WWW. PHARMPRO.

COM • VOLUME 28, NUMBER 8 • OCTOBER 2013
INTERPHEX 2014

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Quality Control and
Microscopy Services
Brazil’s Emerging Market
■ SOLID DOSAGE
Coaters Go High-Tech
■ PACKAGING
Optimizing Pharmaceutical
Packaging
Conquering Glass
Delamination
■ BIOPHARM
Single-Use Pumps for
Biopharm Manufacturing
Genomic Analysis Improves
Mammalian Cell Culture
Potent/Aseptic Parenteral
Manufacturing
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■ IN THIS ISSUE
■ P H A R MP R O . C O M
■ 4
12 Potent/Aseptic Parenteral
Manufacturing
Latest equipment, trends, and observations.
16 Single-Use Pumps Take
Center Stage
Single-use pumps meet the challenges of
biopharmaceutical manufacturing.
20 Pharmaceutical Access in
Emerging Markets
How the latest developments in Brazil will
change your business strategy.
24 Using Genomic Analysis
Trends to improve mammalian cell culture for
biopharmaceutical production.
28 Scanning Electron
Microscopy Services
SEM offers the quality control needed for
ever smaller API particles
32 Coaters Go High-Tech
Achieving high-quality oral solid dosage
manufacturing through continuous tablet
coating improvement.
36 Optimizing Packaging
Active and protective solutions help ensure
product efficacy.
38 Conquering Glass
Delamination
The material selection process may
alleviate ongoing concerns.
■ COVER STORY
8 Enabling Progress
Catalent's clinical-stage biologics facility is a critical
part of the company's global capabilities.
page 12
page 16
page 25
page 28
■ DEPARTMENTS
6 From The Editor
22 What’s Hot
INNOVATIONS
35 Clean Room Equipment
On the Cover:
Catalent's new
state-of-the-art
facility offers
expanded mam-
malian cell line
and biomanufac-
turing capabilities.
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W
Whatever your opinion of the FDA is you really can’t fault the agency
for trying to get new therapies to patients as quickly as possible.
Here’s a brief rundown of some of the programs available:
Fast Track is a process designed to facilitate the development,
and expedite the review of drugs to treat serious conditions and
fill an unmet medical need.
Breakthrough Therapy designation is designed to expedite the develop-
ment and review of drugs that are intended to treat a serious condition
and preliminary clinical evidence indicates that the drug may demon-
strate substantial improvement over available therapies.
Accelerated Approval regulations allow drugs for serious con-
ditions that filled an unmet medical need to be approved
based on a surrogate endpoint that enables faster approval.
Priority Review designation means FDA’s goal is to take action on
an application within 6 months - compared to the usual 10 months.
When a drug gets one of these designations, it’s fairly common
for the developing company to announce this to the press. After all,
achieving one of these designations makes the company look good
both to the public in general and its stockholders – a win all around.
But there is one FDA designation which has been getting some
notice recently due to its lack of use. Expanded Access, sometimes
called "Compassionate Use," is the use of an investigational drug out-
side of a clinical trial to treat a patient with a life-threatening disease
who has no comparable or satisfactory alternative treatment options.
Recently, there have been at least two cases where patients
have appealed to companies to allow access to drugs under the
Compassionate Use designation and have been turned down.
Personally, I think this is wrong. If the denials were based on le-
gal or safety concerns, I’m sure these issues could be worked out.
If companies are quick to announce when developing products re-
ceive one of the other designations – I’m sure the public relations ben-
efits of a compassionate use tag would far outweigh any negatives.
What do you think?
■ FROM THE EDITOR
■ P H A R MP R O . C O M
Compassionate Use
Have a comment or question about Pharmaceutical Processing?
My E-mail is: mike.auerbach@advantagemedia.com
Whatever your opinion of the FDA is you real-
ly can’t fault the agency for trying to get new
therapies to patients as quickly as possible…
■Michael Auerbach, Editor in Chief
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■ 6 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
EDITORIAL ADVISORY BOARD
Michael J. Beier,
Senior Vice President of Operations
TITAN PHARMACEUTICALS, INC.
Dr. James V. Blackwell, PhD, Consultant
BIOPROCESS TECHNOLOGY CONSULTANTS, INC.
Ronald C. Branning,
Vice President Global Quality
GENENTECH INC.
Robert F. Dream, Vice President
H.D.R. COMPANY LTD.
Johanna Carmel Egan,
VGP Project Management
ELI LILLY
Girish Malhotra, President
EPCOT INTERNATIONAL
Allan F. Pfitzenmaier, President
VECTECH PHARMA CONSULTANTS INC.
Susan Polizzotto, Manager,
R&D QA GMP Compliance
US SANOFI PASTEUR
Carlos Villalobos, Sr. Dir. Global Engineering
BRISTOL-MYERS SQUIBB
Richard G. Whitfield, Senior Director
PFIZER
Patrick Wong, Director of Global Engineering
BRISTOL-MYERS SQUIBB (BMS)
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Product is pumped from one room to
another in a completely enclosed sin-
gle-use system.
A
ccording to the
definition found at
businessdictionary.
com an “enabling
technology” is ”equipment and/
or methodology that, alone or in
combination with associated tech-
nologies, provides the means to
generate giant leaps in performance
and capabilities of the user.”
While the pharmaceutical in-
dustry’s past has not been chock
full of advancements that could
be classified as “enabling”, recent
developments have pointed the
way toward a more technologi-
cally advanced future for pharma-
ceutical manufacturing.
Indeed, as many companies
have begun to embrace advanced
technologies they are finding little
use for older technologies, as new
equipment and processes are showing them the way to more
efficient, less costly and higher quality manufacturing.
For companies in the biopharmaceutical contract manufac-
turing segment of the industry this confluence of technology
could not have come at a better time. As the biopharm market
continues to grow, biopharmaceutical product sponsors and
service providers are looking for the best tools and techniques
to bring products to market faster and with the best quality.
One such company is Catalent.
The company has combined the
latest single-use equipment with
their own technologies to design
and commission a world-class
contract manufacturing facility in
Madison, Wisconsin for the devel-
opment of clinical trial materials
that are used worldwide.
BACKGROUND & HISTORY
Catalent is a global leader in
development solutions, and ad-
vanced delivery technologies for
drugs, biologics and consumer
health products. The company
offers numerous technologies at
dozens of facilities around the
globe (see chart).
The biologics site in Madison started as a spin-off from
the University of Wisconsin-Madison with funding from
angel investors and was housed in an old army facility out-
side Madison. The company’s main focus was developing a
process to make pharmaceutical proteins from the milk of
transgenic cows as this was viewed, at the time, as a cheap
way to manufacture pharmaceutical proteins. It was during
this time that the company moved to a larger facility in
Middleton, WI.
In 2003, Cardinal Health bought part of the company and
then bought the rest of it. Catalent as it operates now was
created in April 2007 when The Blackstone Group, a global
investment and advisory firm, acquired the Pharmaceutical
Technologies and Services segment of Cardinal Health.
GLOBAL TECHNOLOGIES & GLOBAL REACH
As it takes a long time to get a cow to the stage where it
can be milked, the company was also concurrently develop-
ing its proprietary GPEx
®
system to make higher expressing
mammalian cell lines. As Gregory Bleck, PhD the company’s
Director, R&D Platforms explains, this turned out to be
Enabling Progress
Catalent's clinical-stage biologics facility is a critical part of the company's
global capabilities
■ By Mike Auerbach, Editor in Chief
■ 8 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M ■
■ C OV E R S T OR Y

MADISON BIOLOGICS MANUFACTURING SERVICES:
• Process development focus with extensive non-GMP and GMP experience,
laboratories and support functions
• Solutions for difficult to express proteins
• Flexible cGMP production scale from 10 L to 1000 L
• Tailored process development for mammalian cell lines
• Extensive use of single use technologies to eliminate cross contamination
• Unidirectional flows throughout facility
• Growing to 100,000+ square feet and 100+ employees
pp1310_coverstory.indd 8 9/20/2013 3:05:00 PM
the capacity for making production material has quadrupled.
For more specifics, the Madison site now boasts bioreac-
tors up to 1,000 liters in size, compare to the 200 liter biore-
actors in the old facility. In addition, through a comprehen-
sive Operational Excellence (OpEx) program, Catalent has
increased the number of runs per suite by 20% which lets
them run multiple products per suite while keeping them
completely separated.
As part of the global Catalent network of facilities, the
team in Madison was able to leverage the experience of oth-
ers within the Catalent organization. “One of the great things
about being part of Catalent,” says Jenkins, “is that at the
end of the day you might think we have a nice manufacturing
facility here in Madison with about 100 people, but it’s really
backed up by the 8,000 people who have a lot of experience
in manufacturing, not necessarily biologics, but they know
how to get stuff to market – which is a great thing to have.
Catalent pays a lot of attention to this business.”
He continues, “Two years ago we were the largest invest-
ment Catalent made in its business. That’s a level of commit-
ment they have to biologics. Think of all of the things going
on in Catalent – all of the other divisions - and they have
a strong commitment to biologics and also integrating this
facility in to the rest of Catalent. It’s a great solution for our
customers.”
“A lot of our customers are small companies – less than
hundred people or even university researchers trying to
get a product to market – and the ability to deal with one
company that is reliable and to be able to go from DNA con-
struct to an injectable in a clinic is very powerful.”
THE TRANSITION TO SINGLE-USE TECHNOLOGIES
For Catalent, the decision to move to single-use technolo-
gies in their Madison facility was a defining moment because
they decided to abandon all of their stainless steel equipment
and jump totally into single-use. “A lot of companies that
make the transition to single-use keep their stainless steel
equipment on the side – we abandoned all of our stainless
steel equipment and you won’t see any stainless steel biore-
actors in Madison,” says Jenkins, “we sold all the stainless
steel equipment to a competitor. We view this as a positive.”
good timing. “At this time, Mad Cow disease was identified,
so even though there was very limited risk, all investors
wanted to stay away from cows, they didn’t want to deal
with any possible connections. We had GPEx
®
to fall back
on.”
In addition to the GPEx
®
cell line platform the company
has also licensed SMARTag

Technology from Redwood
Biosciences which is designed to develop optimized
Antibody Drug Conjugates.
Under the global Catalent umbrella, the Madison facil-
ity, which is currently set-up to manufacture Phase 1 and
Phase II batches for clinical trials, can help a client take a
gene and deliver a product to a clinical trials site anywhere
in the world. Relying on the global network of Catalent fa-
cilities, once the bulk product is released from the Madison
facility it is sent to the company’s clinical fill/finish facility
in North Carolina and then to one of several clinical pack-
aging facilities in the US or Europe, and then on to the com-
pany’s extensive clinical trial distribution network.
Speaking to the capabilities and technologies Catalent
has to offer, Bleck offers his views. “We have unique tech-
nologies all through Catalent – we do more than manu-
facturing - we want to offer solutions to our customers to
make better products. We are continuously developing our
own IP internally and exploring arrangements with other
technology companies to access unique offerings that will
add value to our customers and enable them to provide
better products.”
THE MADISON, WI BIOLOGICS FACILITY
As Catalent’s facility in Middleton, WI began to fill up it
was decided to expand and look for a larger building to
house their growing operations.
The facility they selected was a former electronics man-
ufacturing building and was essentially a big, wide-open
warehouse. This proved to be good choice as this layout
resulted in minimal obstacles in facility design – except
for the required support pillars which were integrated into
the facility. Michael Jenkins, PhD., the facility’s General
Manager explains how the empty facility worked in their
favor. “We wanted an open area with good ceiling height.
Which is absolutely critical to what we do because biore-
actors take up a lot space. We put in the appropriate infra-
structure from the start so things would work - and made
sure the infrastructure was properly sized for our needs.”
Compared to the site in Middleton the new Madison facil-
ity has more than doubled in size. In addition the manufac-
turing area available to the company has tripled in size, and
■ P H A R MP R O . C O M
PHARMACEUTICAL PROCESSING | OCTOBER 2013 9 ■
■ P H A R MP R O . C O M
■ C OV E R S T OR Y
BIOLOGICS TECHNOLOGIES
SMARTag

Technology is a precision protein-chemical engineering technology
for the development of advanced antibody drug conjugates (ADCs). The novel, site
specific protein modification and linker technologies, enable the generation of
homogenous bioconjugates engineered to enhance potency, safety and stability.
GPEx
®
Technology is a proprietary, pseudo-typed, high-titer vector that generates
stable mammalian cell lines - in record time. Virtually any cDNA (mAb and multigenic
applications) can be packaged into the GPEx
®
retrovector and used to transduce a
mammalian cell line. To date, over 400 different mAb and mAb fusions and over 60
different recombinant proteins have been produced using the GPEx
®
system.
Disposable bioreactors eliminate any cross contamination concerns.
pp1310_coverstory.indd 9 9/20/2013 3:05:17 PM
■ P H A R MP R O . C O M
■ C OV E R S T OR Y
■ 10 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
air handling system. Air in that room is
completely separate from the air using in
other areas. In fact, over 25% of the build
out cost was from HVAC. Jenkins explains.
“If you want to get the maximum number of
runs from your process you want to keep
these areas separate – it becomes very ex-
pensive in terms of air-handling. We have
great capacity in our suites and you get
there by investing heavily in separation of
product – and HVAC is a huge part.”
The flow of people and product through
the facility was also carefully thought
through. The lab areas are separate from
the office areas. Personnel enter the GMP
production areas through an entrance
corridor and exit through an exit corridor.
This is a key compliance item and one of
the keys to being Phase III compliant, which
Catalent is looking at for the facility in the
future. Commenting on the facility design
and work area segregation, Jenkins points
Catalent’s GPEx
®
technology as a major
reason. “Almost every cell line we work with
is from our GPEx
®
technology, but we also
work with non GPEx
®
cell lines and we have
a special lab to work with these cell lines
until they have been tested
enough to be released into
the facility. We have great
separation between the GMP
areas and the development
areas.”
FINAL THOUGHTS
There is little doubt that
the implementation of sin-
gle-use technologies and
Catalent’s own intellectual
property has created a world-
class Phase I and Phase II bi-
ologics manufacturing facility
in Madison, WI. By leaving
stainless steel in its past the
team at Catalent has reduced
costs, increased produc-
tion and improved quality.
Looking toward the future the
team is exploring expanding
the facility to include manu-
facturing of commercial scale
products and there is defi-
nitely a sense of anticipation
in the air. “It’s a real exciting
place to be,” says Jenkins. ■
route to the next suite.
By separating the process into multi-
ple rooms more efficient production is
achieved. Product spends about 18 days in
the terminal bioreactor room and then is
transferred through the wall from the TFF
skid to depth filtration, then to the steril-
izing filter and then to a mixing vessel in a
plastic bag. Once product is pumped out of
the first room cleaning can begin, and what
was once a 3 day process with stainless
steel equipment, now takes one day.
“It’s a simple process actually,” says
Jenkins, “but everything that touches the
product will be thrown away at the end – no
cross contamination and it’s a completely
enclosed system.”
ADDITIONAL FEATURES
While single-use technologies get a lot of
the attention in the Madison facility, other
features of the building and its design con-
tribute greatly to the facilities success.
For example, in the bulk fill room where
material is taken out of the disposable
bag and put in a transport container and
shipped to the client features a very robust
One of the key benefits to moving to sin-
gle-use was that team did not have to include
any of the infrastructure necessary to sup-
port stainless steel equipment such as steam
lines, CIP carts, etc. all of that infrastructure
is unnecessary. In addition, the construction
timeline was significantly compressed.
“The typical timeline for a GMP stainless
steel facility is to finish construction in a
year and six months for validation” says
Jenkins. “We went from the start of con-
struction to ready for GMP production in
about a year.Single-use equipment enables
that.”
Being a reliable supplier of quality prod-
ucts is of critical importance to Catalent
and single-use technologies help them ac-
complish that goal. Single-use equipment
allows them to keep their manufacturing
processes in a closed system. The company
employs an ‘alcove strategy’ - suites are
divided into separate rooms and material is
pumped through single-use tubing through
a port in the wall from one suite to another.
This allows products to be separated from
one another and also eliminated product
from being wheeled through hallways en
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W
ith the ever-increasing complexity of paren-
teral products such as cytotoxics and con-
jugations, it has been necessary for pharma-
ceutical/biotech equipment manufacturers
to develop equipment, that not only protects the products,
but also the operators and the environment. This article
traces the development of the use of isolators to accomplish
these tasks, as well as the latest isolator equipment being
offered in the aseptic/potent area.
THE WORLD’S FIRST
The world’ first filling line with freeze drying for aseptic/
toxic products was licensed by the FDA in 1993 (formulation
and compounding was also accomplished in isolators). The
anti-cancer proprietary drug (Navelbine) was the first drug
to be filled in this facility located in southwestern France.
Thereafter, a number of toxic products were filled on this
line on a CMO basis. Filling equipment, at that time, was
not designed for use with isolators, since isolators were a
relatively new concept, except for use in sterility testing ap-
plications and mostly soft wall configurations. The footprint
of the equipment for filling and freeze dryer loading and
unloading was so large, it was necessary to use half-suits
in order to access the necessary areas for interventions. In
addition, the major issue of “tightness through the tabletop”
had to be addressed. Penetration tightness was not only
necessary to contain the toxic material, but also to prevent
vaporized H2O2 being used for de-contamination, from es-
caping into the environment. (See picture of facility below
left.)
LATER DEVELOPMENT
This facility included all of the normal items of equipment
found in a typical aseptic/toxic liquid filling suite today as
well: vial washer, de-pyrogenation tunnel, filler, freeze dryer,
separate capper and external vial washer. As other facili-
ties began to come on line: Switzerland 1995, England 1996,
Germany and Japan 2002, the filling and freeze dryer load-
ing and unloading systems were adapting to isolator technol-
ogy. The width and tightness of the fillers and the automatic
loading and unloading conveyor systems for freeze dryers
were being implemented. It was not until the end of 2004
that two US facilities installed a filling line for aseptic/toxic
applications, without freeze drying capacity, even though
additional facilities were added in Europe. It was not until
2005, when an aseptic/toxic facility with freeze drying ca-
pacity was built, primarily for clinical purposes. This com-
pany was very concerned with potential exposure of the op-
erators to toxic substances being filled. One of the products
had an OEL of 35 nanograms. In the beginning,
they required the operators to use PAPRS to op-
erate the facility. Using extensive monitoring, it
was determined this level of containment could
be reached using the isolators. Eventually, the
operators could reduce their gowning require-
ments to normal Class C gowning. Reduced
gowning represents additional significant sav-
ings over normal Class A or B gowning.
THE BALLROOM CONCEPT
By 2005, the “ballroom” concept of a filling
suite had been initiated. This concept of includ-
ing all of the equipment for aseptic filling and
freeze drying were to be contained in one filling
suit, including vial washer, tunnel, accumula-
tor, filler, freeze dryer loading and unloading
system, capper and external vial washer and
tray-off. Utilizing this system within a Class C
POTENT/ASEPTIC
Parenteral Manufacturing
Latest equipment, trends and observations
■ By Jim Spolyar, SKAN
■ 12 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M
■ PARENTERALS
pp1310_feature_Skan.indd 12 9/18/2013 9:11:00 AM
equipment. This uni-direc-
tional airflow from above to
below, restricts the particles
produced by the filling op-
erations from contaminating
the terminal HEPA filters
above the chamber. This ISO
5 environment in the isola-
tors replaced the previous
method of operation in a
traditional cleanroom of ISO
5 classification. The stainless
steel and glass barrier and
a leak tight chamber, added
additional protection for the
product, operators and the
environment. In addition,
the isolators could operate
in positive or negative pres-
sure. Normally, during the
liquid fill portion of a cycle
for aseptic/toxic products,
the isolators, including the
freeze dryer loading and unloading units operate in positive
pressure. Depending on the toxicity of the product, many
companies choose to operate the isolator over the freeze
dryer unloading operation in negative pressure, since there
New filters can be changed from the outside and fea-
tures many safety features.
room, since normally all process rooms are the same level,
eliminates the need for airlocks between these rooms. In a
“greenfield site”, this could represent a savings of up to 35%
of the floor space.
DECONTAMINATION OF ISOLATORS USING H202
In the beginning of the use of isolators for these applica-
tions and continuing today, decontamination using vapor-
ized hydrogen peroxide is the material of choice. Materials
of construction of the isolators were tested for the best
compatibility with H2O2. Glass and stainless steel are very
good for the de-contamination cycle, while aluminum and
some plastics lengthen the cycle. Gloves made of Chlori-
Sulfate-Polyethylene (CSM), formerly Hypalon, have been
determined to best suited for H2O2 decontamination.(1)
Decontamination of the isolators in the early stages of de-
velopment was accomplished using remote generators deliv-
ering vaporized hydrogen peroxide. These generators were
being offered by companies independent from the isolator
manufacturers. In 1997, the first fully integrated system was
offered, combining the delivery system with the isolator us-
ing the same control systems.
AIR HANDLING
Isolators for sterile filling applications have uni-directional
airflow in the working chambers from the ceiling to the
floor. It is necessary to maintain a Class A (ISO 5) over the
■ P H A R MP R O . C O M
■ PARENTERALS
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pp1310_feature_Skan.indd 13 9/18/2013 9:11:47 AM
■ P H A R MP R O . C O M
■ PARENTERALS
■ 14 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
These small batches of normally high value
products, which need to be aseptically
and perhaps freeze dryed, has required
the filling line manufacturers to develop
new machines which are small and flexible
for batches between 500 to 10,000 units.
Isolators needed to be adapted to this new
reality. Thus, the development of the mod-
ular system with rapid H2O2 airlock for
entry of components for production and
other items. The filler is also modular and
mounted on an L flange which can be ex-
changed with another filler with the same
L flange-ie one with a syringe filler and one
with a vial filler. The modular isolator can
be equipped with FIPA filters as well to
protect the product and operators and elim-
inate cross contamination issues.
REFERENCES
(1) Sigwarth V. and Starek A. “Effect of
Carrier Materials on the Resistance of
Spores of Bacillas Stearothermophilus
to Gaseous Hydrogen Peroxide”: PDA
Journal of Pharmaceutical Science and
Technology, Jan. 2003 Vol. 57 No.1
(2) NA press release: 05.28.2009 New form
of targeted cancer therapie brings new
hope for patients with advanced HER2
positive breast cancer ■
aseptic isolator. The transfer time should
be as short as possible, between 15 to 20
minutes for a complete cycle with a spore
reduction of 10
6
of Geobasillus stearother-
mophilus. By utilizing this device, numer-
ous entries and exit of items can be made
into an aseptic isolator chamber, without
compromising the aseptic nature of the
main chamber. This has become a frequent
addition to aseptic isolators for production,
as well as sterility testing. The airlock is
loaded from the Class C or D cleanroom.
After the de-con cycle, the sliding door to
the isolator is opened and the items trans-
ferred. If there is anything to be removed,
such as trash, it can be placed in the air-
lock, door closed and then removed into the
cleanroom for disposal. Monitoring plates
can also be removed in the same manner.
SMALL SCALE ASEPTIC FILLING
Biotechnologically developed and pro-
duced medicines are increasing. For ex-
ample, a well know Swiss pharmaceutical
concern introduced an antibody conjugation
which showed positive effects for advanced
HER2 breast cancer(2). This and future
similar substances are becoming patient
and illness specific. These developments
require relatively small batches of product.
is potentially powder within the enclosure.
The method of handling airflow is critical
in an aseptic/toxic system, to eliminate the
issue of cross-contamination and for safety
reasons as well. The previous system chan-
neled the air flow through ducts into the
BIBO (bag-in/bag-out) filters located in the
technical area. This required the washing
and drying of the ducts from the filling
equipment to the BIBO’s.
With the development of a patented safe
change filter system (FIBO), the contamina-
tion is retained at the level of the isolator
and the need for BIBO’s is eliminated.
This system has been made possible by
the development of the special filter. It can
be changed from the outside and has all of
the safety features, including a Kevlar liner
to prevent glass shards from damaging the
filter. These filters are built into the return air
channels of the isolator. These filters can be
changed without the use of protective cloth-
ing or breathing apparatus.

THE RAPID H2O2 AIRLOCK
For the entry and exit of packaging
equipment, tools, pre-sterilized vials and
syringes, and material for microbiological
monitoring, the rapid H2O2 airlock was
an excellent addition for attachment to an
Modular isolator with filler and freeze dryer interface.
New air handling system with FIPA filters directly on
isolator.
pp1310_feature_Skan.indd 14 9/18/2013 9:12:08 AM
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into the equation. Not with Captisol. With revolutionary,
proprietary technology, Captisol is rationally engineered
to significantly improve solubility, stability, bioavailability
and dosing of active pharmaceutical ingredients.

SOLVE PROBLEMS WITH CAPTISOL SOLUTIONS.
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Quattroflow 1200 Quaternary Diaphragm Pumps show-
ing the plastic single-use pump-head option.
I
n the multi-billion-dollar global
biopharmaceutical industry, a fur-
ther emphasis is being placed on
the development and manufacture
of advanced biologically derived drugs
(termed here as biologics). These
biologics offer exciting potential
for the development of block-
buster drugs that can provide
as-yet-unknown treatments for
a wide array of diseases. While
pharmaceutical drugs are derived
from more traditional chemical pro-
cesses and reactions, biologic-based
drugs are the result, as the name implies,
of biologically induced processes, such as intracell growth
processes (mammalian cells, bacteria, viruses and such),
and the subsequent harvesting and purifying of target sub-
stances, such as proteins, molecules and enzymes. These
substances are then used to create drugs, vaccines or
antitoxins. In essence, cells are used as miniature process
vessels to create new sub-
stances.
The development of
new biologically derived
drugs, however, is just one
opportunity for manufac-
turers. Another equally
important goal is to com-
mercialize these products
as early as possible in
the typical 20-year patent
window. Patent submission
needs to occur during
the drug-development
process. Following a pat-
ent filing, much occurs,
including further product
development, toxicity
checks and clinical trials.
Hopefully, Food & Drug
Administration (FDA)
Biologics-manufacturing operations take place in extremely
sterile and time-sensitive conditions. Pump technology
like that found in single-use quaternary diaphragm models
are able to satisfy the product containment and speed-to-
market requirements that are paramount in these types of
operations.
approval also occurs during this period.
Following FDA approval, the developers
need to take all the necessary steps to
properly produce the product in commer-
cial scale and execute the market–introduc-
tion plan. If the drug’s development takes ad-
ditional time after patent approval, the patent
may run through a good portion of its window
of protection before the drug has a chance to
be commercialized. In some cases, there are only
about seven years left on the patent for the product
when it goes to market. Every year a drug is covered
by its patent can be worth billions of dollars in sales, so
every day that the development process can be accelerated
means that much more to the bottom line.
From a process-equipment standpoint, permanent and sin-
gle-use quaternary diaphragm pumps, such as Quattroflow™
pumps, represent a growing technology that both helps en-
able the efficient development of new biologic drugs and then
facilitates the speed to market of the end-product. Single-use
pumps, such as those using disposable pump chambers, fea-
ture replaceable wetted parts, meaning that no cleaning and
validation process is needed during a product-development
process that can require multiple trials. This is a great ad-
vantage for drug manufacturers who are looking to maximize
their production operations through the implementation of
cutting-edge pumping technology.
“The biopharm industry is adopting disposables faster than
the general population is trying to recycle,” said Mark Sitcoske,
who heads High Purity New England, Smithfield, RI, USA, a
company that specializes in single-use pump technology.
Essentially, the driving force in the process to create these
target products is to promote growth of biologic material in
a highly controlled, sterile environment with adherence to
strict operational parameters, such as the correct pH (acid-
ity) level, temperature, oxygen level and nutrient feed. An
imbalance in any of these parameters can cause unwanted
biologic processes to occur, such as the formation or growth
of competing and undesirable organisms, or it could cause
the target biologic process to not occur at all. Once the raw
■ By Wallace Wittkoff
SINGLE-USE PUMPS
Taking Center Stage
Single-use pumps meet the challenges of biopharmaceutical manufacturing
■ 16 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M ■
■ B I OP HAR M
t
t
T
T

al
fur-
on
ture
rugs
o-
ed
ti
diti
may
of pro
be com
about sev
when it goe
pp1310_feature_PSGpump.indd 16 9/18/2013 9:14:15 AM
Automated concentration and diafiltration process using only five components.
■ P H A R MP R O . C O M
biologic product is produced, the desired target components
(proteins, molecules, etc.) can be purified by using a num-
ber of techniques. These techniques include filtration (such
as tangential/cross flow and chromatography), separation
(through a centrifuge) or certain chemical reactions.
The critical issue in these target-component extraction
techniques is that biologics are extremely sensitive to
change or damage from outside influences, such as shear,
temperature changes and light. That means the extraction
process that these target components are subjected to re-
quire a type of pump that can reliably deliver the following
desired operational characteristics:
• High purity and sterility
• Very low volume and surface area exposure; 15 ml/73.5
cm2 in the smallest pump
• Low levels of leachables and extractable
• No mechanical spalling/shedding of contact materials
• Controlled/constant flow, as needed
• Low shear, slip and collateral effects
• Low pulsation
• Self-priming and negative suction lift
• Controlled pressure
• No heat addition
• High volumetric efficiency
THE CHALLENGE
The harvesting and purification of biologic target materi-
als is accomplished using separation and filtering processes.
There are generally three purification processes (that can
also be used in combination) as follows:
• Tangential Flow Filtration (TFF)—Also known as cross-flow
filtration. For this process the biologic feed stream flows
horizontally with positive pressure across the filter mem-
brane. As it passes across the membrane, the portion of
the feed stream that is smaller than the membrane’s pore
size passes through the membrane. This is different from
what is known as normal-flow (NFF), or “dead-end,” fil-
tration, in which the feed flows entirely through the filter
membrane with the size of the pores determining which
portion of the feed is allowed to pass through and which
will remain trapped in the filter membrane. TFF is different
from NFF in biologics applications because the tangen-
tial motion of the fluid across the membrane causes any
trapped particles to be “rubbed” off, similar to passing
your hand across a piece of sandpaper. This mode of oper-
ation means that a TFF process can operate continuously
with relatively high solids loads without fouling of the fil-
ter, which is also known as filter blinding.
• Chromatography Columns—A typical chromatography col-
umn is a glass, steel or plastic tube that is filled with res-
ins that are compressed in a certain format through which
a feed stream product flows to either capture or purify
this feed stream. These chromatography columns contain
filter media that need careful handling. A resin, for exam-
ple, can cost as much as $10,000 an ounce, making proper
feeding of the resin extremely important
• Centrifuges—A centrifuge, really a separator and not a
filter, consists of an elaborate vessel that can be fed with
a biologic substance and spun around a central axis in
order to separate the materials according to their different
specific gravities/weights, or to separate particles that are
suspended in the liquid. The biologic’s target product can
be the high, intermediate or low specific-gravity substance
that is spun out of the centrifuge. As centrifuges spin at
high speeds, a proper, constant feed rate is essential in
order to minimize potentially severe vibration that could
cause equipment damage.
In all three processes that are used for target feed stream
purification, the requirements of the pump are precise:
constant, low-slip, and low-shear, low-pulsing flow. Any de-
viation from these requirements can result in deleterious
effects for the substance being handled, as well as damage
to the media that are used in the filter (membranes for TFF
and resins for chromatography columns), which are costly.
Improper flow and transfer rates can also produce the un-
balanced operation that results in a damaged centrifuge.
SINGLE-USE PUMPS NEEDED
One key manufacturing trend that can reduce develop-
ment cost and increase speed-to-market is the adoption
of single-use technologies. In certain cases, permanent
stainless-steel process lines are very costly to set up, lack
the production flexibility in biologic development, and
have complex and time-consuming cleaning and validation
requirements. Therefore, much expense and time can be
saved by simply starting each trial process with a fresh,
sterile set of single-use process-equipment components.
These components can consist of bags instead of stain-
less-steel vessels, special agitators instead of stainless-steel
shaft agitators, single-use tubing, coupling and valves in-
stead of their stainless-steel equivalents, and filter systems,
many of which are single-use by their very nature.
“Many of the leading filtration and purification system
designers worldwide prefer Quattroflow pumps; there’s a rea-
son for that,” said Jeff Blease, President of Triangle Process
Equipment, Wilson, NC, USA, a pioneering company behind the
PHARMACEUTICAL PROCESSING | OCTOBER 2013 17 ■
■ P H A R MP R O . C O M
■ B I OP HAR M
pp1310_feature_PSGpump.indd 17 9/18/2013 9:14:33 AM
■ P H A R MP R O . C O M
■ B I OP HAR M
■ 18 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
buying public as quickly as
possible, an additional $500
or more for a replaceable
pump head essentially be-
comes an attractive cost of
doing business. The total
cost of using a single-use
pump is less because the
cost to replace the head may
pale in comparison to the
cost of validating the clean-
ing (which can run in the
tens of thousands/millions
of dollars), plus the entire
cost to install a permanent
stainless-steel process line.
A common notion in this in-
dustry is that the cost of the
paper backing up the equip-
ment used is higher than the
equipment itself. The Quattroflow, by using
a standardized and documented single-use
variation, reduces that paper and cost.
For cases where the total cost of a per-
manent stainless-steel process line is more
attractive, the Quattroflow pump head can
be converted to a stainless-steel head with
the same controlled flow, low-shear, low-slip
and high-purity operation, with the addition
of desirable high-cleanability attributes.
CONCLUSION
Advances in the ability to produce and
use biologically derived drugs has created
an exciting opportunity for manufacturers
in the biopharmaceutical market. However,
while this continuing trend is packed with
possibilities, they can only be realized if
the development and manufacturing pro-
cesses for these products are optimized,
both in regards to speed-to-market consid-
erations and contaminant-free production
requirements. Single-use positive displace-
ment quaternary diaphragm pumps— can
dependably meets these challenges and
allows biopharmaceutical manufacturers to
confidently meet many of their most crucial
biologic-handling and manufacturing needs.
ABOUT THE AUTHOR:
Wallace Wittkoff is the Director, Global
Segment Marketing – Hygienic for Pump
Solutions Group (PSG®), Oakbrook Terrace,
IL, USA. He can be reached at +1 (502) 905-
9169 or Wallace.Wittkoff@psgdover.com. ■
As biologics go from development to
clinical trials and then to commercializa-
tion, proper scale up is essential. The same
pump technology in a lab needs to handle
flowrates as low as 1 L/hr (o.0047 gpm), as
well as commercial production flow rates of
20,000 L/hr (88 gpm) or more. This scale-up
capability assures that the pump’s opera-
tion does not adversely affect repeatability
and production rates.
Quattroflow pumps also possess the ver-
satility to be fitted with explosion-proof mo-
tors, DCA motors or air motors; essentially
you can drive Quattroflow pumps in any way
you can drive other pumps. Because of the
controlled low-slip aspect of this pump tech-
nology and high turn-down capability, this
pump also benefits from new generations of
vector drives for precision applications.
The essential element that Quattroflow
pumps help to contribute to speed to market is
the commonality of single-use configurations.
Basically, a single-use pump enables biophar-
maceutical manufacturers to optimize the cost
of cleaning and validating their pumps. The
result is not only a quicker production pro-
cess, but one that delivers preferred levels of
product purity and sterility with no chance for
cross-batch or cross-product contamination.
Single-use pumps that are made from
FDA/USP class VI conforming/approved ma-
terials also have a lower cost compared to
their stainless-steel counterparts. Further,
for example, with a 500-liter batch of bi-
ologics, which has a market value of $5
million-plus and the need to offer it to the
use of quaternary diaphragm
pump technology in the
Americas. “The Quattroflow
pump gives you the low
shear of a peristaltic pump
along with the low pulsation
and high-pressure capabili-
ties of rotary lobes without
the inherent dangers and
drawbacks of either technol-
ogy, such as burst tubing,
excessive temperature rise,
or rubber and metal shav-
ings contaminating the pro-
cess from upset conditions.”
THE SOLUTION
For a growing number,
the solution to the strict
single-use pumping require-
ments that are demanded in the biologics-fil-
tering process can be found in the positive
displacement quaternary diaphragm technol-
ogy that has been developed by the German
company, Quattroflow, which also introduced
to the market the single-use configuration for
use in critical product-handling applications
in the pharmaceutical and biotech industries
Quaternary diaphragms are driven one
after another by a connector plate, which
moves back and forth out of its central po-
sition in a stroke that is generated by an ec-
centric shaft, with the length of the stroke
determined by the angle of the eccentricity.
This technology has been modeled on the
operation of the human heart—which is
eminently capable of pumping whole human
blood, one of the most shear-sensitive prod-
ucts around—with its four pumping cham-
bers and check valves keeping product flow
constantly moving forward.
The Quattroflow’s pump chambers con-
tain no rotating parts that can be subject
to friction, meaning that there is no oper-
ational heat buildup that can compromise
the product. This mode of operation also
means that the pumps can run dry, are
self-priming, and produce little or no shear
because of low slip. In addition, they offer
low-pulsation, leak-free operation while hav-
ing great dry/wet suction-lift capabilities.
These pumps can provide constant flows
from 1 L/hr (0.0047 gpm) to 20,000 L/hr (88
gpm) with some of the highest turn up/
down capabilities in the industry.
pp1310_feature_PSGpump.indd 18 9/18/2013 9:15:08 AM
Xcellerex

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fermentor system
GE Healthcare
Life Sciences
What happens when you stir the benefits of
single-use technology and GE Healthcare Life Sciences‘
expertise into the field of microbial fermentation?
You get the only system available on the market offering
purpose-built performance and flexibility suited for
microbial fermentation. It’s optimal design maintains
high-mass transfer, provides exceptional
temperature control, and increases gas
dispersion — all with the added benefits
of single-use technology.
To download the application note, or
to inquire about our complimentary
process modeling service, visit:
www.gelifesciences.com/xdr-50mo
Xcellerex, imagination at work and GE monogram are
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© 2013 General Electric Company – All rights reserved.
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largest pharmaceutical market by 2020, after the US and China.
Despite its strong economic growth, Brazil is facing increasing
pressure to control healthcare expenditure and, at the same
time, to promote innovation and improve access to healthcare.
In pursuit of this difficult task, decision-makers are dis-
cussing several initiatives, some of them already converted
into law, which will reshape the pharmaceutical market in the
next few years. In the context of increasing competition and
stricter regulatory hurdles, Brazil will become a much more
challenging business environment.
DECREASING TAXATIONS ON PHARMACEUTICALS
Even though international companies operating in the
Brazilian healthcare market represent approximately 20 per-
cent of the total healthcare manufacturers based in Brazil,
they represent 75 percent of market share.
Decreasing taxation on medicines for human use is seen
as an effective way to promote and incentivize the 550+ lab-
oratories in the internal pharmaceutical sector. Two different
measures adopted in the last year confirm this strategy:
1) On November 28, 2012, the Brazilian Committee on
Constitution, Justice and Citizenship approved a replace-
ment bill proposing a constitutional amendment that would
prohibit the collection of taxes on medicines for human
use. The import tax, however, will remain in place as it
“serves as an instrument of government economic policy,
which should continue providing the flexibility to manoeu-
■By Davide Zaganelli, Global Emerging Markets Manager, Alliance Life Sciences
E
Emerging markets are considered the new frontier for pharma-
ceutical companies, and represent hope for an industry seek-
ing new strategies and partnerships to balance the stagnation
in more mature markets. With expectations of reaching 30
percent of the nearly $1.2 trillion US global spend -- and 50-70
percent of the $70 billion annual US growth forecasted in the
pharmaceutical sector by 2016 -- it is clear why emerging mar-
kets present an enticing opportunity for pharma.
But emerging markets defy the effectiveness of a uniform
approach and call for local business planning based on a com-
prehensive and global perspective. For this reason, interna-
tional pharmaceutical companies must be willing to implement
market-specific strategies and local thinking within their global
business strategy. Furthermore, evolving political stances, in-
creasing international competition, and rising local manufactur-
ers are toughening market access environments and creating
new, and sometimes unexpected, risks for drug makers.
Brazil provides one of several examples in which business
conditions for drug makers are quickly changing, emphasizing
the importance of identifying, evaluating, and foreseeing such
changes as early as possible in order to improve and consoli-
date market positioning.
LATEST REFORMS AND NEW CHALLENGES
With over $220 billion of healthcare expenditure, strong eco-
nomic growth, and drug prices adjusted annually (2.7-6.31 percent
increase estimated in 2013), Brazil is destined to become the third
■EMERGING MARKETS
■ P H A R MP R O . C O M
Pharmaceutical Access in Emerging Markets
How the latest developments in Brazil will change your business strategy
■ 20 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
t
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Number of generic drugs registered in Brazil
pp1310_feature_globalbusiness.indd 20 9/18/2013 9:19:22 AM
vre its rates and the need to protect the domestic market
from indiscriminate entry of foreign products.”
2) On March 13, 2013, a tax deferral measure was officially pub-
lished to suspend goods circulation taxes in the state of São
Paulo for domestic products and imported pharmaceutical
ingredients or intermediate drug products purchased by the
Foundation of Popular Medicines (Fundação para o Remédio
Popular). The Foundation is linked to the Department of
Health of the state of São Paulo and is responsible for devel-
oping, producing and distributing pharmaceutical products
in Brazil. This rule is valid for imported generic or biosimi-
lars not yet available in the country.
SEEKING NEW PARTNERSHIPS
Brazil recognizes that the development of technology in
healthcare is necessary to strengthen national industrial man-
ufacturing, reduce dependency on product importations and
achieve better control over expenditure.
To date, 34 technology transfer partnerships between pub-
lic and private laboratories have been agreed upon for the
production of 28 drugs (including Pramipexole, Tenofovir,
Clozapine, Quetiapine, Olanzapine, Tacrolimus, Rivastigmine,
and Donepezil), and three vaccines. According to the Ministry
of Health, at least 20 new partnerships are expected over the
next four years, including biological products and medical
devices.
For instance, in October 2012, Boehringer-Ingelheim and
the Institute of Drug Technology (Farmanguinhos) agreed
on a partnership for the local production of Pramipexole for
Parkinson’s disease treatment. Boehringer-Ingelheim will sup-
ply the active ingredient that Farmanguinhos will convert into
tablets. The expectation is to produce internally 50 percent of
the country’s demand by 2016 and 100 percent by 20181.
In the medium- and long-term, stakeholders are not only
seeking internal development, but they are also hoping to
increase competitiveness of Brazilian pharma companies
abroad. A further step in this direction was made earlier
this year when Brazil’s President Dilma Rousseff announced
that the recently created Brazilian Enterprise for Research
and Industrial Innovation (Embrapii) will be responsible for
promoting partnerships between public innovative research
institutions and private companies to create new products
and processes.
INCREASING GENERICS MARKET SHARE
Generics were introduced in Brazil 30 years ago, and met
with general consumer and prescriber distrust. Today, gener-
ics market share in Brazil is still lower than in other markets,
e.g. 26 percent in 2012 compared to 66 percent in Germany,
and 60 percent in the UK and US, but it is expected to in-
crease to 45 percent by 2020. According to the Pro-Generics
association, by the end of 2013 the market share of generic
drugs should increase to 30 percent.
The Brazilian government is aggressively promoting the
use of generics and seeking to further increase confidence in
patients and prescribers by ensuring rigid quality controls
and lower prices. With a price at least 35 percent cheaper
than brand-name drugs, and with several Brazilian companies
operating in the sector, generic manufacturing was identified
as an ideal way to increase budget control and boost local
manufacturing.
WHAT DOES THIS MEAN FOR YOUR COMPANY?
In the coming years, the favorable healthcare environment
will allow local companies and generic drug makers to rapidly
increase their market share and negatively impact on inter-
national manufacturers of branded products. Moreover, key
decision-makers are expected to adopt stricter regulatory,
pricing and reimbursement regulations to further develop in-
ternal pharmaceutical manufacturing.
As a direct consequence, market access in Brazil will be-
come increasingly challenging for international pharmaceuti-
cal companies, making it necessary for global businesses to
evaluate and adapt their business strategy to local realities.
Strategic offerings, including technology transfer agree-
ments, will be a key factor to secure continued market sales
growth in the next few years. International pharmaceutical
companies should also consider financial/outcome-based
pricing agreements and other alternative approaches to meet
the increasing demand for access to healthcare without im-
pacting excessively on budget.
Keeping track of legislative, pricing and reimbursement
changes, foreseeing how competitors’ launches will impact
your portfolio, and linking Brazil to global decisions and in-
ternational referencing pricing are essential for identifying
and bending gaps and trends that shape the pharmaceutical
market in your favor.
REFERENCES
1 http://www.brazilpharmanews.com; Accessed 19th April
2013
2 ANVISA and brazilpharmanews; Accessed 19th April 2013 ■
■ P H A R MP R O . C O M
PHARMACEUTICAL PROCESSING | OCTOBER 2013 21 ■
Despite its strong economic growth, Brazil is facing increasing pressure to
control healthcare expenditure and, at the same time, to promote innovation
and improve access to healthcare.
pp1310_feature_globalbusiness.indd 21 9/18/2013 9:34:38 AM
Field Portable NIR
Spectrometer ᭤
The SM-3500 field por-
table NIR spectrometer
can help combat coun-
terfeiting by allowing
identification and
authentication using
spectral matching and
principal component
analysis. Steps involved in
these measurements include
taking sample spectra of authentic drugs to form a known reference
and checking target drugs against those spectra for authentica-
tion. The SM-3500’s portability makes it well-suited for counterfeit
screening applications, as it can be used at manufacturing facilities,
warehouses, hospitals, pharmacies and field locations for govern-
ment agencies. The UIV/VIS/NIR/SWIR range of the SM-3500 across a
350-2500nm spectral range, allows it to deliver a number of benefits
including minimal or no sample prep, rapid analysis — as quickly as a
sample per second, non-destructive – analysis can be performed with
the drug still in its packaging, information on structural and chemi-
cal characteristics can be measured, and criminal and sub-standard
counterfeits can be identified. It also has third party chemometrics
analysis programs can be used to provide more quantitative analy-
sis of active ingredient concentrations and excipients, useable with
physical/chemical identifiers/markers in genuine drugs and it is e
asy-to-use, potentially operated by non-scientific personnel. ■ Spec-
tral Evolution , Lawrence, MA 01840. www.spectralevolution.com or call
978-687-1833
Vision Module ᭤
The LabelSync

450
Vision Module is de-
signed to capture and
sync a bottle’s unique
serialized label with its
individual line code. The ma-
chine can handle bottles 30-1500
milliliters in volume at speeds up
to 300 per minute. Seamlessly
compatible with a wide range of
serialization software and vision
components, the LabelSync 450
verifies each code’s readability,
confirms that each bottle belongs on the
line (line security), establishes a one-to-
one relationship between the two codes, and enables high-integrity iden-
tification processes downstream. The LabelSync 450’s vision system is
comprised of four cameras whose combined viewpoints offer 360-degree
label inspection, as well as a fifth camera to read secondary line code.
The stainless steel module’s transfer belts are servo-controlled, and its
height adjustment is quick and repeatable. The LabelSync 450 can be
equipped with its own print capability, so that it can print, inspect, and
synchronize codes all in one efficient footprint. LabelSync 450 can print
on the bottom of bottles, as well as on caps and topserts; this versatility
helps enable secure end-of-line aggregation. In the process, the module
codes the bottles, verifies these codes’ readability and commissions the
codes for tracking. Should a top or bottom code not be required at the
unit level, Labelsync 450 also can be used to track loose bottles heading
into a case packing station. ■ Omega Design Corporation, Exton, PA 19341.
www.omegadesign.com or call 800-346-0191


v
v
■ WHAT' S HOT
WHAT’S HOT
■ P H A R MP R O . C O M
■ 22 OCTOBER 2013 | PHARMACEUTICAL PROCESSING P
᭣ Single-Use Laboratory Bioreactor
The UniVessel
®
SU is a second generation of single-use bioreactor. This single-use stirred tank
bioreactor can be operated in a choice of working volumes ranging from 0.6L to 2L, and it is
suitable for the cultivation of mammalian cells, including stem cells, insect and plant cells.
Typical areas of application for the UniVessel
®
SU are process development and optimiza-
tion, as well as production of seed cultures and cell banks. It combines the proven design
of conventional glass vessels with the efficiency and flexibility of single-use systems.
Supplied as a completely preassembled and presterilized unit, this laboratory bioreactor is
instantly ready to use right out of the box. It eliminates the need for labor-intensive steps,
such as autoclaving or installation of probes, minimizing the time needed for preparation.
The new UniVessel
®
SU can be used interchangeably with glass vessels to help laborato-
ries better manage peak workloads despite challenging timelines. Each UniVessel
®
SU is
equipped with integrated single-use sensors for pH and dissolved oxygen measurement. ■
Sartorius Stedim Biotech , Bohemia, NY 11716. www.sartorius.us or call 631-254-4249
R
n
ude
ma-
30-1500
eeds up
essly
ange of
d vision
nc 450
ability,
belongs on the
i h t
pp1310_whatshot.indd 22 9/18/2013 9:06:08 AM





Braid-Reinforced Silicone Hose ᭤
Silicone hose is reinforced for enhanced pressure capabilities.
Called APSH, its applications include those in the pharmaceutical
process industry. APSH is braid reinforced and ad-
dresses applications involving greater flow
volume needs - those where the fluid path
must handle a higher pressure rating than
unreinforced tubing is able to. The braiding
also gives the user a much higher safety factor if there’s concern that
the pressure-handling ability of unreinforced tubing may be marginal
for the intended application. APSH hose is suitable for air transfer as
well as fluid and works within a wide range of temperatures: 100°F
(73°C) to 400°F (204°C). ■ AdvantaPure, a Division of NewAge Industries ,
Southampton, PA 18966. www.advantapure.com or call 888-755-4370
Fabricated
Vessels ᭤
High-quality tanks and ves-
sels are used for a wide range
of processes and industries.
Fabrication projects of virtually
any size or complexity can be
completed with greater effi-
ciency and faster deliveries.
Fabrication capabilities include
vessel capacities up to 100,000
gallons, vacuum and/or high
internal pressure design, and
variable speed agitators. There
are many choices for materi-
al of construction available
including carbon steel, stain-
less steel, aluminum, titanium, Monel, Hastelloy and Inconel. They
include custom ports, manways and nozzles. The tanks and vessels
have heating/cooling jacket or coils, heat tracing, and sheathing and
insulation. They have a sanitary design as well as special coatings and
tank liners. The units meet code requirements such as ASME, USFDA,
BISSC, ABS, API650, API620 and U142. ■ Ross Engineering Inc. , Savannah,
GA 31405. www.mixers.com or call 800-524-7677

■ PHARMPRO. C OM
■ WHAT' S HOT
PHARMACEUTICAL PROCESSING | OCTOBER 2013 23 ■
Ampule Filling
and Sealing
Machine ᭤
The RSF3L has a capacity
of up to nine thousand
ampules an hour, and it
offers features to satisfy
the demands for liquid
products in a sterile envi-
ronment. It has perfect re-
peatability of the ampule
filling and sealing, simple
and quick size change-
overs, and the possibility
to easily connect it to a
sterilization tunnel installed upstream from the machine itself. The
structure of the machine facilitates efficient cleaning, which is import-
ant for this particularly delicate product. Glass fragments do not enter
the ampule feeding lines because, if there are any, they drop into the
basin in the bottom of the machine. The filling unit installed on the ma-
chine’s work surface is easy to dismantle and sterilize. The ampules are
automatically loaded directly from boxes or open-sided baskets onto
the conveyor where they are held firmly in position by a support. From
here, they are subsequently transferred by a continuous-motion scroll
to a variable speed star wheel and then to the rake conveyor. Ampule
presence on the rake conveyor is controlled electronically on the neck.
Sterilization-In-Place (SIP) of the entire dispensing system. ■ Marchesini
Group, Pianoro (Bo), Italy. www.marchesini.com or call +39 051.651.87.11



᭡᭡᭡᭡


ure capabilities.
the pharmaceutical
d ad-
pp1310_whatshot.indd 23 9/24/2013 8:57:20 AM
T
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s
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B
iopharmaceuticals continue to be a growing,
important class of pharmaceutical products on
the market, and many of these products are pro-
duced using mammalian cell culture. Monoclonal
antibodies, currently the dominant class of biopharmaceu-
ticals, generally require mammalian cell culture production
to enable addition of critical post-translational modifications
such as glycosylation. Since these products are often given
to patients at high doses, total bulk drug requirements for
a single product can be as high as 7,000 kg per year. When
monoclonal antibodies first entered the market, there was
significant concern over the ability of the industry to pro-
duce enough product to treat eligible patients worldwide.
To be able to meet this high demand, the industry has
developed cell line development and cell culture technolo-
gies that improve the overall performance and viability of
production cell lines in the bioreactor. This article reviews
emerging approaches to improving biopharmaceutical pro-
duction cell lines and cell culture performance through the
application of genomics and related technologies. Together
these technologies are positioned to cause significant
changes that will enable each and every mammalian cell cul-
ture run to provide high yields of biopharmaceutical prod-
ucts with desired quality attributes.
INTRODUCTION
Demand for biopharmaceutical products, especially mono-
clonal antibody-related products, continued to grow at a
very healthy pace in 2012 with total biopharmaceutical sales
reaching nearly $130 billion, or approximately 13% of the total
pharmaceutical market
1 2
. In 2012, there were 34 biopharma-
ceutical “blockbuster” products with annual sales over $1
billion, of which over 60% were produced in mammalian cell
culture. Five of the top ten selling pharmaceutical products
are now biopharmaceuticals, four of which are monoclonal
antibodies
3
. These products, Humira, Enbrel, Remicade and
Rituxan, combined with Avastin, Herceptin and the long
list of monoclonal antibody products in development make
monoclonal antibodies the fastest growing class of biophar-
maceutical products. In addition, as the patents governing
the exclusive rights to many of these blockbuster biophar-
maceutical products begin to expire, the pharmaceutical in-
dustry worldwide has shown a growing interest in developing
follow-on biologics or biosimilars to provide lower cost alter-
natives to the current innovator products on the market.
Despite the growing market demand for innovator and
biosimilar biopharmaceutical products and the associated
requirement for increasing amounts of mammalian cell culture
capacity to meet this demand, ongoing advances in cell culture
process yields coupled with significant expansion of manufac-
turing capacity in the last decade, have enabled the industry to
meet the market demand for these products to date. However,
as these advanced medicinal products reach expanded mar-
kets worldwide and as newer, higher dose innovator products
progress through clinical trials and onto the market, additional
advances in cell line development and cell culture technology
will be required to continue to produce enough product using
the available mammalian cell culture capacity.
Cell line development and cell culture advances in the past
2-5 years include many orthogonal approaches to improve
expression levels and productivity in the bioreactor. These
include improvements in the parental cell lines, advances in
genetic methods to improve gene expression through a vari-
ety of means, improved media and feed composition, alterna-
tive supplements or analysis to enable enhanced productivity
in the bioreactor, and single use bioreactors that enable di-
versified manufacturing strategies and local production. Each
of these advances utilized alone or in conjunction will con-
tribute to improvements in supply of bulk biopharmaceutical
products over the next decade and will enable these life-sav-
ing medicines to reach greater patient populations worldwide.
Using Genomic Analysis
Trends to improve mammalian cell culture for biopharmaceutical production
■ By Susan Dana Jones, Ph.D., Vice President and Senior Consultant, and Dawn M. Ecker, Consultant,
BioProcess Technology Consultants
■ 24 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M ■
■ C E L L C UL T UR E

Figure 1. Total sales in the US and Europe of traditional pharmaceuticals (blue) and biopharmaceuti-
cals (green) are shown by year for the past decade. Sales information was obtained from company
annual reports and other publically available sources.
pp1310_feature_BPTC.indd 24 9/18/2013 9:49:03 AM
protein expression. Of the 392
proteins that were identified
in the proteomic analysis, 32
were differentially expressed.
In the high-producing cell cul-
ture, several proteins related to
protein metabolism were up-regu-
lated, including eukaryotic translation
initiation factor 3 and ribosome 40S.
In addition, several intermediate filament
proteins such as vimentin and annexin, as well
as histone H1.2 and H2A, were down-regulated in the
high producer. These studies provide additional insight into
methods to engineer host CHO cell lines for better growth,
viability, and transgene expression.
Nicolas Mermod’s group at the University of Lausanne
have focused their efforts on understanding the mechanism
of transgene recombination into the genome during the initial
phases of cell line development and the secretory pathway
functions that are essential for cell health and productivity of
the secreted product encoded by the transgene.
8
This work
could lead to advances at the cell line development stage that
could create production cell lines with greater genetic stabil-
ity, cell health, and ability to produce the desired protein.
Many mechanisms for integration of transfected plas-
mids into mammalian cell genomes such as CHO cells have
been suggested in publications, but none of the proposed
mechanisms explains the results that are obtained when
analyzing the genomes and transgene structures of CHO pro-
duction cell lines. In collaboration with the Swiss Institute of
Bioinformatics and Selexis SA, a cell line development and
engineering company co-founded by Dr. Mermod, his group
has evaluated the data from CHO cell production cell lines
and proposed a novel molecular integration model that may
explain transgene integration. Dr. Mermod’s laboratory is cur-
rently evaluating this model and has shown that when they
block competing recombination pathways and use plasmids
containing matrix-attachment regions, transgene expression
levels are significantly increased compared to control cul-
tures. Therefore, the integration model they have developed
has some scientific merits, and it also may have a practical
value to allow improved methods for cell line construction.
9

Overall, the studies of the CHO genome and differential ex-
pression have successfully identified target pathways for molec-
ular engineering of the parental cell lines and for identification
of high producers using biomarkers. Exploitation of these ad-
vances in cell line engineering has only recently been initiated
within the industry but the productivity impact on newer CHO
production cell lines can already be seen. For example, Selexis
has recently launched a series of engineered versions of their
host CHO-M cell line designed to address many of the secre-
tory bottlenecks associated with difficult to express proteins.
10
Leveraging their knowledge of the CHO-M cell line genome
and transcriptome, Selexis identified potential issues with the
CHO-M secretory pathways such as stalled translocation, im-
IMPACT ON CHO CELL LINE ENGINEERING
In the past decade, numerous companies and academic
groups have focused significant efforts on using genomic,
proteomic, and transcriptomic studies to generate a complete
understanding of CHO cell biology under different conditions.
The hope and promise of these studies was that they would
provide actionable results that could facilitate CHO host
cell and production cell line engineering for greater viability
and productivity, and could contribute to better control of
overall performance in the bioreactor. Goals of these studies
included identification of unique biomarkers that indicate
better performance or identification of targets for knock-in
or knock-out cell line engineering. Since a rapid rate of cell
growth to achieve maximum biomass quickly and sustained
viability throughout the culture should lead to greater pro-
duction of the desired protein from a bioreactor, many of the
studies focused on achieving one or both of these goals. The
publication of the CHO genome in 2010
4
provided the exten-
sive information that is necessary to implement such studies
and reach actionable conclusions.
Colin Clark and his colleagues at the National Institute for
Cellular Biotechnology in Dublin, Ireland, have published nu-
merous studies on differential expression analysis in a vast
number of production CHO cell lines. These studies have in-
cluded proteomics, transcriptomics, and microRNA (miRNA)
analysis to filter out false positive and false negative results and
obtain a clear understanding of those genes that are actively
involved in enabling high viability and productivity of CHO
production cells in culture. In one such study, Doolan et al.
5

performed microarray and proteomics analysis of CHO cells to
identify specific genes that contributed to faster cell growth.
The analysis of mRNA levels and protein levels was performed
on two CHO production cell lines that expressed the same
transgene but grew at different rates. They report that they
identified 118 transcripts and 58 proteins that were expressed
at different levels in the two cell lines, and of those 21 gene can-
didates showed up in both sets. By using silencing RNA (siRNA)
to inhibit expression of selected gene candidates, the group
found that a protein known as valosin-containing protein (VCP)
is a major contributor to CHO cell growth and viability. VCP is
therefore one example of a protein that could be manipulated
by engineering parental or production CHO cell lines to im-
prove growth and viability. In another publication by the same
group, Sanchez et al.
6
showed that the tumor suppressor MiR-7
also appears to inhibit proliferation of CHO cells in culture.
Therefore, inhibition of MiR-7 is another approach to improving
cell growth and viability in the bioreactor.
Carlage et al.
7
studied the impact of a known inhibitor
of apoptosis, Bcl-X(L), on expression patterns of host cell
genes in a CHO cell line that was expressing a transgene.
Production CHO cells transfected with the gene encoding
this apoptosis inhibitor had higher levels of transgene
expression than a parallel non-transfected culture. Using
proteomic analysis, the two cell lines were compared at
various times during cell culture to identify any differential
gu-
slation
40S.
e filament
annexin, as well
down-regulated in the


■ P H A R MP R O . C O M
PHARMACEUTICAL PROCESSING | OCTOBER 2013 25 ■
■ P H A R MP R O . C O M
■ C E L L C UL T UR E
pp1310_feature_BPTC.indd 25 9/18/2013 9:49:20 AM
■ P H A R MP R O . C O M
■ C E L L C UL T UR E
Corporate/Press%20Room/Top-Line%20
Market%20Data%20&%20Trends/Top_20_
Global_Products_2012_2.pdf
4 Xu X et al. “The genomic sequence of the
Chinese hamster ovary (CHO)-K1 cell
line,” Nat Biotechnol. 2011;29(8):735–741
5 Doolan P. et al. “Microarray and Proteomics
Expression Profiling Identifieds Several
Candidates, Including the Valosin-
Containing Protein (VCP), Involved in
Regulating High Cellular Growth Rate in
Production CHO Cell Lines,” Biotechnol
Bioeng. 2010 May 1;106(1):42-56
6 Sanchez, N. et al. “MiR-7 triggers cell cycle
arrest at the G1/S transition by targeting
multiple genes including Skp2 and Psme3,”
PLoS One. 2013 Jun 6;8(6):e65671. doi:
10.1371/journal.pone.0065671. Print 2013
7 Carlage T. et al. “Proteomic profiling of a
high-producing Chinese hamster ovary cell
culture,” Anal Chem. 2009 Sep 1;81(17):7357-62
8 Mermod, N. “CHO genome sequencing and
engineering to improve clone selection and
expression” Presented at IBCUSA Cell Line
Development and Engineering Conference,
20-22 May, 2013, La Jolla, CA
9 Dr. Nicolas Mermod, Personal communication
10 Dr. Pierre-Alain Girod, Personal communi-
cation ■
tion cell line allowing for better understanding
of culture conditions and paving the way for
maximum productivity of the cell line. With
these industry-wide advances in understand-
ing CHO cell biology and their application to
the production of biopharmaceuticals, the
industry continues to evolve to more efficient,
more productive, and more robust cell culture
approaches that should be able to meet the
growing demand for these products.
REFERENCES
1 Data derived from the BioProcess
Technology Consultants
Biopharmaceutical Database.
2 IMS Health Inc. Total Unaudited and Audited
Global Pharmaceutical Market, 2003 – 2012
[Internet]. Danbury (CT): IMS Health Inc;
2013 Aug [cited 2013 Aug 13]. 1 p. Available
from: http://www.imshealth.com/deployed-
files/imshealth/Global/Content/Corporate/
Press%20Room/Total_World_Pharma_
Market_Topline_metrics_2012.pdf
3 IMS Health Inc. Top 20 Global Products
2012 [Internet]. Danbury (CT): IMS Health
Inc; 2013 Apr [cited 2013 Aug 9]. 1 p.
Available from: http://www.imshealth.
com/deployedfiles/ims/Global/Content/
proper folding, incomplete post-translational
modifications or insufficient cellular respi-
ration to handle the increased protein load.
They then used transposon-based vectors to
express over 100 different auxiliary proteins
which could overcome secretion bottlenecks
associated with the CHO-M cell line and built
combinatorial CHO libraries containing differ-
ent combinations of these proteins. Using the
resulting SURE CHO-M Library, Selexis was
able to boost productivity of a non-natural
mini-body by over 10 fold without any changes
in gene copy number or transcription levels.
Such improvements are emerging throughout
industry as it exploits the wealth of data that
has recently become available through genom-
ics and associated technologies.
CONCLUSION
As more products enter the market and as
biopharm sales expand into new geographic
areas, mammalian cell culture must become a
more efficient production method to meet this
continually increasing market demand. Many
have recognized this need for improvement in
cell culture and have made significant efforts
in understanding and engineering the produc-
W
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r
e

I
n
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o
v
a
t
i
o
n

F
l
o
w
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Quattrofow

positive displacement quaternary (four-piston) diaphragm pumps
ofer high purity, containment and one of the highest turn up/down capabilities in
biologics and pharmaceutical production applications.
Scale-up capability assures pump operation does not adversely afect results
Constant fow rates from 1 L/hr (0.0047 gpm) to 20,000 L/hr (88 gpm)
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Ensures product safety, efciency and reliability
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pp1310_feature_BPTC.indd 26 9/18/2013 9:49:37 AM
Nano Particle Size and Zeta
Potential Analyzer
The NanoPlus utilizes photon correlation
spectroscopy and electrophoretic light
scattering techniques to determine particle
size and zeta potential. Compact and easy
to use with an extended analysis range,
intuitive software, and multiple sample cells
to fit the user’s application, the instrument
can measure particle size in the range of
0.1 nm to 12.30 µm with sample suspension
concentrations from 0.00001% to 40% and
zeta potential of sample suspensions in the
-500 mV to +500 mV range with concentrations from 0.001% to 40%. The instrument is available
in three model configurations: a nano particle sizing instrument; a zeta potential instrument;
and a combination nano particle sizing and zeta potential instrument. The NanoPlus has an
array of compatible sample cells for both zeta potential and nano particle size measurements.
The optional NanoPlus AT automatically controls the pH of sample suspensions and conducts
titrations in a pH range from 1 to 13. ■ Micromeritics Instrument Corp. , Norcross, GA 30093.
www.micromeritics.com or call 770-662-3688
■ PHARMPRO. C OM
PHARMACEUTICAL PROCESSING | OCTOBER 2013 27 ■
■ I NNOVATI ONS
Energy Management System
The company has been working with its clients to solve humidity and moisture control chal-
lenges specializing in pharmaceutical process applications including gel cap production, pill
production, moisture regain prevention, packaging, and storage applications. The dehumidifi-
ers precisely control the environmental conditions by independently controlling temperature
and humidity levels eliminating moisture problems while increasing product consistency and
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Abrasive Cloths
ABRATEC™ abrasive cloths are made with vari-
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fabric. The two sided cloth remediates
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fabric is durable and abrasion resistant. This
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ogy allow the Quiltec side to remove sanding
debris without contributing additional particles
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cloths are designed to work with solvents, in-
cluding IPA/water blends, improving the ability
to remove biofilm buildup. Cloths are also avail-
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helps maintain the integrity of sterile environ-
ments. ■ Contec, Inc., Spartanburg, SC 29303.
www.contecinc.com or call 864-503-8333
EQUIPMENT
CLEAN ROOM
Integrated Custom Air Handler
Dehumidification System
The Integrated Custom Air Handler (ICA)
dehumidification system simplifies the integra-
tion of a desiccant dehumidifier with other air
conditioning components. ICA is customizable
to multiple configurations, offers ten rotor sizes,
seven desiccant options, and a range of stan-
dard components engineered for maximized
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pp1310_innovations_cleanrooms.indd 27 9/24/2013 9:07:22 AM
T
oday, all pharmaceutical and biopharmaceutical
companies follow testing requirements which set
standards for inspection of visible particulates,
and also for examining the size and quantity of
sub-visible particulates in final products. These quality con-
trol mechanisms are typically employed at the end of the
production cycle, and are typically done via optical inspec-
tion. However, pharmaceutical developers and manufactur-
ers are finding that they need the high resolution provided
by a scanning electron microscope (SEM) to characterize,
control, and elementally quantify the size and shape of
these particles.
In particular, the con-
tinuing trend toward
smaller particles for
active pharmaceutical
ingredients (API), and
better quality of the final
product, has pushed particle dimensions into the sub-mi-
crometer regime, which is beyond the capability of optical
measurement tools.
1

This article will review some different types of unwanted
particulate matter found in pharmaceutical products and
the advantages of using scanning electron microscopy with
energy dispersive spectrometry (SEM-EDS) as a means to
fully characterize particle matter during the manufacturing
process. In addition, periodic sampling of the final product
for the active matrix and coating thickness will be pre-
sented.
PARTICLE CONTAMINATION
Particulate matter can range in size from sub-microns
up to several hundreds of microns. In most cases, parti-
cle size distribution and total count are required. Foreign
particles or particulate matter in drug powder products
is an area of extreme concern. Unwanted particles should
be controlled and their sources identi-
fied. Contamination due to an excessive
amount of particulate matter in pharma-
ceutical products might lead to quality
and safety problems. Particle contamina-
tion in manufacturing sites might even re-
sult in the suspension of production.
Scanning electron microscopy provides
visual information about the organic and
inorganic submicron particles (size, shape,
and morphology), and also chemical iden-
tification based on the X-ray energy lines.
TYPICAL SOURCES OF PARTICLE
CONTAMINATION
Depending on the nature of the sample
(organic, inorganic, or metallic), and the
type of information desired, the imaging
and chemical characterization capabilities
of SEM-EDS lead many pharmaceutical
laboratories to use this technology to
evaluate morphology, size, shape, and
elemental composition of metallic and or-
ganic sub-visible particles.
Sources of particulate matter vary
Scanning Electron
Microscopy Services
SEM offers the quality control needed for ever smaller API particles
■ By Gary Brake, Marketing Manager, SEMTech Solutions
■ 28 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M ■
■ MI C R OS C OP Y
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Above: Figure 1. SEM Images and EDS spectra of common
pharmaceutical contaminants.
Right: Figure 2. Backscattered electron image and EDS map
of a multi-vitamin cross-section.
pp1310_feature_SEM.indd 28 9/18/2013 9:04:21 AM
Above: Figure 3. Oxygen (O) EDS map of the
multi-vitamin in Fig. 2.
Right: Figure 4. Coating thickness of an ibupro-
fen tablet.

■ P H A R MP R O . C O M
depending on the development process, equipment used,
location, and overall facility cleanliness. But, even the clean-
est rooms can produce particulate matter shed by gowns,
gloves, skin, sample preparation equipment, and glassware.
Containers and closures, specifically rubber closures, con-
tribute particulate matter due to leaching, chemical reac-
tions, friction, and changes in physical properties.
Some of the most common materials identified in pharma-
ceutical environments are stainless steel, silica, aluminum,
salts, minerals, organic fluorinated compounds, and carbo-
naceous materials in varying sizes and shapes.
2
SEM Images
and EDS spectra of some of these particles are shown in
Figure 1.
ACTIVE INGREDIENTS IN PHARMACEUTICAL
TABLETS
Pharmaceutical tablets are composed of a number of
different materials, each of which is designed to improve
performance. The Active Pharmaceutical Ingredient (API) is
intended to act on the particular disease or the symptoms
of the disease. The other components, referred to as ex-
cipients, act as fillers, bulking agents, tablet disintegrants,
and tablet coatings (to protect the core and to mask taste).
Consistent performance of the tablets depends directly
upon the amount of each excipient in the tablet.
During development, it is useful to have a means to in-
vestigate the distribution of excipients and API within the
tablet itself. The use of EDS maps and BSE (Back Scattered
Electron) images of tablet cross-sections are two related
means of directly examining excipient and API distribution
within a tablet. The example shown in Figure 2 highlights
the quantitative methods using a multi-vitamin tablet as a
test case using a backscatter image of the tablet cross-sec-
tion along with the accompanying EDS map.
3
In addition to visually seeing all of the elements, the EDS
system can provide quantification by percent of the total
elements as shown in Table 1. Of note in the table is the in-
corporation of oxygen that was purposely excluded from the
EDS map of Figure 2.
Since oxygen bonds tightly with other elements to form ox-
ides, it was left out of the comprehensive EDS map. Shown in
Figure 3 is the oxygen element EDS map in green. It is inter-
esting to note the various elements that the oxygen binds to
by overlaying Figure 3 on top of Figure 2. As a note, the green
that is shown in Figure 2, is the combination of the mutliple
colors from the Iron (Fe), Zinc (Zn), and Calcium (Ca).
QUALITY CONTROL
Besides monitoring for particulates in a production line,
and quantifying the API within the tablet, another quality
control check can be obtained by measuring thickness of the
tablet’s coating. Figure 4 shows the thickness value of a tab-
let coating from an Ibuprofen sample using a Back Scattered
Electron (BSE) Image.
Tablet coatings have numerous functions including
strengthening, controlled release,
ease of handling and packaging, pro-
tection of the tablet from moisture,
improved taste, facili-
tate swallowing, and to
provide tablet identity.
The adhesion of a
coating to the tablet
is influenced by the
strength of the interfa-
cial bonds between film
and tablet. Poor adhe-
sion results in peeling,
which reduces film func-
tionality. The mechani-
cal protection provided
by the coating can also
be compromised by loss of adhesion, leading to the accumu-
lation of moisture at the film-tablet interface. This could affect
the stability of moisture sensitive drugs.
SUMMARY
Implementing a SEM-EDS particle-characterization program
is a key step towards optimizing the design and therapeutic
effect of new pharmaceutical products, and controlling unde-
sirable contamination. SEM imaging provides the resolution
required to evaluate both the size and shape of nanometer
scale particles. The large depth of focus of the SEM reveals
fine surface detail, even over large, irregularly-shaped par-
ticles. SEM and EDS image-based particle analysis provides
qualitative and quantitative capabilities for nanoscale parti-
cles far beyond the capability of optical microscopy.
REFERENCES
1. Lich, B., Wilfen, U., 2009, When Size & Shape Matter, Drug
Discovery & Development. Vol. 12 Issue 2, p. 26
2. Vicens, M.C., 2012, A New Picture of Particles, Drug
Discovery & Development.
3. Carlton, R.A., 2010, Image Analysis of EDS and Backscatter
SEM Images of Pharmaceutical Tablets, Microscopy and
Microanalysis, v. 16 (Suppl2), p. 662-663. ■
PHARMACEUTICAL PROCESSING | OCTOBER 2013 29 ■
■ P H A R MP R O . C O M
■ MI C R OS C OP Y
Table 1. Quantitative Analysis of the Multi-vitamin Tablet
Elt. Intensity (c/s) Atomic % Conc Units
C 84.95 37.169 25.796 wt.%
O 93.39 49.951 46.179 wt.%
Mg 46.42 3.310 4.648 wt.%
Si 6.49 0.295 0.479 wt.%
Ca 233.44 8.133 18.834 wt.%
Fe 7.89 0.456 1.472 wt.%
Zn 6.54 0.686 2.593 wt.%
100.000 100.000 wt.%
pp1310_feature_SEM.indd 29 9/18/2013 9:04:43 AM
A powerful alternative for
pharmaceutical dosage forms
Polymer choices in pharmaceutical
dosage forms have always been a
balancing act between performance
and development time, and historically
has been shaped by the interactions
of gelatin. The first generation of
HPMC capsules, which relied on
a secondary gelling agent, were
recognized by formulators as having
issues with dissolution performance
and product stability. Fortunately, new
scientific discoveries in polymers and
capsule manufacturing have resulted
in the creation of the next generation
of capsules – one that offers better
performance and reduced development
time compared to gelatin and first-
generation capsules.
Capsugel, the market leader in research
and development in this area, is now
offering these second-generation HPMC
capsules under the trade name, Vcaps®
Plus capsules.
In a number of studies, Vcaps Plus
capsules have been shown to deliver
optimized compound stability and
predictable in vitro dissolution while
also helping to eliminate the complexity
in formulation development. Known
globally for their reliable and predictable
performance, Vcaps Plus capsules are
well suited for over-the-counter (OTC)
or off-patent products as well as for new
chemical entities (NCEs).
True pH and ionic media
independent performance
Traditionally, HPMC capsules were
created using secondary gelling agents
and ionic gel promoters, which have
been found to interact with dissolution
media and delay compound release
from the capsule. The activity of the
gelling agent kappa-carrageenan, for
example, is enhanced by potassium and
calcium cations contained in many foods.
The extent of the resulting delay in
dissolution time was shown in an in vitro
test in which caffeine-filled traditional
HPMC capsules were dissolved in a
number of dissolution media. In the
simulated normal acidic environment
of the stomach (pH 1.2 USP), 90%
of the caffeine was dissolved within
approximately 15 minutes (Figure 1).
Adding 2 g/L of potassium chloride
(KCl) to this medium resulted in no
dissolution after 15 minutes and a
caffeine dissolution between 70%
and 80% after more than one hour.
Increasing the KCl content to 9 g/L
delayed caffeine release even further,
with a dissolution rate of just over 10%
in 45 minutes. Results with simulated
milk fluid were equally disappointing.
Similar delays in dissolution times were
observed and attributed to carrageenan
in an independent study (Ku et al.,
2011). Of course, such long delays in
capsule dissolution are unacceptable
particularly for rapid-relief products.
Capsugel addressed this situation by
developing a proprietary new thermal
gelation manufacturing process for Vcaps
Plus capsules that eliminates the need for
gelling systems all together and provides
true pH and ionic media independence
in disintegration. In vitro tests showed
that these second-generation HPMC
capsules had similar rates of dissolution
at pH levels of 1.2 and 6.8 and with
simulated milk fluid, achieving a nearly
complete dissolution of the caffeine
contents within approximately 30 minutes
(Figure 2). Even adding 2 g/L or 9 g/L
of KCl to the dissolution medium did not
affect the performance of Vcaps Plus
capsules, with dissolution of over 90%
within 30 minutes, even under the most
disadvantageous condition.
These findings were supported by an
independent study that compared the
dissolution performance of traditional
and second-generation HPMC capsules
(Ku et al., 2011), and underscores the
superior performance of Vcaps Plus
capsules.
Ideally suited for moisture
sensitive compounds
While gelatin capsules have been
effectively used for over a hundred
years, due to their excellent flexibility and
highly desirable dissolution properties,
they are not typically the polymer choice
for moisture sensitive compounds. Vcaps
Plus capsules on the other hand have
a three-fold lower moisture content
than gelatin capsules and are less
hygroscopic. That equates to fewer
broken capsules due to brittleness and
less of a chance of drug degradation
compared to gelatin capsules.
Next generation HPMC capsules
greatly expand pharmaceutical uses
by Dominique Cadé, PhD
Advertisement
■ 30 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
pp1310_Capsugel_Content.indd 30 9/17/2013 9:57:36 AM
Improved stability at high and
low temperatures
Capsugel in-house studies and an
independent study conducted at Wyeth
(Ku et al., 2010) have demonstrated
the superior stability of Vcaps Plus
capsules. An exposure of up to one
week to temperatures ranging from
4°C to minus 18°C did not change the
appearance or performance of unfilled
Vcaps Plus capsules in closed high-
density polyethylene (HDPE) bottles.
The same stability was found with empty
Vcaps Plus capsules in fully-filled glass
bottles that were heated for 24 hours
to temperatures ranging from 40°C to
60°C.
In long-term storage condition studies,
including a 6-month storage at 40°C
and 75% relative humidity and 2 years
at either 25°C and 65% relative humidity
or 30°C and 70% relative humidity,
Vcaps Plus capsules disintegration and
dissolution characteristics remained
unchanged. The wider temperature
capabilities of Vcaps Plus capsules make
them the perfect choice for longer term
storage and when used in progressively
unpredictable home environments.
Superior machinability
Traditional and second-generation
HPMC capsule attributes have been
compared on many common high-
speed capsule filling machines (Ku et
al., 2010). With respect to filling and
rejection rates, Vcaps Plus capsules
performed much like gelatin capsules
and were superior to traditional HPMC
products. In addition, Vcaps Plus
capsules can be adapted for use with
liquid compounds.
Wide regulatory and industry
acceptance
Vcaps Plus capsules are manufactured
in certified ISO 9001 facilities and in
accordance with IPEC’s (International
Pharmaceutical Excipient Council) Good
Manufacturing Practice (GMP) Guide
for Bulk Pharmaceutical Excipients.
They are acceptable for use in
pharmaceutical and dietary supplement
oral dosage applications in major
markets of the US, Canada, EU, Japan,
and Australia. In addition, Vcaps Plus
capsules are certified Kosher Ko and
Halal by IFANCA, and are approved for
vegetarians by the Vegetarian Society.
References
Ku, S.M., Li W., Dulin, W., Donahue, F., Cadé,
D., Benameur, H., Hutchison, K., Performance
qualification of a new hypromellose capsule:
Part I. Comparative evaluation of physical,
mechanical and processability quality
attributes of Vcaps® Plus, Quali-V and
gelatin capsules. Int. J. Pharm. Vol. 15;
386(1-2):30-41, 2010.
Ku, M.S., Lu, Q., Li, W., Chen, Y., Performance
qualification of a new hypromellose capsule:
Part II. Disintegration and dissolution
comparison between two types of
hypromellose capsules. Int. J. Pharm. Vol. 15;
416(1):16-24, 2011.
0
10
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90
100
%

C
a
f
f
e
i
n
e

d
i
s
s
o
l
v
e
d
Time in minutes
0 3 6 9 12 15 18 21 24 27 30 35 40 45 50 55 60 75
Influence of gelling systems on HPMC capsules in dissolution testing
pH 1.2 USP
pH 6.8 USP
pH 6.8 JP2
Simulated milk fluid
pH 1.2 – 2 g KCI/L
pH 1.2 – 9 g KCI/L
0
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0 3 6 9 12 15 18 21 24 27 30 35 40 45 50 55 60 75
In vitro dissolution of caffeine in Vcaps
®
Plus capsules
pH 1.2 USP
pH 6.8 USP
pH 6.8 JP2
Simulated milk fluid
pH 1.2 – 2 g KCI/L
pH 1.2 – 9 g KCI/L
For more information about Vcaps® Plus capsules visit VcapsPlus.com.
Advertisement
Figure 1 Figure 2
PHARMACEUTICAL PROCESSING | OCTOBER 2013 31 ■
pp1310_Capsugel_Content.indd 31 9/17/2013 9:57:52 AM
T
he bottom line, it’s a hot topic for life sciences
companies fighting to stay competitive in today’s
pharmaceutical marketplace. More than ever, oral
solid dosage manufacturers are paying closer
attention to the overall operational costs of processing equip-
ment and not just the upfront capital cost of acquisition.
To stay on top of their game, pharmaceutical companies
are demanding manufacturing facilities that yield high-ef-
ficiency processing while lowering the overall cost of drug
development. This has resulted in continuous improvements
in the design of processing technologies, which has led to
operational cost savings and higher efficiencies.
Specifically, tablet coaters are undergoing technology ad-
vances that are increasing cost efficiencies and changing the
ways companies bring their solid dosage drugs to market.
NEW TABLET PAN GEOMETRY
The tablet pan may seem like a basic part of a coater, but
it’s playing an increasingly important role in the efficiency of
pharmaceutical campaigns. Different pan sizes and shapes
can affect the overall number of defects in a batch.
Traditional tablet pans are short in length and large in di-
ameter. This creates a thick tablet bed when solids are put in
the coater. A thicker tablet bed has a zone in the middle that
is slow moving, and tablets in this area do not get exposed to
the surface of the bed as often. That means it takes longer and
uses more coating solution to get the tablets fully covered.
Manufacturers of high-efficiency coaters have changed the
geometry of coating pans, making them longer in length and
smaller in diameter. With these pans, the tablet bed spreads
wider, so there is no slow-moving zone. Because the tablets
stay in constant motion, they enter the spray zone more often
for higher efficiency and better uniformity. The shallow tablet
depth also produces less static force on the cores. This re-
sults in gentler handling and less damage to the tablets.
A smaller diameter coating pan also prevents twinning, or
tablets sticking together in the tablet bed. Twinned tablets
must be sorted out and are often counted as rejects, which
impacts overall batch consistency. If the tablet bed is thin-
ner in the narrow pan, the tablets will stay in motion and
thus prevent twinning. This benefit is particularly valuable
to pharmaceutical companies manufacturing elongated or
flat tablets. These tablets are more likely to stick together
than their round counterparts.
Coaters Go High-Tech
Achieving high-quality oral solid dosage manufacturing through continuous
tablet coating improvement
■ By Martin Hack, Vice President and General Manager, L.B. Bohle, LLC
■ 32 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M ■
■ C OAT I NG
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Advances in tablet coating technology is leading to increased efficiencies for pharmaceutical
manufacturers.
pp1310_feature_coating.indd 32 9/18/2013 8:59:22 AM
■ P H A R MP R O . C O M
BETTER MIXING CAPABILITIES
Mixing is a prerequisite for homogenous and uniform
tablet coating. Tablet consistency is a large factor in quality
control and time-to-market for tablet drugs. To achieve high
uniformity tablets must be mixed adequately. For cosmetic
coatings drug manufacturers can typically get uniform tab-
lets with traditional coaters but the process is inefficient.
More time and coating solution are required, increasing the
operational costs of the manufacturing process.
For example, with conventional coaters, tablet weight
must increase 4 to 5 percent to achieve a uniform coat. But
through advances, the newest coaters achieve the same
coverage with only 1.5 to 2 percent weight gain. These ma-
chines also can achieve a 4 percent coefficient of variation,
which is better than any traditional coater.
High uniformity is also realized with the latest mixing
systems. The most advanced systems use spiral baffles to
constantly move tablets through the coating pan. One of the
baffles moves tablets to the back of the pan, while the other
brings them forward. The upper and lower baffles expose all
tablets to the spray equally. This enables higher spray rat-
ers, which shortens the time required to coat tablets in each
batch. Additionally, pharmaceutical manufacturers can attain
tablet homogeneity in each batch, with tablet coating unifor-
mity at less than 4 percent relative standard deviation (RSD).
AIR FLOW BED TECHNOLOGY
Conventional tablet coaters send air flowing from the top
or side of the coater. The air travels across the spray zone,
through the tablet bed and out of the coater. However, this
brings hot air into direct contact with the coating spray as it
is airborne and it can dry part of the solution before it con-
tacts the surface of the tablets.
With the airflow entering from the top or side traditional
coaters are also prone to producing a spray cloud effect
where the coating spray meets turbulent air. This spreads
the solution out causing it to cover the pan and spray arms
in addition to – and often times instead of – the tablets. All
that coating material is wasted. When dried the spray solu-
tion gets trapped in the machine’s filter system. The spray
cloud can also cost manufacturers tablets by causing them
to stick to the pan. Those tablets must then be rejected.
Advances in air flow bed technology are increasing manufac-
turing efficiency by eliminating this spray drying. New designs
allow the airflow to enter the coater from beneath the tablet
bed. It is distributed much more evenly and it covers the entire
length of the pan. That means all the air flowing through the
tablet bed is in the direction of flow, so no hot air is left in the
spray zone. Spray drying is almost eliminated entirely.
When spray drying is drastically reduced, manufacturers
will also decrease the volume of wasted coating solution. When
airflow partially dries an airborne droplet of coating material it
tends to bead, bouncing off the core and landing on the tablet
pan instead of dispersing on the tablet surface. That tiny dried
bead is wasted material. That, ultimately, means that the cam-
paign will use more coating solution in total, at an increased
cost to the manufacturer. Modern air flow bed technology
reduces airborne drying, ensuring that droplets are wet when
they hit the tablet surface. That results in less coating solution
used to achieve uniformity and less total material consumed.
REDUCED CLEAN-UP
Pharmaceutical manufacturers want to campaign batches
until they absolutely need to stop. Design improvements
have helped manufacturers reduce the amount of wasted
coating solution left on the tablet pan and spray arms. This
means manufacturers can campaign longer without stopping
to clean the coater.
A reduction in cleaning time helps to boost a company’s
overall efficiencies in terms of waste management. A typi-
cal coater’s wash cycle uses 400 gallons of water. Because
newer machines require fewer cleanings, manufacturers
PHARMACEUTICAL PROCESSING | OCTOBER 2013 33 ■
■ P H A R MP R O . C O M
■ C OAT I NG
Top: The latest coaters feature new technologies that can uniformly coat a tablet with signifi-
cantly less weight gain. Bottom: Maintaining proper gun-to-bed distance is critical for functional
coatings. A laser measurement sensor mounted in the spray arm of the coater monitors this criti-
cal parameter.
pp1310_feature_coating.indd 33 9/18/2013 8:59:45 AM
■ P H A R MP R O . C O M
■ C OAT I NG
■ 34 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
gained more importance in the last few
years. Equipped with additional function-
ality, such as gastro resistance for drug
delivery in the intestine or insolubility for a
sustained drug release, these coatings sig-
nificantly improve drug delivery.
Active coating also allows the combina-
tion of several drugs into a single dosage
form. This eases up the development of
new fixed-dose combinations, which are
growing in the market. Sophisticated coaters
are required to produce the high coating
uniformity and low spray losses that these
functional coatings demand.
Some of the latest functional coating
technology has the ability to measure the
gun-to-bed distance online by way of a
laser measurement sensor. This sensor is
mounted in the spray arm of the coater.
Maintaining proper gun-to-bed distance is
critical for functional coatings. Typically, these
coats are a high weight gain application, with
the coating adding 10 percent to 15 percent
more weight to the tablets. This large weight
gain will cause the tablet bed to grow, and the
gun-to-bed distance is narrowed over time.
Now coaters can automatically retract or
extend the nozzles via a recipe parameter.
Manufacturers can make this gun-to-bed
distance a control variable. With a PID loop,
the sensor will measure the gap and the
system will automatically adjust to maintain
the proper distance between the gun and
the bed.
With the latest improvements in tablet
coating technology, pharmaceutical manu-
facturers can be assured they are providing
customers with the best solid dosage drugs,
all the while reducing their operational
costs.
ABOUT THE AUTHOR
As vice president and general manager of
L.B. Bohle, Martin Hack oversees all compa-
ny operations in North America and Puerto
Rico. In his 13 years with the company, he
also served as a supervisor for project man-
agement, service and parts. Prior to joining
L.B. Bohle, Mr. Hack was a control engineer
for Niro Inc. (Columbia, Md.), where he
was responsible for equipment projects in
the pharmaceutical industry. He holds a
Bachelor of Science in electrical engineering
from Virginia Polytechnic Institute and State
University. ■
make it onto the tablets. With an inefficient
machine, expensive filters will require fre-
quent replacing, increasing overall manufac-
turing operating costs.
FUNCTIONAL COATING
Besides instant release, or so-called cos-
metic coatings, functional coatings have
potentially can save thousands of gallons
of water and reduce wastewater processing
costs each month.
Furthermore, advanced coaters do not
waste as much coating solution so manufac-
turers don’t need to change filters as often.
All coaters have dust collectors or filter sys-
tems to catch solidified solution that doesn’t
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Temperature Data Loggers ᭤
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pp1310_innovations_cleanrooms.indd 35 9/24/2013 9:07:43 AM
Top right: Desiccant packets on a continuous
strip can be automatically cut and dropped
during the packaging process.
Right: Integrating desiccants and barriers
into plastic containers is a viable alternative.
P
rotecting the efficacy of pharmaceutical products
through packaging solutions typically requires
a combination of active agents and passive bar-
riers. Packaging experts have turned to various
types of protective packaging to safeguard drug products
against degradation, which can lead to loss of stability,
shortened shelf life or an ineffective drug delivery. These
agents, primarily moisture, oxygen and odor adsorbents,
complement and enhance passive barriers.
Although sorbents are essential to the quality, stability and
appearance of packaged pharmaceuticals, such products can
increase the complexity of the manufacturing process. The
added steps can slow cycle times and provide opportunities
for errors and rejects. They also involve multiple materials and
components that must be sourced and managed, impacting the
supply chain. Some technologies may even require proprietary
equipment that ties the manufacturer to a single provider.
Thus, it is key that pharmaceutical packagers utilize active
packaging solutions that minimize complexity and enhance
efficiency, and pharmaceutical packaging innovators such as
Clariant have developed technologies to do just that.
UNIVERSALIZED PLATFORMS OFFER FLEXIBILITY
In all types of containers, desiccants play an active role in
controlling the impact of humidity on drugs, which can af-
fect degradation, dissolution or the therapeutic properties of
APIs. Because the plastic containers used for most drug prod-
ucts are semi-permeable, they allow some moisture to enter
through the container walls.
Placing “drop-in” style desiccant
packets and canisters in plastic con-
tainers is an affordable and effective way
to take advantage of plastic’s cost advantages
and resilience, while maintaining the necessary conditions in-
side the product package.
To accelerate the speed and improve the efficiency of adding
drop-in desiccants, high-speed insertion technology, such as
desiccant packets on a continuous strip, have been developed.
These packets are automatically cut and dropped during the
packaging process. As a further enhancement to reliability and
efficiency, strip packets with holes in each seal facilitate optical
detection of the cut point. Clariant’s Continu-Strip
®
Hole Punch
packets feature a hole in between every seal to avoid mis-cuts
during automatic insertion.
The pharmaceutical industry’s demand for even faster inser-
tion is driving increased use of desiccant canisters, which offer
a rigid, uniform shape to enable high-speed processing. Because
canisters are already separate parts, they allow the use of a
fast, efficient hopper system for continuous, seamless insertion,
and eliminate the step of cutting desiccants from a reel.
Because of process optimization advantages - potentially
doubling insertion speeds compared to packets - desiccant
canisters have become the gold standard for protection.
Further, the industry has developed canister-style oxygen
scavengers, such as PharmaKeep
®
humidity-neutral oxygen
scavengers, to provide active absorption of oxygen within
the drug package. Like desiccants, these canisters can be
inserted using high-speed equipment.
Care should be taken with manufacturers who have taken a
proprietary approach to their canister/equipment solutions, re-
quiring packagers to use only their desiccants on their specific
insertion machinery. A more prudent strategy is to choose a
universalized platform combining standard equipment and des-
iccants that can be used on any insertion machine.
INTEGRATING PROTECTION INTO THE POLYMER
Another strategy for process optimization is integrating pro-
■ By Mark Florez, Marketing & Communications Manager, Clariant Healthcare Packaging
■ 36 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M ■
■ P AC K AGI NG
s
t
s
t
t
T
C
us s
Optimizing Pharmaceutical
Packaging
Active and protective solutions help ensure product efficacy
Desiccant canisters' rigid shape enables high-speed processing.
pp1310_feature_clariant.indd 36 9/18/2013 9:01:22 AM
■ P H A R MP R O . C O M
tection such as desiccants and bar-
riers directly into the plastic struc-
tures of containers. This approach
can be seen in the use of multi-layer
blow-molded bottles that incorporate
passive barriers to oxygen, ultraviolet
light and other threats. By custom-
izing the layers, materials and design,
packagers can create bottles that will work on
any line, using standard equipment.
Active polymers can be molded into various
shapes and sizes to provide protection directly
into container walls or devices. Applications
include vials, dosers, dispensers, inhalers and
bottles. Plastic housings and delivery device
components can be molded from these poly-
mers to maintain low humidity levels and pro-
tect sensitive reagents from moisture.
The main advantage of integration is
avoiding the cost and complexity of sourc-
ing, purchasing, inserting and verifying the
presence of a separate desiccant. Designing
packaging using polymers with integrated
sorbents can lower material and processing
costs and reduce the number of suppliers
involved. Fewer packaging components also
lighten the burden posed by change manage-
ment - including regulatory review.
Integrated actives eliminate the possibility
that drop-in desiccants will be removed from
the packaging by a pharmacist or consumer,
leaving the contents without protection.
They also conserve space, allowing smaller
packages to be used or enabling more prod-
uct to be put in an existing container.
COMBINING PROTECTION
Other advancements in pharmaceutical
packaging take integration a step further, build-
ing active protection directly into the package
closure for part consolidation and other pro-
duction benefits. Integration of a desiccant into
a cap or other closure device, for example, can
reduce a three- or four-component package
down to just two pieces: the container and the
closure. This approach reduces part handling
and the burden of managing changes in mate-
rials, components and suppliers. Multi-function
closures with integrated active agents can de-
liver production advantages to pharmaceutical
companies and packagers, beginning with the
elimination of desiccant insertion. An example
is Clariant’s IDC® Integrated Desiccant Closure,
a screw-on or snap-on pharmaceutical cap that
combines tamper-evident, child-resistant and
twist-off functionalities with a built-in desic-
cant, while eliminating the induction seal.
As with polymer integration, including the
desiccant in the closure avoids the equip-
ment and processing time needed to insert a
drop-in desiccant separately. Both methods
can reduce cycle time because there is no
longer a need for quality checks to verify
that a desiccant was placed in each bottle.
PHARMACEUTICAL PROCESSING | OCTOBER 2013 37 ■
■ P AC K AGI NG
t
r
tu
c
b
pa
ligh
izing
packagers
any line, u
Active p
shapes and
into contai
CONCLUSION
Pharmaceutical manufacturers rely on
active and passive protection to maintain
the efficacy of their products. Innovative
packaging options such as high-speed desic-
cant insertion and integration of protective
elements into the packaging itself are making
a significant contribution to streamlined pro-
cessing and overall cost reduction. ■
pp1310_feature_clariant.indd 37 9/18/2013 9:01:52 AM

■ 38 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M
■ B I OP HAR M
S
ince 2008, glass delamination has been the sub-
ject of recalls for a variety of drug products.
Manufacturers of pharmaceuticals and glass
containers have joined together to identify risks
for delamination and have developed strategies that could
reduce occurrences. The compatibility of a glass container
for a given drug formulation is associated with methods of
glass manufacture, formulation and surface composition.
Action can be taken to mitigate the risk of delamination and
include tighter controls over glass manufacturing and han-
dling of glass containers, predicting delamination potential,
coating glass surfaces or using alternative plastic materials.
As the pharmaceutical industry continues to advance bio-
therapeutics, complex drug formulations are inevitable, which
could be a challenge to any container material. In certain cases
it is possible the pharmaceutical formulation may need to be
modified to be suitable with today’s common container mate-
rials. Selection of appropriate container materials early in drug
development stages will provide added assurance of successful
development and commercialization of quality medicine
There are various aspects to be considered when selecting
the appropriate container closure system. Glass delamination
is a serious issue, but overall compatibility through-out shelf
life encompasses several factors of risk. The container must be
compatible with the drug or biologic formulation as well as the
pharmaceutical manufacturing process, and protect the final
product during storage and shipping. Hazards can include inter-
actions between the container materials and the pharmaceutical
product resulting in leachables; shift in pH; reduced activity or
potency of active, pharmaceutical ingredients; and/or formation
of particles in addition to glass lamella. Another critical consid-
eration for sterile drug
products is for all com-
ponents in a system to
be compatible, ensuring
proper fit. Dimensional in-
consistencies, fine cracks
or chips can compromise
the container closure
integrity, putting the final
product and patient at
risk. Choosing the proper
container material early
in the development pro-
cess can help to prevent
compatibility issues while
maintaining the safety and
efficacy of the drug product. There are a variety of benefits and
potential risks to the use of both glass and polymeric materials.
Knowledge of the compatibility of container closure materials
with the drug product, as well as the intended use, can help
pharmaceutical manufacturers make the right choice when se-
lecting materials for their pharmaceutical products.
UNDERSTANDING COMPATIBILITY OF CONTAINER
CLOSURE MATERIALS
The process for selecting container closure materials
compatible with pharmaceutical products and the intended
use is an important aspect of delivering safe medicines to
patients. In today’s regulatory environment assessing and
managing risk is key to successful drug development and
commercialization. The physical and chemical nature of ma-
terials used in a container closure system can exhibit behav-
ior that has the potential to compromise the drug or biologic
product, resulting in harm to a patient.
Even though glass has a long history of use with a variety
of pharmaceutical products, it has been the subject of several
recalls often associated with delamination. Review of Medwatch
FDA safety alerts, associated with glass, included as many as 15
recalls in 2010. This number decreased to 12 in 2011 and 10 in
2012; through second quarter of 2013 only five were noted. It is
s not clear if the recent reduction in recalls is due to increased
control measures, improved quality of glass, or if the events are
fairly random and unpredictable. Considering the multiple vari-
ables associated with numerous drug or biologic products , it is
difficult to ascertain the ultimate cause of delamination. While
there is a concerted effort to improve glass quality and tighten
manufacturing controls, the fact remains that the material se-
lection is significant when ensuring container closure suitability
throughout the pharmaceutical lifecycle.
The manufacturing and use of pharmaceutical products in-
cluding its container components entail some degree of risk and
therefore, an informed decision relies on understanding potential
hazards. Whether the container material is a polymer or glass
there are multiple formulations and manufacturing and processes
that can influence the chemical and physical nature. Challenges
include understanding current weakness in a given application in
addition to unexpected hazards that could be experienced such
as those associated with formulations enhanced for solubility
with novel excipients. Recent estimates show that approximately
90% of pipeline drugs fall into low solubility categories of the
Biopharmaceutical Classification System BCS.
1
The approaches
to overcome poor drug solubility employ use of co-solvents,
emulsified systems, molecular complexes, amorphous drug
Conquering Glass Delamination
The material selection process may alleviate ongoing concerns
■ By Diane Paskiet, Director, Scientific Affairs, West Pharmaceutical Services, Inc.
Figure 1: Material Suitability Risk Chart
pp1310_feature_West.indd 38 9/18/2013 2:49:45 PM
PHARMACEUTICAL PROCESSING | OCTOBER 2013 39 ■
■ P H A R MP R O . C O M
■ B I OP HAR M
n
forms and modification of the aqueous microenvironment. It is
not always readily understood if these novel medicines will pres-
ent unforeseen challenges to container materials.
It is important to realize that no one material can perform
optimally under all conditions. Material compatibility and per-
formance data will guide benefit to risk analysis. Major consid-
erations for selecting materials suitable for the drug product’s
intended use include permeation, leaching, sorption, chemical
interaction, dimensional consistency , alteration in the physi-
cal properties and ensuring functional characteristics during
rigors of processing, storage and distribution.
CONSIDERATIONS OF GLASS AND POLYMER
CONTAINER MATERIALS
Glass is an non-permeable transparent material that
is typed or rated for use based on chemical resistance
but this test alone will only indicate the solubility of
glass in waterafter autoclave. All glass is not equal, dif-
ferent elemental compositions, manufacturing and form-
ing processes will influence suitability for use. The risk
of using glass stems beyond this challenge since this test will
not indicate the potential for delamination, surface adsorption
or extractable elements that could leach and interact with
the pharmaceutical product. The variability in dimensions is
another critical concern since a poor fit can result in leak-
age and loss of sterility. Glass does have high compression
strength, yet can be broken easily, and applied strain can
cause a crack to propagate, leading to fractures during filing
or distribution. Data should be acquired at the appropriate
time to scrutinize overall suitability of glass for intended use.
Polyethylenes (PE), polypropylenes(PP) and cyclic olefin poly-
mers (COP), such as Daikyo Crystal Zenith
®
(CZ), or copolymers
(COC) are commonly used materials for injectable containers.
The type of polymer selected, as well as the drug product for-
mulations and manufacturing processes will influence suitability
for use. Just as with glass, not all polymer types or formulations
behave in the same manner. The same container attributes and
risks should be scrutinized for all materials being considered.
Table 1 shows a broad based comparison of vital properties of
glass and two different polymer types derived from materials
data sheets. In general terms, all materials will have weaknesses
and need to be examined relative to function with other compo-
nents in the system, final drug or biologic form, filling/manufac-
turing, processing, storage and distribution.
The comparison of two types of plastic with glass indicate
glass and cyclic olefin polymers have the highest performance
ratings; however, there will be allowable tolerance for each
pharmaceutical product/container closure combination depend-
ing on final formulation and intended use. Data on the candi-
date materials should be gathered at the appropriate stages to
show shelf-life compatibility by understanding the impact of
potential leaching, degradation, formation of particles, transmis-
sion or permeation of gases or vapors, dimensional consistency
or material instability in various environments. The propensity
of a drug or biologic formulation to interact with a specific
material’s surface and other sensitivities related to the active
ingredient or excipients is case by case and may not be readily
observed. A high level Material Suitability Risk Chart (Figure 1)
derived from literature and material data sheets illustrates the
likelihood of quality impact with concern of relative occurrence.
The drive to improve quality is for industry to move toward
proactive approaches providing innovative solutions rather
than to react to failures or even worse, recalls. Identifying suit-
ability pitfalls of current and innovative container closure ma-
terials will result in a greater upfront investment by the phar-
maceutical company, but scrutiny of components and systems
early in the development cycle can reduce risk of failure due to
material incompatibility.
RATIONALIZATION FOR EARLY QUALIFICATION OF
CONTAINER CLOSURE MATERIALS
Only one out of approximately 8,000 new chemical entities
makes it to the market, and the related overall research and
development process takes on average approximately 13.5
years.
3
Failures or interaction of container closure materials
Table 1: Comparison of Vital Properties of Glass and Polymers
pp1310_feature_West.indd 39 9/18/2013 2:50:05 PM
■ P H A R MP R O . C O M
■ B I OP HAR M
with pharmaceutical products can occur over
short (days) or long (years) periods of time
and may only occur after being subjected to
certain processing, storage conditions and
possibly near the end of the drug product’s
shelf life. The container closure qualification
process is dynamic and progresses throughout
the pharmaceutical development cycle with
an initial step of assessing risk for intended
use. It is difficult to determine failures when
a final dosage form or the processing con-
ditions have not been confirmed, but early
understanding of the probability of a hazard
occurring for a specific use can help narrow
down material options and alert to mitigating
these risks. Recent cost estimates for full de-
velopment of novel medicine vary and range
to $1.8bn for the full development (capital-
ized).4 Will the cost for a science based- data
driven material selection process for container
closure suitability tip the economic scale at
this level of investment? The benefit of a com-
prehensive container closure risk assessments
will certainly outweigh a product recall and/
or adverse event. While it is uncertain if the
mysteries of glass delamination have been un-
locked, it is clear that due diligence in the ma-
terial selection process will play a central role
in supplying quality medicines to patients.
REFERENCES:
1. Ralph Lipp, Ph.D. , “The Innovator
Pipeline: Bioavailability Challenges
and Advanced Oral Drug Delivery
Opportunities,” American Pharmaceutical
Review, April 30, 2013.
2. Stephen Perrett and Gopi Venkatesh at
Eurand, “Enhancing the Bioavailability,”
Innovations in Pharmaceutical Technology,
Issue 19, Samedan Ltd. 2006.
3. S.M. Paul, D.S. Mytelka, C.T. Dunwiddie,
C.C. Persinger, B.H. Munos, S.R. Lindborg,
A.L. Schacht, “How to improve R&D pro-
ductivity: the pharmaceutical industry’s
grand challenge,” Nature Reviews Drug
Discovery, vol. 9, 203-214, 2010.
4. S.Morgan, P.Grootendorst, J.Lexchin,
C.Cunningham, D.Greyson, “The cost of
drug development: a systematic review,”
Health Policy, vol. 100, issue 1, pg. 4-17,
April 2011.
ABOUT THE AUTHOR
Diane Paskiet has more than 20 years of expe-
rience in polymer analysis relating to product
failures, deformulation and migration studies.
She has served as a project advisor in sup-
port of qualification studies associated with
container closure systems for IND and NDA
filings. Her current responsibilities as Director
of Scientific Affairs include coordination of
studies for technical support and innovations
as well as providing a forum for education
of those technologies. Previous to this role,
she was in charge of site operations for West-
Monarch Analytical Laboratories.
Diane is currently serving a five-year term
on the United States Pharmacopeia (USP)
Packaging, Storage and Distribution Expert
Committee and Chair of the PQRI Parenteral
and Ophthalmic Drug Product (PODP)
Leachables and Extractables Working
Group. She holds a degree in chemistry
from the University of Toledo and a QA/RA
Graduate Certificate from Temple University
School of Pharmacy. Diane has authored
national and international papers on the
subject of leachables and extractables and
is a faculty member of the PDA Training
Institute as well as a frequent speaker and
organizer of conferences. ■
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■ MARKETPLACE
■ P H A R MP R O . C O M
The Advertisers Index is provided as a reader service. Although every attempt has been made
to make this index as complete as possible, the accuracy of all listings cannot be guaranteed.
■ ADVERTISERS INDEX
■ 42 OCTOBER 2013 | PHARMACEUTICAL PROCESSING
Brookfield Engineering. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Capsugel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13, 30-31
Cook Pharmica LLC. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Elizabeth Companies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7, 41
EMD Millipore Corporation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Hamilton Company. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11, 41
Hospira Worldwide Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41, 44
Ligand Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Precision Fabrics Group Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40, 41
Quattroflow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Ross, Charles & Son Company . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41, 42
Tri-Mer Corporation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34, 41
Vac-U-Max . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37, 41
Veltek Associates Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5, 41
Xcellerex Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19, 41
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BILL KOENEN
E-mail:
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Phone: 973-920-7793
Fax: 973-607-5682
Average No. Copies
Each Issue During
Preceding 12 Months
No. Copies of Single
Issue Published
Nearest to Filing Date
20,627 18,489
14,175 13,045
0 0
48 40
0 0
14,223 13,085
5,840 4,895
0 0
332 350
6,172 5,245
20,395 18,330
232 159
20,627 18,489
69.7% 71.4%
required and will be printed in the October 2012 issue of this publication.
17. Signature and Title of Editor, Publisher, Business Manager, or Owner
Gail Kirberger, Associate Director, Audience Development
(3) Non-Requested Copies Distributed Through the USPS by Other Clases of Mail
g. Copies Not Distributed
h. Total (Sum of 15f and g)
i. Percent Paid and/or Requested Circulation (15c divided by f times 100)
16. Publication of Statement of Ownership for a Requestor Publication is
(2) In-County Paid/Requested Mail Subscriptions Stated on PS Form 3541
(3) Sales Through Dealers and Carriers, Street Vendors, Counter Sales, and Other
Paid or Requested Distribution Outside USPS ®
(4) Requested Copies Distributed by Other Mail Classes Throught the USPS (e.g.
(4) Non-Requested Copies Distributed Outside the Mail
e. Total Nonrequested Distribution (Sum of 15d (1), (2), (3) and (4))
f. Total Distribution (Sum of 15c and e)
c. Total Paid and/or Requested Circulation (Sum of 15b. (1), (2), (3) and (4))
d. Nonrequested Distribution
(1) Outside County Nonrequested Copies Stated on PS Form 3541
(2) In-CountyNonrequested Copies Stated on PS Form 3541
United States Postal Service
STATEMENT OF OWNERSHIP, MANAGEMENT, AND CIRCULATION
a. Total Number of Copies (Net Press Run)
b. Legitimate Paid and/or Requested Distribution
13. Publication Title: PHARMACEUTICAL PROCESSING 14. Issue Date for Circulation Data Below: September 2013
(1) Outside County Paid/Requested Mail Subscriptions Stated on PS Form 3541
1. Publication Title: PHARMACEUTICAL PROCESSING 2. Publication Number: USPS # 001-314 3. Filing Date:
10/01/13 4. Issue Frequency: Monthly, except bi-monthly in January/February, and November/December 5. No. of Issues
Published Annually: 10 6. Annual Subscription Price: USA $57 CAN $75 MEX & FOR AIR $87 7. Complete Mailing Address of
Known Office of Publication: Advantage Business Media, 100 Enterprise Drive, Suite 600, Box 912, Rockaway, NJ 07866-0912
Contact Person: Barbara Cavallaro, Telephone: (973) 920-7477 8. Complete Mailing Address of Headquarters or General Business
Office of Publisher: Advantage Business Media, 100 Enterprise Drive, Suite 600, Box 912, Rockaway, NJ 07866-0912 9. Full
Names and Complete Mailing Addresses of Publisher: Bill Koenen, Advantage Business Media, 199 E. Badger Road, Suite 201,
Madison, WI 53713; Editor: Michael Auerbach, Advantage Business Media, 100 Enterprise Drive, Suite 600, Box 912, Rockaway, NJ
07866-0912.
10. Owner: Advantage Business Media, LLC, 100 Enterprise Drive, Suite 600, Box 912, Rockaway, NJ 07866-0912 11. Known
Bondholders, Mortgagees, and Other Security Holders Owning or Holding 1 Percent or More of Total Amount of Bonds, Mortgages, or
Other Securities: none 12. Tax Status: The purpose, function, and nonprofit status of this organization and the exempt status for
federal income tax purposes has not changed during preceding 12 months
15. Extent and Nature of Circulation:
Requestor
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