
As a result, this will increase the
probability of these methods being
taken into consideration when
designing new instrumentation.
Modifying pharmacopeial
guidelines

New products challenge the current

pharmacopeial guidelines. Ingo Spreitzer envisages, New types of products are going to affect the future of
endotoxin testing. I predict that we
will need to develop a much more detailed and product-specific set of risk
assessments in the future. Therefore,
in order to ensure the industry and

Pharmaceutical Manufacturing www.pharmamanufacturing.comNovember 2015

39

regulators move forward in parallel, every stakeholder

will need to be involved to ensure a rapid mutual progression amongst the endotoxin testing community.
LOOKING TO THE FUTURE

The endotoxin testing community is increasingly aware

of the imminent transformative period ahead. Hence,
regulatory bodies, pharmaceutical manufacturers, reagent vendors and horseshoe crab conservationists will
need to work together to align goals and set clear objectives to ensure innovative methods, which improve upon
current assays, are incorporated into the pharmacopeia
and adopted in the QC laboratory. Change is inevitable
throughout this process. Therefore, it is necessary to
have a responsive system in place to ensure prompt
implementation of alternative tests while still maintaining patient safety, which remains the utmost priority for
the pharmaceutical industry.
Given the research currently underway to fully
understand LER and to assess potential solutions,
it is likely that the problem will soon be solved and
without becoming a risk to human health. Endotoxin

testing may be improved upon if the industry can be

encouraged to carry out the additional validation steps
required by the regulators when using an alternative
method, as these tests deliver comparable results yet
offer a number of additional benefits for the user in
addition to reducing the strain on lysate supply and
protecting the horseshoe crab populations.
Evidently, change is coming and the global endotoxin
industry will need to adopt a collaborative approach to
realize sustainable BET operations and ensure patient
health and well-being remains at the forefront of all
future endeavors.
ABOUT THE AUTHOR
Lakiya Wimbish, product manager for Endotoxin Detection at Lonza
is responsible for alternative methods like the PyroGene recombinant Factor C Assay, Testing Services and Rapid Microbial Detection
platforms. She joined Lonza eight years ago as an Applications Development Scientist for Rapid Microbial Detection platforms before
transferring into her current marketing role. Prior to Lonza, she was
a contractor for the United States Navy/Biological Defense Research
Directorate and graduated from the University of Pennsylvania.

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