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■ IN THIS ISSUE
■ P H A R MP R O . C O M
■ 4 JULY 2011 | PHARMACEUTICAL PROCESSING
12 Cool Technology
Freeze dryers adapt to changing products and
market demands.
14 Continuous Solid Oral
Dosage Processing
Converting from a batch to a continuuous
process leads to more efficiency and less waste.
20 Recall Remediation
How to successfully manage a recall and
prevent future problems.
26 Steam Trap Tips
The right steam trap saves money and increases
uptime in SIP applications.
28 Brainstorm
Have sponsor requirements for qualification as
a preferred vendor become more strict?
30 Delivering Process
Improvements
By leveraging single-use operations and lean strategies
companies can deliver real value and reduce costs.
■ COVER STORY
8 Under One Roof
Acceleron Pharma leverages single-use technology
and capable suppliers to meet their goals.
page 14
page 24
page 19
■ DEPARTMENTS
6 From The Editor
18 What’s Hot
INNOVATIONS
22 Weighing
24 Vial and Syringe Processing
29 Coating Equipment
On the Cover:
In order for
Acceleron Pharma
to manufacture their
products in-house
they have relied
heavily on single-use
technologies.
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I
I’ve been thinking a lot lately about packaging.
We all know how important packaging is to our lives and how
packaging has, for the most part, made our modern, high-tech
lives possible.
But what happens when you look past the big picture – and get
down to the real nitty-gritty of packaging – down to the individual
consumer level – and how they interact with packaging on a daily
basis. For this survey of modern packaging I took a look at my
own experiences with packaging.
For starters, there are some winners and, to be chari-
table, some non-winners.
Let’s start with a standout.
Due to more than his fair share of sports-related broken
bones, my son was drinking a very popular nutrition supplement
high in calcium. This product, marketed primarily to older people
worried about osteoporosis and other age-related bone diseases,
has an ingenious cap that with just a few easy twirls is open. The
packaging designers clearly had their target consumer in mind
when designing this easy open container.
Moving on to some less than stellar examples of packaging – I have
to say that I have had some issues with modern blisterpackaging
products. I know there are many benefits to blisterpackaging, and I
don’t have the space here to go into them but they are well known.
However, some forms of blisterpackaging, particularly the type where
you have to peel a layer off before you can push out the product can
be maddening, especially when you can’t get the corner started to
start the peel. And, more often than not, only half of the film peels off,
leaving you to try and squeeze the pill through the opening.
And finally, does anyone ever get the little tab at the top of the
cereal box to stay in the slot on the other flap? I rarely get it to stay
in place, especially after I’ve mangled the top trying to open it up.
Do you have any packaging winner or losers? I would love to hear
about them.
■ FROM THE EDITOR
■ P H A R MP R O . C O M
Packaging Points
Have a comment or question about Pharmaceutical Processing?
My E-mail is: mike.auerbach@advantagemedia.com
When it comes to packaging there are
some winners, and let's just say, some
that don't quite make the cut…
■Michael Auerbach, Editor in Chief
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■ 6 JULY 2011 | PHARMACEUTICAL PROCESSING
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pp1107_from the editor.indd 6 7/7/2011 8:49:48 AM
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Above: The large cell culture production area.
Left: The small cell culture suite.
Acceleron made a decision to internalize protein production.
The initial production and purification of the proteins was
done by the company’s own personnel in development labs.
This initial facility was a simple, 1600 ft
2
facility which
was designed and constructed in a relatively short period of
time, minimizing capital and validation costs, and allowed
the company to adopt a ”pay as you go” approach to the
costs associated with pre-clinical and clinical production.
As the company got closer to the need for making preclini-
cal and clinical material for its first product, the question of
whether to outsource its product or do it internally resurfaced.
Again a number of CMOs were contacted and asked for quotes
for the work to make the initial development candidate. As the
quotes came back the company realized that the cost of out-
sourced production would limit the number of projects which
they could pursue into Phase I clinical studies. In addition,
given the aggressive timelines critical to creating value for
existing investors by showing the utility of these molecules in
the clinic, company management had a strong desire to have
better control of the timelines for production. Bob Steininger,
SVP Manufacturing at Acceleron Pharma explains the compa-
ny’s thought process at the time, “My goal here was to figure
out a way to get a small company to control their destiny,
which is really tough and frustrating when you have a great
idea and you can’t act on it fast enough and you can’t learn
w
t
S
t
A
A
t
T
he old adage, “If you want something done right,
you should do it yourself” can be applied to
many situations. Perhaps nowhere is it more
appropriate, at least in the pharmaceutical indus-
try, is at Acceleron Pharma in Cambridge, Massachusetts.
Acceleron was established in 2004 to focus on growth
and differentiation factors in the TGF beta super family. The
company’s main purpose is to develop biologics that modu-
late the growth of bone, muscle, fat, and the vasculature in
order to treat patients with diseases with high unmet medi-
cal needs – many of which are know as “orphan diseases”
for which there are no other available treatments. As the bi-
ology is complicated, a substantial number of novel proteins
are required as tools for in vivo experiments. Due to the
complex biology, Acceleron has developed numerous protein
antagonists as tools to understand the biology initially and
has developed similar molecules as therapeutics.
DOING IT ALL IN-HOUSE
Early in the company’s history, management compared
production at Contract Manufacturing Organizations (CMOs)
to “in-house” protein production. Based on several factors in-
cluding the difficulty of expressing these proteins, the internal
knowledge and insight of the properties of the members of
this protein family, and the more favorable economics for the
internal production of many reagents projected to be needed,
Under One Roof
Acceleron Pharma leverages single-use technology
and capable suppliers to meet their goals
■ By Mike Auerbach, Editor-In-Chief
■ 8 JULY 2011 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M
■ COVER STORY

pp1107_coverstory_acceleron.indd8 8 7/1/2011 11:09:27 AM
Above and left: Acceleron Pharma's facility is located
in the heart of Cambridge, Masssachusetts.
Right: Diagragm of the facility layout.
along the way.” He continues, "we are
making relatively complicated molecules.
It is more difficult for an outside firm to
deal with these. We had the expertise in
house. Whenever it was sent out it took
longer and more times to do the process,
and it wasn’t clear when we would get into
a CMO. For a small company like ours, for
us to get data as quickly as possible, it
was necessary to have control of the timeline.”
Based on the first facility's success and the company’s desire
to control their destiny and costs – the decision was made to
build a larger, second generation facility. The result is a 12,000
ft
2
facility with approximately 4500 ft
2
of processing space.
SINGLE-USE
In order for Acceleron to make the facility as cost-effec-
tive and as nimble as possible, the company relies heavily
on single-use technologies. The heavy reliance on what
many might consider a “new” technology, was actually
based on years of experience, as Steininger explains, “I was
previously at Millenium, and technology was being devel-
oped to use single use – and I accepted that technology and
made it work for a process that we had. It appeared to be
reasonable. We probably did the first Phase 1 material made
in bags. We put together a facility very quickly and made
material – everything was delivered and made in single-use
bags – which is very similar to what we do here.’
He adds, “The facility here and our whole effort; develop-
ment, production, pilot production and GMP production has
been based on the use of single-use technology from the
get-go. It has really helped us by enabling us to make mate-
rial quickly, particularly the complicated material we make.”
ADDITION BY SUBTRACTION
W hile many companies are exploring single-use technolo-
gies and realizing the benefits that this technology provides,
Acceleron needed to push the envelope a bit more with their
new facility. As the facility is based in a rather crowded ur-
ban environmen t with little space to expand, and considering
the company’s desire to contain costs as much as possible,
the company came up with the revolutionary idea to elimi-
nate in-house production of water and steam.
Steininger explains how they accomplished this, “In order
to do this you have to be very confident that your media
and buffer suppliers have a very good system to provide wa-
ter and buffers appropriately.”
“Its very much like the Japanese auto industry – a very
close relationship with your suppliers. All the parts have
to fit together and fit together well with the appropriate
tolerances. That’s not any different from what we are doing
here. The companies that supply us with media and buffers
have to do that well and as accurately as possible. That’s a
dependence that most people
have not taken a risk with,
but it can be done given that
there are a number of com-
panies that will supply you
liquid and plastic, etc."
And Acceleron has found
those suppliers. “There are
three reputable suppliers of
buffers and there are lots of
people who will supply you
with media,” says Steininger.
“Our media comes from
California and our buffer comes
mostly from Maryland. We are
transporting water over a dis-
tance which doesn’t seem to be
a limiting factor.”

FACILITY DESIGN INPUT
As mentioned, Acceleron
sought to keep the process, and
perhaps more importantly, the
process knowledge as much
PHARMACEUTICAL PROCESSING | JULY 2011 9 ■
■ P H A R MP R O . C O M
■ COVER STORY
■ The initial pilot\phase 1 facility
at Acceleron was based on the
following design principals:
■ Focused limited development\production
personnel on the process, not support.
■ Simple facility design focused on con-
trolled areas using one HVAC.
■ “One product at a time” facility.
■ The facility has no water system. All pro-
cess solutions delivered in sterile containers
■ The facility has no steam. All material is
delivered sterilely unless cleaned as part of
in-process sanitization (column cleaning).
■ All process equipment is mobile, to facili-
tate its movement at a future time.
■ The processes are based on a platform,
where equipment and number of process
steps are substantially the same among
different product candidates.
pp1107_coverstory_acceleron.indd9 9 7/1/2011 11:09:41 AM
■ P H A R MP R O . C O M
■ COVER STORY
■ 10 JULY 2011 | PHARMACEUTICAL PROCESSING
as possible, in-house. This knowledge, which
isn’t stored on a computer, is found in the
experience and talent of their personnel. “To
a certain extent, we have called them manufac-
turing (personnel) but they are in fact scien-
tists,” says Steininger. “In this early phase, you
really want people who can understand how
the process works, how it can translate into a
larger scale, and how to adapt equipment from
a vendor to what we are doing. That is in fact, I
think what Acceleron has tried. We have manu-
facturing scientists who can adapt the single-
use technology, the connectors, etc. and make
it work. Many of these people worked in our
first facility, they then transferred that technol-
ogy into our new facility and made it run. That
has worked well for us.”

A SMALL-SCALE FLEXIBLE FUTURE
With the success of Acceleron's facility,
the question that needs to be asked is this
the wave of the future? Are small-scale,
flexible facilities, using predominantly
single-use technologies the nail in the cof-
fin for older facilities and technologies? “I
think it is certainly one of the ways,” says
Steininger. “One of the aspects that have
come clear over the last few years is that
there hasn’t been a lot of big stainless steel
facilities built recently. This is because ex-
pression levels have gone up and there are
more than enough plants in the area. You
are seeing a lot of old and new companies
using this technology. (In our case we used
it) to see how we can minimize our capital
costs and maximize the utility of what we
have and if we need to add more (capacity)
lets use this technology (single-use) rather
than another way. It is enabling us to use
capital more effectively – especially on the
smaller scale. For a small company, it’s a
very big advantage. ”
FACILITY HIGHLIGHTS
Steininger and the folks at Acceleron
have designed, built and are operating a
very unique facility and one which they are
rightly very proud of, “I think the ability to
set it up where you actually made a facility
that could depend upon, at least initially,
other people supplying all your liquid and
designing a gray space in a way that helps
keep a lot of the "junk" out of the process
(is what I’m most proud of)," says Steininger.
“This design also allows us to think about
the future - to build out our facility so we
can make our own water and buffers.”
THE FUTURE
With their facility operating the way they
want it to, Acceleron is planning for the fu-
ture, as Steininger explains, “We have four
drugs that will be in the clinic from Phase
1 – 2b in the next few years. Depending on
how the trials go some we will make our-
selves, some we might use a CMO. If it has
to be done real fast we will make it here. If
it gets too big, too fast, we will transfer it.
We will have to focus on how we can make
clinical supplies and make sure our prod-
ucts move through the clinical process. We
will expand if need be depending on the
clinical data.” ■
■ The additional capabilities of
the new facility were accomplished
through the following design
features:
■ A separate, independent area for cell
culture which can be used for cell bank
production.
■ Space for at least 2X 1000L single use reac-
tors (potentially 2000L) and inoculum train.
■ Two larger, more integrated purification
areas.
■ Extensive use of grey space and pass-thrus
to enhance movement of solutions into the
facility from the warehouse, and from one
processing area to another.
■ Use of same systems of grey space and
pass-thrus to facilitate the removal of
waste from the facility
■ Juxapositioning QC and Warehouse func-
tion to the production area
■ Creation of a clear path of movement of
raw materials (particularly liquids) from
loading dock, through QC sampling, and
into the facility
■ Separate air handling systems for each of
the four processing areas, and a separate
entry to each process area entering from a
common clean corridor
Top: Large purification production area.
Bottom: Small purification production area.
Top: Grey space for solution delivery.
Bottom: Miniature pass-thru.
■ T he following companies contributed
to the success of Acceleron Pharma's
facility:
Advanced Scientific
Finesse
GE HealthCare
Hyclone Laboratories, Inc.
Millipore
Pall Flowstar
Sartorius North America, Inc
Spectrum Laboratories, Inc.
VWR International, Inc.
W.L. Gore & Associates (Amesil)

pp1107_coverstory_acceleron.indd10 10 7/1/2011 11:09:55 AM
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A
t its most basic – freeze drying or lyophilization is
a process in which water is removed from a per-
ishable material first by freezing the material and
then reducing the surrounding pressure to allow
the frozen water in the material to shift directly from a solid,
frozen state to a gas state. The greatest benefit of freeze drying
to the pharmaceutical industry is the creation of a product that
can now be maintained at room temperature without the need
for further storage costs.
To get an update on the latest freeze drying trends and tech-
nologies affecting the pharmaceutical industry, Pharmaceutical
Processing spoke to several freeze drying experts.
NEW PRODUCTS – NEW EQUIPMENT DESIGNS
Developing new products is important to every industry,
but perhaps none more important than the pharmaceutical
industry. With millions spent on R&D, the industry has a lot
riding on new products. We asked our experts if the devel-
opment of new types of drugs have had an influence on the
design of freeze dryers.
“Definitely,” says Mark Shon from SP Scientific, “You are
seeing cytotoxic type drugs, you are seeing more demand
for barrier interface and for auto loading capability – even
on some of the small pilot units. Even on the small units we
are getting requests for CIP capability. You may have to de-
velop a freeze dryer where historically you never had any of
that and now the user wants to freeze dry cytotoxic drugs
with some type of barrier isolation along with ability to
wash out anything inside.”
“New types of products have influenced the design of freeze
dryers,” says Millrock’s T.N. Thompson. “Many new products
are more potent and more expensive, requiring changes to the
freeze dryer design. It is very common to have 2ml vials in use
which require a higher stoppering pressure. The higher value
of product being freeze dried also requires the highest reli-
ability components to be used and more sophisticated control
systems to monitor and control the process.”
“I do see that there are a lot new product formats, notes
Cook Pharmica’s Zach Yim. “You have vaccines, monoclonal
antibodies, liposomes, and small molecules that all require
different approaches to stabilize them via lyophilzation.
They all have different requirements.”

NEW PRODUCTS – NEW CONTAINERS
Traditionally, freeze dried products have been processed
in glass vials – with new products being developed we asked
our experts if glass was still the preferred container material
or if other types of material are being tested and used.
“Within glass there are a variety of different developments to
improve the flatness of the glass and therefore reproducibility
of manufacturing, because how flat vials sit on the shelf is a
fairly large determinant regarding the quality and time
of the freeze drying, says SP’s Shon. “There are some
plastic vials that have come into
the market – that’s a little trickier
A Cool Technology
Freeze dryers adapt to changing market and product demands
■ By Mike Auerbach, Editor In Chief
■ 12 JULY 2011 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M ■
■FREEZE DRYING

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Freeze dryers are available in many sizes and capacities. One of the newest features is "con-
trolled nucleation". Controlled nucleation allows all of the vials to be nucleated at the same
time - allowing for better product quality and faster processing.
pp1107_feature_freezedrying.indd12 12 7/7/2011 9:14:50 AM
■ P H A R MP R O . C O M
■ S L UG
■ P H A R MP R O . C O M
■FREEZE DRYING
– because of the thermal characteristics of the heat transfer into a plas-
tic vial. You also have some development work in the closure. There is a
new closure that does the stoppering and capping in one step. If you can
take out a step and make things easier – that’s a good thing.”
“One company has introduced plastic vials and another has come
out with a coating that prevents collapse during lyophilization and
is also hydrophobic, so you can completely retrieve liquids. Of
course, nothing is perfect, people need to test these new products
first,” adds Cook’s Yim.

MORE THAN JUST A “FREEZE DRYER”
Many pharmaceutical companies in the present economic climate
are looking for all the assistance they can get. Are pharmaceutical
companies looking to equipment vendors for more than just a piece
of processing equipment? Are they looking for integrated lines along
with the engineering and validation support to get the lines up and
running as quickly as possible?
Millrock’s T.N. Thompson offers his views, “Pharma companies
first look for the right solution to their problem, rather than a single
vendor to supply all their equipment. Freeze dryers are made-to-or-
der and vary greatly, so the vendor and the customer need to work
through the details of the equipment to get the right solution for
their application. The area where a single vendor would provide a
complete line would be in an automated loading application, which
might also include the fill and capping equipment."
"Validation and training have become a large part of the freeze dry-
ing equipment business. FDA regulations require a significant amount
of documentation and performance testing to verify the equipment
performs to the requirements.”

CONTROLLED NUCLEATION
All of our experts agree that controlled nucleation is one of the big-
gest advancements to come along for freeze dryers in a long time. So
what, exactly, is controlled nucleation?
"Controlled nucleation was introduced because vials freeze at dif-
ferent and random temperatures,” says SP’s Shon. “This created a
problem, as now each vial is different. They each have a different
thermal history. So the time for drying is also changed. Controlled
nucleation technology allows the user to instantly nucleate all of the
vials at the same time – so they all will behave the same – and allows
you to shorten your cycle time and improves the consistency of your
batch. This is probably the biggest advancement in freeze drying”.
Cook’s Yim agrees, “The most exciting development in freeze dry-
ing is controlled nucleation. It used to be nucleation was random
and not controlled. This (controlled nucleation) can provide better
uniformity, and accelerate the primary drying process by 20%. Also
the product quality is better.”
“Controlled nucleation is a very important trend,” adds Millrock’s
Thompson. “By controlling the nucleation process the crystal struc-
ture of the material can be more uniform resulting in shorter pri-
mary drying cycles.”
FUTURE TRENDS
With controlled nucleation grabbing much of the freeze drying
“headlines” are there any other trends or technologies we can look
to in the coming years?
Cook Pharmica’s Yim offers several to look for “The use of wire-
less temperature probes which allow you to map the sublimation
rates and to compare temperatures from the front to back and side
to side will allow people to design their cycles better.”
He continues. “There is also the non-destructive determination of
moisture in vials so you can inspect vials 100% for moisture content
and loss of vacuum due loss of closure integrity. These are very ex-
citing things that people can use to improve their product.”
And finally, Yim states, “People are also beginning to realize they
need an intermediate size freeze dryer for small batch size clinical
materials. This would facilitate further scale – up. This would elimi-
nate partial loading of larger freeze dryers for small, clinical batch
work and make it more efficient and eliminate bottlenecks in larger
freeze dryers.” ■
PHARMACEUTICAL PROCESSING | JULY 2011 13 ■
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P
rocessing individual ingredients toward a more
useful end is as old as humankind. Witness the
magnificent cave paintings of our ancestors as
an expression of their daily lives that became
possible by mixing common ingredients to manufacture pig-
ments. Of course, manufacturing efficiency has very little
influence when much of your day is given to collecting nutri-
ents and avoiding predators, so providing a pigment batch
at irregular intervals is sufficient to the purpose.
Fast forward to our current century where most process
manufacturing is still being accomplished one batch at a time.
Pharmaceutical manufacturing in particular is biased toward
batch operations for various reasons. Some reasons are due
to prior regulatory environments that favored batch validation
and general stasis of the manufacturing situation. One may ar-
gue that the unique relationship pharmaceutical manufacturing
has to human health abets the batch inertia. However, the reg-
ulatory environment has significantly changed in recent years
with renewed emphasis on deep process understanding.
(1,2)
. In
addition, other industries have been involved with continuous
manufacturing and they enjoy high success rates.
In these industries, there are examples of formulation ana-
logues to solid oral dosage formulations that utilize continuous
techniques to manufacture their
products. One application involves
cross-linking polyethylene (PE) pel-
lets with organic peroxides. The
organic peroxide may be thought
of as the active ingredient in liquid form and thereby requires
fine control of its addition to maintain the functionality of the
extruded wire coating. The PE pellets are similar to a phar-
maceutical unit dosage and each pellet must have the proper
amount of peroxide applied. The components exit as effluent
in a real time release scenario to an extruder. Inconsistencies
in content uniformity may be reflected in poor extruder per-
formance or more importantly in a coating failure in the field.
Considering that some of these wire coatings are undersea ap-
plications, one can see the impact of such a failure.
A second application with analogies to pharmaceutical
manufacturing, particularly with regard to formulation con-
stituents, is processing detergents. These formulations contain
builders that are analogous to pharmaceutical diluents, clean-
ing agents analogous to the active pharmaceutical ingredient
(API) and flow aids analogous to silicon dioxide. They also
contain a striking analogue to the lubrication step. The for-
mulation contains a chlorinated component that will degrade
under the aggressive agitation necessary to mix the main for-
mulation constituents and thus requires a secondary, gentle
tumble mixing step. This, of course, mimics the requirements
of lubrication addition in solid oral dosage formulations.
Each of the above operations is processed at several
thousand kilograms per hour (kg/hr) with good content uni-
formity and high yields.
AMENABLE PROCESSING OPERATIONS
Many manufacturing applications are transferable from
batch to continuous processing. The continuous processes
often maintain similar abilities on the ultimate result be-
cause the basic unit operation remains the same. An influ-
ential criterion for choosing between batch and continuous
processing is the throughput requirement. Continuous oper-
ations generate substantial amounts of product and several
tons per hour are common rates. These high rates are inap-
propriate for solid oral dosage manufacturing but vendors
now offer pharmaceutical-ready, low throughput devices
that have much lower throughputs; often a 5 kg/hr and less.
Continuous Solid Oral
Dosage Processing
Converting processes from batch to continuous leads to more
efficiency and less waste
■ 14 JULY 2011 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M
■ SOLID DOSAGE

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Figure 1.
12.5 centimeter
low throughput
continuous mixer.
■ By Thomas Chirkot, Ph. D., Patterson Kelley
pp1107_feature_continuousprocess14 14 7/7/2011 10:34:40 AM
Figure 2. 1500 liter batch mixer.
A non-exhaustive list of operations
that transfer well to continuous may
include tumble powder blending, high
intensity powder mixing, wet granula-
tion of various varieties, drying and hot
melt extrusion. Because of its ubiquity
in general process schemes, the continu-
ous mixing application will be dealt with
in some detail in the succeeding para-
graphs that detail the positive and nega-
tive aspects of continuous processing.
To make the contrast more effective, we
will assume a continuous operation de-
livering 100 kg/hr (figure 1) versus a sin-
gular batch operation utilizing a 1500 liter
vessel (figure 2). In both examples, an 8
hour production run will yield about 800 kg of drug product.
POSITIVE ASPECTS OF CONTINUOUS PROCESSING
It is difficult to overstate the extensive advantages of con-
tinuous processing.
These systems are built to operate on a 24 hour per day
and 7 day per week work cycle resulting in impressive utiliza-
tion efficiencies. By contrast, the batch unit operation encom-
passes only a small portion of the production day. A typical
mixing time for a 1500 liter vessel would be on the order of
about 30 minutes. Substantial additional time would be en-
countered in ancillary duties including staging the raw mate-
rials, loading the materials, sampling, discharging, and clean-
ing the vessel in preparation for a subsequent process run.
Cleaning downtime may be minimized with continuous pro-
cessing as these systems are offered with the ability for a quick
changeover of the vessel and agitator bar. A single drive station
is capable of accepting several sizes of the continuous vessels,
allowing wide process ranges that are typically between 5 and
200 kg/hr. The attachment point to the drive station is similar
to the familiar multi-vessel processing stations seen with batch
offerings. Consequently, the vessel and agitator bar may be
quickly removed (< 15 minutes) and replaced by a fresh system
as the previous system is sent off for cleaning.
Analytical processing is simplified within continuous applica-
tions. When assessing batch uniformity, a small group of sam-
ples is collected to represent the entire batch. This sampling, of-
ten done with a sampling thief, has its own inherent drawbacks
that include drawing down surface material to the sample site as
the thief enters the powder bed, preferential filling of the thief
cavity by better-flowing formulation constituents and entrap-
ment of smaller particles in the annular space of the thief’s tube
within a tube design. The analysis requires high value employ-
ees for evaluation and the samples themselves may languish for
several weeks in the analytical queue. Continuous applications
are ideal for on-line analysis with technologies like near infrared
spectroscopy (NIR) that provide the analytical assessment very
quickly, do not require sample preparation and are suitable
to remote sampling via fiber optic probes. There is an initial
method development phase where NIR, a secondary technique,
must be established versus a primary method, but once this is
accomplished the continuous analysis may be monitored within
software-developed, standard operating procedures that are
quite easily adapted to the operator level.
The other advantage of this type of analysis is the reduc-
tion of in-process inventory, as immediate release is now
feasible. Perhaps even more important is the pervasiveness
of sampling available. A large portion of the effluent stream
is monitored continuously and a much broader profile of the
system is available. Consequently any uniformity issues can
be reconciled quickly. The actual at-risk mass is very small
and is generally a kilogram or less as represented in the
hold-up volume of the mixer. Novel statistical techniques
have been proposed to deal with the larger sample size
(3)
.
There are a few other more esoteric advantages within
continuous applications. Scale-up becomes much less com-
plex. With batch applications, similarity criteria (generally
geometric, kinematic and dynamic) are established in the
pilot scale vessel. These criteria are promoted to the larger
vessel, with varying degrees of success, as the scale-up
factor. Continuous scale-up is time related and based on a
common period of residence among the vessel sizes. A re-
tention time of 180 seconds in a 5 kilogram per hour opera-
tion can easily be replicated to a 100 kilogram per hour op-
eration by increasing the hold-up volume, which, in effect, is
merely placing a larger vessel on the common drive station.
Another advantage is the simplicity within which continu-
ous fits into efficient experimental design, especially when real
time analysis with NIR has already been established versus
a primary method. A factorial sequence with replicates that
evaluates machine factors such as agitator bar tip speed, ves-
sel tip speed and vessel slope with respect to a critical quality
attribute such as mix uniformity, thereby proving a proven
acceptable range, may be accomplished in one day of testing.
Contrast that with the time that would be necessary to a com-
plete a similar factorial sequence in a small batch vessel as
thief samples are drawn for analysis by the laboratory.
Finally, the space utilization difference of batch versus
continuous is another profound advantage. A general ar-
rangement for the continuous scenario of delivering 100 kg/
hr will fit on a table top while the batch scenario of utilizing
a single 1500 liter batch requires a large processing suite.
DRAWBACKS TO CONTINUOUS PROCESSING
There are disadvantages to continuous processing but
many of them may be reconciled through judicious planning.
For example, if the continuous process is not well-character-
ized and controlled in the experimental stage, it is possible to
have substantial material manufactured before one is aware
of any problem. The batch unit may also contain significant
material but the only at-risk portion is what is contained in
the blender and the possibility exists to re-work this material.
Manufacturing complex formulations with multiple ingredi-
ents may also be a limiting factor for continuous processing.
PHARMACEUTICAL PROCESSING | JULY 2011 15 ■
■ P H A R MP R O . C O M
■ SOLID DOSAGE
pp1107_feature_continuousprocess15 15 7/7/2011 10:34:53 AM
It is fairly easy to stage 2 or 3 feeders at the
input end of the continuous process but if the
formulation contains 6 or more ingredients,
staging this many feeders may be impossible
or economically prohibitive considering the
cost of additional feeders. A second issue
related to the complexity of the formulation
is the addition of the lubricant. The main for-
mulation components with a low dosage API
require a high speed mixing environment to
achieve uniformity. However, the functionality
of the lubricant would degrade under such
an environment and the lubricant must be
blended in a gentle tumble mixing situation.
In a batch process, it is simple to utilize the
agitator bar for the high energy step, then
add the lubricant and continue the process
without the agitator and achieve a simple
tumble blend. In a continuous process, this
may involve two mixers in sequence; one for
the high speed portion and the second for lu-
bricant addition. There are continuous mixing
technologies that overcome the problem by
dividing a single continuous mixer into sec-
tions that are capable of high speed mixing
followed by gentle tumbling.
A final issue is related to environmental
control. In the batch unit, dust-free transfer
of the raw materials and subsequent dust-
free transfer of the finished formulation to a
receiving container is well-established. The
continuous may also achieve an environ-
mentally clean transfer but with the multi-
plicity of feeders and the outflow transfer
to a tablet press, environmental control be-
comes more problematic and sophisticated.
UNDERSTANDING FIRST PRINCIPLES
AND THE GRAND ALGORITHM
The ultimate advantage of continuous
processing is the potential to build into a
grand algorithm for efficient process control.
Experimental design can readily establish
proven acceptable ranges for critical process
inputs like agitator bar tip speed, vessel tip
speed and agitator bar design as these inputs
relate to critical quality attributes like blend
uniformity and particle size. Available technol-
ogy can constantly monitor the critical qual-
ity attributes in near real time and then make
adjustments of the critical process inputs
according to the process algorithm developed
in the experimental phase. Sophisticated feed-
back loops are possible within many common
PAT software packages.
(4,5)


REFERENCES
1. Pharmaceutical cGMPs for the 21st
Century-A Risk-Based Approach: Second
Progress Report and Implementation Plan,
Department of Health and Human Services,
US FDA, September, 2004.
2. Guidance for Industry PAT- A Framework for
Innovative Pharmaceutical Development,
Manufacturing and Quality Assurance. US
Department of Health and Human Services,
US FDA, Center for Drug Evaluation and
Research, Center for Veterinary Medicine,
Office of Regulatory Affairs, Pharmaceutical
cGMPs, September, 2004.
3. “Continuous Verification-Providing an
Alternative Approach to Process Validation,”
R. Kettlewell et al. Pharmaceutical
Engineering, Jan/Feb 2011.
4. “Process Analytical Technology(PAT)-PAT
and Batch Recipe Execution,” Emerson
Process Management White Paper, Life
Sciences, May 2010.
5. “SIPAT The Software Heart of PAT,” Siemens
Product Brochure, Siemens NV, Belgium,
November, 2007. ■
■ P H A R MP R O . C O M
■ SOLID DOSAGE
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pp1107_feature_continuousprocess16 16 7/7/2011 10:35:19 AM
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■ 18 JULY 2011 | PHARMACEUTICAL PROCESSING P
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PHARMACEUTICAL PROCESSING | JULY 2011 19 ■
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A
t one time or another everyone has heard the
mantra, “The customer is always right!” When a
company is in the midst of a regulatory recall and
its new “best friend” is the FDA, the company must
clearly understand that the FDA is their customer AND it is
imperative to get the recall “right.”
Over the past year there have been a number of highly vis-
ible recalls that have laid waste to companies who did not meet
FDA standards. What a company does both publicly and with
the regulatory agencies is critical to an organization's ability to
survive and thrive. This is a true test of resilience as the FDA is
not the only concern. People who buy the company’s products
could be the ones to decide their fate.
The FDA and other regulatory agencies have entered a
phase of intense regulatory scrutiny of companies who do
not decisively address audit findings. The result has been
not only closer scrutiny of the company subjected to the
recalls, but to other sites or business units as well. These
actions on the part of the FDA make it very clear that
they mean business.
However, all is not lost. There are effective courses of
action an organization can take to successfully manage cur-
rent recall status and prevent future recalls.
ASSESSMENT OF KEY PERFORMANCE
INDICATORS (KPIS)
A company scorecard of metrics for investigations and
Corrective Action Preventative Action (CAPA) is the start-
ing point for the remediation efforts. Each company does
this in different ways and to varying levels of sophistica-
tion. In order to assess the scale and scope of the recall,
an organization needs to review the measures, metrics,
and trends from the past two years to determine
the extent of the recall. Some of the data points
needed include:
• Number of open investigations and CAPAs
• Reportable vs. non-reportable incidents
(counted by level)
• Time to close investigations and CAPAs
• Resources required to close investigations
and CAPAs
• First-time fix rates
• Mean time to resolution (tracked by person-
hours)
In order to launch a remediation effort, this information
must be quickly accessible and available to all involved in the
remediation effort. This is crucial for proper analysis of KPIs.
Next, current workflows that impact the recalled product
need to be reviewed. These should include troubleshooting
methodology, performance environment and performance sup-
port work flows as well as the standard operating procedures
(SOPs) for investigations, CAPAs and investigation training.
This information, along with the metric information above, will
serve as a basis for verifying the improvements recommended
at the conclusion of the project.
INVESTIGATION ASSESSMENT
Consistency, stability and capability of business processes
are necessary to reduce variations caused either by common
causes or by incursion of external factors or special causes.
Analysis of the current business and investigation processes
regarding the use and implementation of CAPA methods - and
root cause analysis (RCA) tools - will identify a framework to
address quality events in a holistic fashion. This will reduce the
time required to complete investigations and provide a blue-
print for future CAPAs to be transparent and traceable and can
be adopted at other sites throughout the company.
To achieve this, a company should start with a structured re-
view of the organization’s SOPs against past investigations in a
“should vs. actual” analysis to judge outcomes. This structured
review includes analyzing the SOPs as compared to the written
investigations, as well as reviewing the actions of the employ-
ees involved. By this approach, the gaps and shortcomings not
found in typical audits can be identified and addressed.
CAPA ASSESSMENT
To continue with the recall remediation, it is important to as-
sess the company’s CAPAs. That process begins with a review
of the SOPs. Once this is complete, a company should meet
with its CAPA approval team to identify the gaps between the
SOPs and the actual work flows that drive CAPAs as described
by the CAPA approval team. This meeting will yield valuable
data that will help a company zero in on the “sweet spot” for
improving their CAPAs. It is important to note that there typi-
cally is a gray area associated with how to choose the most
effective and efficient corrective action, among the many that
are available. For these decisions, companies should consider
working with outside vendors, who can look at these potential
actions with an objective mindset, thus removing any emo-
tional elements.
RCA TOOL ASSESSMENT
Integrity of the RCA tools used in investigations is essential
for achieving scalability, repeatability, improved hit rate, and
■ 20 JULY 2011 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M
■ R E GUL AT OR Y
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Recall Remediation
How to successfuly manage a recall and prevent future problems
By Michael Curran-Hays , Senior Partner, Life Science, Kepner-Tregoe, Inc
pp1107_feature_Kepner.indd 20 7/7/2011 10:51:58 AM
■ P H A R MP R O . C O M
■ R E GUL AT OR Y
PHARMACEUTICAL PROCESSING | JULY 2011 21 ■
ensuring the use of the least amount of re-
sources. Consequently, a review of current
RCA tools and the training programs that uti-
lize these tools will help identify weaknesses
and/or limitations that can hinder the level
of results. This is essential to keep problems
from reoccurring.
Often times, companies use multiple tools
to assess RCA, which can result in experts
racing down parallel paths towards the same
goal - determining the root cause. However,
these experts are separated by “virtual walls”
because they typically work in different func-
tional areas of the company, and the effect
of separation results in redundant work and
little synergy. One solution to this remediation
problem is to establish a companywide RCA
tool chest where employees receive train-
ing and have access to the basic set of RCA
tools, such as “5 Whys,” Fishbone and Kepner-
Tregoe (KT) Problem Analysis. Then, as inves-
tigations unfold and possibly become more
complex, experts of particular RCA tools get
assigned to the investigation team so they can
apply the more complex set of tools.
In the remediation effort, looking at the
interaction between quality investigations
and manufacturing production will greatly
increase the probability of effectively address-
ing issues. Finally, continuous improvement
in the use of RCA tools and methods will only
guarantee a reduction in recalls if the current
RCA tools are in line with training programs. A
review of training manuals and seminars is a
key element in any remediation effort.
ASSESSMENT OF ROLES AND
RESPONSIBILITIES
Understanding the people performance and
the dynamics of team performance in cur-
rent investigations and CAPAs is THE most
overlooked area during remediation efforts.
Our work with companies indicates this is
often overlooked in standard audits. Yet, when
performing a review and remediation of a
company’s Investigation/CAPA processes, this
is where most of the time is spent.
All meetings associated with investigations
and CAPAs, such as CAPA In-Process Status
Reviews, Investigation Reviews, Disposition
Meetings and Problem-Solving, should be re-
corded in order to obtain a summary picture.
Once this is achieved, interviews should be
conducted with operators, quality control
analysts, supervisors and quality assurance
personnel, to get a better understanding of
why people are not getting the appropriate
performance during investigations.
The results and trends from those inter-
views should be explored and clarified with
focus groups. Once completed, a full, and
comprehensive picture may begin to emerge
regarding the rewards and consequences the
workplace and the quality or the lack of qual-
ity of feedback given to employees. It may also
reveal the encouraging consequences man-
agement offers the organization to get to root
cause and close out CAPAs effectively.
The Performance Environment is an area
where the majority of systemic failures can
be found. Looked at another way, perfor-
mance systems, if designed correctly, and
with individual levers pulled appropriately,
are the most significant area that WILL ensure
a reduction in the likelihood of recalls AND
drive dramatic improvements in a company’s
“in-process” investigations. Effective perfor-
mance systems are the silver bullet for recall
remediation. These need to be in place at both
leadership and operational levels.
CONCLUSION
In the end, recall remediation is hard work.
Somewhere, in all those previous audits, were
the nuggets of information and “ah ha” mo-
ments that, if exposed earlier would have kept
the recall from happening. Somewhere during
your past efforts, the blinders were left on and
issues were looked at through rose-colored
glasses. Now, things have gone sideways in the
worst possible way for the company. All pro-
cedures, processes and SOPs need to be seen
through a new set of eyes with renewed pas-
sion to get to the bottom of what is happening.
Unfortunately, in a recall those new eyes are
now many pairs of eyes, some within the com-
pany and many outside of the company. The
rush to judgment by many will be uninformed
and very damaging, unless the company takes
the time to start over and drive the remedia-
tion effort across all aspects of the business. ■

ABOUT THE AUTHOR:
Michael Curran-Hays coordinates Life Science
operations for Kepner-Tregoe (KT) globally
with a focus on pharmaceutical, medical
device, biotechnology, generic and the health-
care provider industries. His area of expertise
extends to business process and operational
improvement as well as strategy formulation.
single use systems
Contact us by calling
800-724-4158
As a part of Advanced ScientiÀcs’
Single Use Systems, the company
offers a multitude of solutions for
single use bags. With sizes ranging
from 50 mL to 3,500 L, Advanced
ScientiÀcs can produce single use
bags of nearly any conÀguration.
These bags are currently utilized
throughout the industry and
throughout the manufacturing
process.
In addition to specializing in custom
solutions, we offer a large variety of
catalog products.
Advanced ScientiÀcs is an FDA registered, ISO 13485:2003
certiÀed manufacturer.
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pp1107_feature_Kepner.indd 21 7/7/2011 10:36:16 AM
᭣ Weigh Feeders Offer A Small
Footprint For Space Constrained Areas
Model 407 Series "Weight-Loss" weigh feeders feature
an extremely compact design with a small footprint which
results in low overall space requirements. The feeders are
versatile and are available with a variety of different
metering mechanisms which are capable of feeding a
broad range of even the most difficult-handling dry sol-
ids materials. The feeders incorporate a robust design and
feature a high-resolution, non-load cell based weigh-
ing mechanism that never requires field calibration
or adjustment. Additionally, the feeding equipment
is specifically designed for the industrial environ-
ment. The weighing system, including its associated
electronics, is unconditionally guaranteed for five full
years. ■ Acrison Inc., Moonachie, NJ 07074. www.
acrison.com or call 201-440-8300
Checkweigher Eliminates Steps in Production ᭤
Designed for speeds up to 250 pieces per minute, the new HC-MEDIUM (HC-M)
features the same control concept as the high-end checkweigher,
HC-A, making cross training between various controllers unneces-
sary. The new model features a modular sub-frame for cost-effec-
tive scaling to various applications and individualized integration
with metal detectors, cameras, etc. Additionally, it can be outfitted
with a range of reject devices to discharge products of an incorrect
weight without disturbing the ongoing flow of production. ■ OCS
Checkweighers, Inc., Snellville, GA 30039. www.ocs-cw.com or call
678-344-8300
■ I NNOVATI ONS
WEIGHING
■ P H A R MP R O . C O M
■ 22 JULY 2011 | PHARMACEUTICAL PROCESSING
EQUIPMENT
᭣ Weighbelt Feeders for Sanitary Wash-Down Applications
Designed for pharmaceutical and other sanitary processing environments, the
open frame weighbelt feeder is designed to handle high pressure wash-down
settings. The design of the weighfeeder makes it easy to clean and maintain. A
cam-operated lever lets users remove the belt virtually in seconds, and special
clean-out ports and sanitary grade bearings enable the weighbelt to be pres-
sure washed to remove any material or debris build up. The stainless steel
DEA open frame weighbelt feeder utilizes a direct drive system that reduces
the use of grease, belts, and chains. Hermetically sealed stainless steel strain
gage load cells and a design that incorporates watershed angles optimize drainage
and simplify cleaning. The feeder can be custom built in 12-inch (300 mm) or 24-inch (600
mm) widths. Feed rates up to 1,680 cubic feet per hour are achievable. ■ Schenck AccuRate,
Whitewater, WI 53190. www.accuratefeeders.com or call 800-558-0184
᭡ Weighing and
Transporting Device
The Ergo-1000-OBS-BC is a simple-to-use
drum transporting device that allows the
operator to handle steel, plastic, or fiber
drums. The series uses a manual foot pump
to lift and lower each drum vertically up to
20 inches (32 inch optional lift heights also
available). The drum is lifted using the com-
pany’s exclusive “Parrot-Beak
®
” clamping sys-
tem. The “OBS” model offers a digital readout
of each drum’s weight (registered in pounds
or kg.). This weighing device allows for sim-
ple product weight verifications as well as
formal weight management. Accuracy is with-
in one pound or 0.25 percent for up to 1,000
pounds in weight. Available options include
power lift, spark resistance, wheel choices
for varying floor conditions and a printing
feature. ■ Liftomatic Material Handling, Inc.,
Buffalo Grove, IL 60089. www.liftomatic.com
or call 800-837-6540
pp1107_innovations_weighing.indd22 22 7/1/2011 11:13:47 AM
pp1107_Ads.indd 23 7/1/2011 12:21:43 PM
Leak Tester with Particle and
Cosmetic Inspection Capabilities ᭤
The PK V Vis Combi is a fully automatic leak tester
and visual inspection machine for ampules and
vials. This leak testing method follows the ASTM
and is fully validated. Because it is equipped with
cameras, the machine is able to perform particle,
level and cosmetic inspection. When the container
is inserted in an airtight chamber, it is tested by
applying vacuum. Once testing is completed, the
same container is spun and stopped, and several
photos are taken. Container is checked for any
particles in the product or cracks, and fill levels are also tested. ■ Bonfiglioli Engineering S.p.a.,
44049 Vigarano, Pieve (Fe), Italy. www.bonfiglioliengineering.com or call 39 0532 715631
᭣ High-Output Filling and Closing Machine
The SFM5110 fills and closes ready-to-fill syringes, vials, and cartridges that are supplied in
nests. The intermittent-motion machine achieves a maximum output of 11,300 containers per
hour. Depending on the required capacity, the SFM5110 is available for processing 2 or 5 posi-
tions at each machine cycle. The compact design and the streamlined work area enhance the
effect of a laminar air flow. The filling process can be carried out by means of rotary piston
pumps, peristaltic pumps, or a time-pressure dosing system. In order to prevent air from becom-
ing trapped in the tip of the syringe, the filler/closer can be equipped with a vacuum-assisted
dosing station. Immediately after filling, the containers are closed by precisely positioning a
stopper in the syringe. The stopper insertion is carried out by means of a vent tube or under
vacuum. A fully-automatic in-process control (IPC) system allows for controlling the automatic
dose adjustment optimization process when starting up the machine, and for performing regular
weight checks during production. ■ Bausch + Stroebel Machine Company, Inc., North Branford,
CT 0647. www.bausch-stroebel.com or call 866-512-2637
■ I NNOVATI ONS
VIAL&SYRINGE
■ P H A R MP R O . C O M
■ 24 JULY 2011 | PHARMACEUTICAL PROCESSING
PROCESSING
Automatic
Ampule Filler and Sealer ᭡
The Ampulmatic
®
-10 speeds and automates
filling and sealing of glass ampules at rates of
up to 10 per minute. The gas and liquid filling
units have been redesigned for increased
service life and ease of maintenance. The
optional ampule filling unit can be configured
to fill each ampule automatically with an inert
gas or a precisely measured of liquid. This
new feature will be available in the second
half of 2011. The base unit automatically
indexes each ampule on a carousel rack,
available in 1, 2, 5, 10, 20 and 50 ml standard
sizes, for a consistent hemispherical flame
seal. The filler and sealer can be operated on
natural gas, MAPP or propane, with technical
grade oxygen at 10 to 20 psi. Supply voltages
can range from 110 or 240 VAC and power
consumption is 100 watts. ■ Bioscience, Inc.,
Allentown, PA 18109. www.bioscienceinc.com
or call 800-627-3069
᭣ Bench-Top Dual Syringe Filler
The Model 1100 is a highly precise dual syringe filling
system designed to fill two syringes simultaneously
in as little as two seconds. Dispense cycles on each
syringe remain independent, making it possible to fill
syringes with separate materials. This bench-top system
is ideal for down packing or filling syringes with a wide
variety of materials including pharmaceuticals, creams,
cosmetics, and dental products. The model’s precision is attrib-
uted to its unique, nozzle-end filling method and individual, automatic
shut-off sensors. Materials are filled through the tip of the syringe allowing the syringes to be filled
with pre-inserted plungers, which increases accuracy of fill by eliminating air pockets and material
stringing. ■ DYMAX Corp., Torrington, CT 06790. www.tridak.com or call 877-396-2988
pp1107_innovations_syringeproces24 24 7/1/2011 11:41:23 AM
pp1107_Ads.indd 25 7/1/2011 12:21:55 PM
t
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Fig 1: Example of an SIP process
P
harmaceutical and biochemical plant owners must
adhere to regulatory standards that govern the
cleaning and sterilization of pipes, valves, tanks
and reactors. These standards assure the integ-
rity of the process and the batches produced. The hygienic
processes associated are very demanding on the controls and
equipment, and can be quite expensive.
Sterilization-in-place (SIP) and cleaning-in-place (CIP) provide
an economical method of meeting the goals of batch integrity
and regulatory compliance at a fraction of the cost of breaking
down a process to clean it. The goal of SIP and CIP is to oper-
ate plants efficiently with reduced down time and maximum re-
liability. Selecting the correct steam traps is crucial to ensuring
the stability of the process, as well as maintaining the required
cleaning schedules. However, these valves are not always given
the attention they deserve and thus customers can miss an op-
portunity to maximize cost savings.
The first step in the overall
process is CIP. The process liquid
is drained, and water and acid are
forced through the entire system
to clean out contaminants such
as dirt and viruses. This process
allows for cleaning and disinfect-
ing without having to break down
or reassemble the process com-
ponents, promoting uptime and
process availability. With a CIP pro-
cess, parameters such as tempera-
ture, speed, concentration of the
cleaning medium, and the cleaning
duration must be considered.
Once the CIP process is com-
pleted, the subsequent SIP process focuses on killing microor-
ganisms by heating the entire system, without disassembling it.
Depending on the kind of organisms, the system is heated up to
150°C. The SIP process uses saturated steam from a clean steam
generator. This is the only type of steam with a combination
of temperature and moisture that offers a suitable medium for
dependable sterilization. The success of the sterilization proce-
dure then depends on whether the temperature in the system
remains constant. Following sterilization, the system must be
cooled down; this is done by purging it with sterile air.
The SIP process is regulated at a constant temperature by
selecting the correct pressure for the saturated steam. Any
condensate that is produced will reduce the temperature. An im-
portant process step is therefore to detect the physical state of
the medium and to achieve an adequate response time for the
steam trap. Plant components that are difficult to reach - as well
as the endpoints of the system - are especially critical. These
sensitive positions are monitored by temperature sensors and
provide the basis for validation of the production plant.
SUITABLE STEAM TRAP PROPERTIES
All internal components in contact with the fluid should
be made of stainless steel type 316L. There is a fundamental
principle that special requirements are best served by a
more precise definition of the desired specifications, since
a variety of materials in this “material group” may be used,
depending on the manufacturer. Body gaskets are usually
made of polytetrafluoroethylene (PTFE), ethylene propylene
diene monomer (EPDM) or fluoroelastomer (FPM). All meet
the requirements of the FDA.
With regard to the surface roughness (Ra) of the interior
surfaces, a roughness value of Ra Յ0.8 µm (32 microinch) has
become standard. The goal is to prevent active ingredients
from the batch to embed in the pores of the process com-
ponents. Some manufacturers offer values down to < 0.4 µm
(16 microinch). In some cases, electropolished surfaces are
requested, with a view to preventing batch material active in-
gredient deposits and contamination from the very start. The
most important functional unit of the steam trap is its control
component. Thermostatic steam traps are offered in a choice
of bimetallic, membrane and bellows types (Fig. 3).
With bimetallic regulators, the opening and closing opera-
tions are controlled by the interaction of the temperature sensor
(consisting of bimetallic plates) and the stage nozzle. Because
of its propensity to trap dirt and potential for contaminating the
process, it is generally not suitable for use in pharmaceutical
Steam Trap Tips
The right steam trap saves money and increases uptime in SIP applications
n By Alexander Hofmann, Key Account Manager Pharmaceutical Industry, Steam Traps And Valves,
Flowserve Corporation
■ 26 JULY 2011 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M ■
■ C L E ANI NG

Fig 2: Condensate produced in a ¾” pipe of stainless steel during sterilization with saturated
steam at 43.5 psi/291.2°F
pp1107_feature_steamtrap.indd 26 7/7/2011 10:37:01 AM
plants. The same applies to the bellows regulator, although this
type is very similar in function to the membrane regulator.
In contrast, the membrane regulator offers a decisive
advantage over bimetallic and bellows regulators for phar-
maceutical applications. Because of its small surface area, it
responds quickly to changes in temperature and other oper-
ating conditions. When condensate flows through the trap,
the control medium in the capsule is completely liquid, as a
result of the low ambient temperature. This gives operators
the ability to drain air and cold condensate during the start-
up process, minimizing start-up time.
When the pressure within the capsule is lower than the sur-
rounding pressure (surface pressure), the membrane with the
valve disc is pushed open (Fig. 4, left). When the condensate
temperature rises, the liquid starts to evaporate. When the in-
ternal pressure of the capsule rises, the membrane is pressed
in the closing direction (Fig. 4, right). The function is not af-
fected by a fluctuating upstream pressure or by back pressure.
Since the membrane regulator detects the change of the
medium’s physical state from steam to condensate and
Fig 5: Structure of the Flowserve Gestra steam trap type SMK 22-81
Fig 6: Functional test of the FlowserveGestra capsule 5Hi
Upstream pressure = 46,4 psi / TS = 293 °F
25.8 lb/h condensate
Practically constant plant temperature T2 with minimal banking of condensate through use of a
capsule when sterilizing a 32.8 yard section of pipe with the nominal size ¾”.
Fig 4: Functional principle of the Flowserve thermostatic capsule
-


■ P H A R MP R O . C O M
■ C L E ANI NG
quickly discharges the condensate, downtime is reduced
and a stable batch process is maintained. Membrane regula-
tors also have an advantage in their structural design. Since
they have almost no crevices, the risk of process contami-
nation is reduced dramatically. This permits a long service
life and a reliable, safe SIP process.
Outages and maintenance downtime can be reduced to a
minimum. Nevertheless, it is necessary to take steps during the
planning phase to ensure good accessibility to these valves. In
order to minimize the need for gaskets, orbital welding ends
are frequently used for the connections to pipework. There are
also body versions which allow a rapid and easy exchange of
the regulator (i.e. the functional unit). Only two gaskets are re-
quired in this case (Fig. 6).
With the correct selection and sizing of the steam trap sys-
tem, sterilization-in-place is a safe, reliable and cost-saving pro-
cess. Temperature fluctuations, and hence the risk of unwanted
contaminants entering the process, need not jeopardize ef-
ficient production, high system availability, and profitable
operation of the plant. ■
PHARMACEUTICAL PROCESSING | JULY 2011 27 ■
■ P H A R MP R O . C O M
Fig 3: The various types of thermo-
static steam trap regulators. From left
to right: bimetallic regulator, bellows
regulator, membrane regulator.
pp1107_feature_steamtrap.indd 27 7/7/2011 10:37:14 AM
■ BRAI NS TORM
■ P H A R MP R O . C O M
■ 28 JULY 2011 | PHARMACEUTICAL PROCESSING
Terry Novak, President, Norwich Pharmaceuticals
Requirements to qualify as a preferred service provider have become
stricter and sponsors now hold preferred providers to higher standards
than in recent years. The key requirements haven’t changed, how-
ever, I see greater scrutiny being focused towards security of sup-
ply and financial stability. While regulatory compliance will remain
the cornerstone of a successful due diligence process for service
providers, sponsors are increasing demand for on-time delivery, re-
questing historical performance metrics and including accountabil-
ity measures within contracts that guarantee performance. As large
companies continue to consolidate and outsource more services,
the greatest difference now occurring is centered upon financial
stability to ensure that service providers will be financially viable partners
for the long term. RFI’s are now much more detailed regarding the financial
information needed to become a preferred provider. Driving the focus on fi-
nancial stability is the increasing number of financially troubled service pro-
viders that can't meet the rapidly expanding technical needs of the industry.
Have sponsor requirements for qualification as a preferred
service vendor become stricter? If so, can you explain what
the drivers are behind this change?
Veda Walcott, Vice President of Qual-
ity, Cook Pharmica
I am not sure I would describe our
client’s qualification requirements as
more strict; however, the process has
definitely become more complicated. An
increasing number of biopharm companies are forming
one or more strategic partnerships, which is adding to
the complexity of the process. As a result, becoming a
qualified vendor requires partner due diligence visits
and at times multiple quality system audits to support a
single client relationship. In addition, with the goal being
successful integration of multiple quality systems, qual-
ity agreement negotiations with our clients necessitates
consideration of the partner(s) requirements. All of
these factors can influence our qualification status as a
preferred vendor, but it also it provides us the opportu-
nity to demonstrate our flexibility and responsiveness.
IMA ACTIVE Division
mktg.soliddose@ima.it • www.ima.it
IMA NORTH AMERICA, INC.
sales@imausa.net
IMA perforated and solid wall
coating pans: always the best
solution for your requirements
The new Perfima perforated pan
guarantees the best results in coating
processes.
Having the same shape, and with the mixing
baffles in the same position as the established
IMA GS coating pans ensures perfect mixing,
uniform coating and high flexibility allowing
a wide range of batches to be processed
in the same drum.
The drying of cores is carried out using
a minimum quantity of air, thereby
saving energy.
PERFIMA the perfect
perforated solution
HANDLI NG • GRANULATI ON • TABLETI NG • CAPSULE FI LLI NG AND BANDI NG • WEI GHT CHECKI NG • COATI NG • WASHI NG
pp1107_brainstorm.indd 28 7/1/2011 12:42:35 PM
Fluid Bed Dryer-
Granulator-Coater ᭤
The 3-in-1 fluid beds allow drying, granulating
and coating on the same machine using one
single product bowl with no need for insert,
Wurster column, or rotor. The product’s unique
features include a discjet bottom plate which
distributes the drying air from the bottom of
the fluid bed at the same 45-degree angle as the
nozzles deliver the coating liquid, as well as a
Hüttlin 3-fluid nozzle design which includes a
compressed air supply for ‘microclimate air’.
The 3-fluid nozzle blows a protective ring of air around the tip of the nozzle to prevent any block-
age and ensure that the coating of the particles happens at the correct distance from the nozzle.
■ OYSTAR USA Process Division, Edison, NJ 08837. www.oystarusa.com or call 732-346-7600
Self-Contained, Portable Coaters ᭤
The LDCS-Pro system is an extension of the highly successful
LDCS Hi-Coater product line that utilizes multiple interchange-
able fully perforated pans.The coater is a self-contained and
portable system for pilot scale and small production, aqueous,
solvent and sugar coating applications. Five interchangeable
pans are available to provide maximum batch size processing
flexibility. Pan volume capacities are 20, 40, 55, 110 and 150
liters and each pan has the capability to process as low as 25
percent of the rated volume capacity. System features include a
touch screen recipe-driven control system with manual and auto-
matic operation modes, an integrated solution pump system, anti-bearding spray guns, and anti-
marking mirror-finished coating pans along with removable anti-slide and mixing baffles. ■ Vector
Corporation, Marion, IA 52302. www.vectorcorporation.com or call 319-377-8263
᭡ Perforated Pan for
Tablet Coating
The PERFIMA is a highly flexible and reliable
perforated pan for tablet coating. The shape
of the pan and the mixing baffles’ position
ensure a perfect mixing of the cores and a
uniform distribution of the coating mate-
rial. The machine can work a wide range of
batches, from 25 to 100% of the pan capacity,
maintaining mixing capability when work-
ing with a minimum or a maximum quantity
of product. Position and dimensions of the
outlet air duct allow for uniform drying of
the product, thus saving energy. The spray
guns fitted on a sliding support arm can
be positioned and adjusted from outside.
Automatic product loading and discharge
are available on request. Complete isolation
of all the parts in contact with the product
is obtained with special seals, allowing full
containment installations and a completely
automatic clean-in-place system. A “through
the wall” installation is also available. The
front and side doors fitted on the machine
provide excellent accessibility. PERFIMA is
available in four models: 200, 500, 800 litres
and Perfima Lab for R&D purposes. ■ IMA
North America, Inc., Leominster, MA 01453.
www.ima.it or call 978-537-8534
᭣ Tablet Coater Reduces Processing Times
Tablet coater reduces processing times up to 35% compared to conventional
tablet coating systems, yielding significant cost savings and improved cam-
paign efficiency while maintaining cGMP standards. The company’s patented
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while lengthening campaigns between cleaning. It also promotes uniform
tablet coating with a high-quality, defect-free film coat. The tablet coater’s
elongated coating pan provides a larger tablet spraying surface accom-
modating up to 10 spray nozzles, which delivers more suspension solution
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baffle design provides 100% tablet discharge, increasing campaign efficiency. ■ L.B. Bohle LLC,
Warminster, PA 18974. www.bohle-tablet-coater.com or call 215-957-1240
■ I NNOVATI ONS
EQUIPMENT
■ P H A R MP R O . C O M
■ 29 JULY 2011 | PHARMACEUTICAL PROCESSING
COATING
pp1107_innovations_coating.indd 29 7/1/2011 12:41:55 PM
I
ntense pressure to demonstrate increased productiv-
ity and a robust return on R&D investment is leading
the pharmaceutical industry to focus aggressively on
cost control and process improvement. To address
these challenges, drug developers are increasingly leveraging
lean manufacturing initiatives. Based on principles largely
developed by Toyota, lean manufacturing seeks to identify
and eliminate waste in order to reduce the cost of bringing a
product to market. Centered on creating more value with less
work, lean manufacturing generally focuses on reducing eight
specified wastes to improve overall customer value (Table 1).
In parallel with this focus on lean process improvement,
the industry is actively evaluating and leveraging single-use
products and systems to reduce costs, increase productivity,
and speed time to market. The move to single-use solutions,
either alone or in conjunction with stainless steel, is likely to
continue growing in an effort to address these imperatives.
When managed properly, implementation of single-use sys-
tems can deliver key benefits as defined in the principles of
lean manufacturing:
• Improved quality
• Reduced waste
• Increased productivity
• Optimized resource utilization
This article will highlight industry trends that are driving
adoption of single-use systems and describe the implementa-
tion of single-use filtration to deliver lean process improve-
ment efficiencies and drive waste out from the manufacturing
workflow.
A MARKET IN TRANSITION
The biopharmaceutical industry is undergoing a number of
changes that are having a significant impact on manufactur-
ing (Table 2).
Where once a few major drug companies were the industry
leaders and had little competition, contract manufacturing or-
ganizations (CMOs) and generic manufacturers are now play-
ing an increasing role in bringing drugs to the market. Adding
to this new reality is the need to evolve from a focus on large
batches manufactured at a single facility to production of
numerous, low volume, high variability batch runs at multiple
facilities around the world.
Delivering Process
Improvements
By leveraging single-use operations and lean strategies companies
can deliver real value and reduce costs
■ By Vikas Gupta, EMD Millipore, Group Product Manager, Mobius
®
Single-Use Products and Services
■ 30 JULY 2011 | PHARMACEUTICAL PROCESSING
■ P H A R MP R O . C O M
■ S I NGL E - US E
v
t

EMD Millipore has the capability to mimic a customer’s pilot manufacturing setup in their Biomanufacturing Sciences and Training Center.
pp1107_feature_millipore.indd 30 7/1/2011 11:14:34 AM
One of the most challenging trends is the shift of drug
development phases (research and development, pilot scale,
commercial scale manufacturing) from single, vertically inte-
grated facilities to separate locations around the world. While
use of multiple sites across multiple countries can bring great
value into the system, the practice puts increased demands
on technology transfer processes.
Different manufacturing equipment, materials, and design
may be used in each phase, presenting significant process
optimization and validation challenges due to inconsistencies
among bioprocess equipment across scales. Rapid and seam-
less technology transfer processes are thus essential to main-
tain consistency across all scales.
In an effort to address these challenges, many manufactur-
ers are turning to single-use manufacturing solutions. The
benefits of single-use products in manufacturing are widely
known and well-documented. When implemented properly,
PHARMACEUTICAL PROCESSING | JULY 2011 31 ■
■ P H A R MP R O . C O M
■ S I NGL E - US E
Table 1. Eight Types of Wastes Targeted by Lean Process Initiatives
TYPE OF WASTE WHAT IT IS
Overproduction Processing too soon or more than is required. Product(s) are made just-in-case and not just-in-time, which results in excess
orders, high inventory, high scrap and unnecessary labor.
Defects Product defect is the most easily identified waste and has a direct impact on customer satisfaction.
Inventory Lack of balance between inventory and process flow can result in excess inventory being created.
Overprocessing Having a complex tool or product design can cause unwanted activity, resulting in unnecessary labor, overdesigned functionality,
and is often a result of legacy processes.
Transportation Moving product unrelated to processing such as moving equipment to meet layout constraints, long distances between process
setups, fixed capital equipment results in difficulty in moving assembly manifolds and lack of modularity.
Waiting Unnecessary waiting for the next production stop, without adding value, such as waiting for approvals, shared resources,
sub-optimal workflow, insufficient labor, results in long vendor lead times and long assembly set-up time.
Motion The unnecessary movement of people beyond the minimum required can be caused by sub-optimal SOPs, poor process design
and/or poor work area layout.
Underutilized People Perhaps due to a lack of open communication or lack of integration among employees, employee creativity can be overlooked.
Table 2 – Evolution of Biopharmaceutical Manufacturing
PAST FUTURE
Large drug companies maintained leadership position with no
major competition
Increasing competition from CMOs and generic manufacturers
Single product facilities Multi-site, multi-product facilities
Large-scale batches Small to large scale batches with a lot of variability
High volume-low variety formulations Low volume-high variety formulations
All stainless steel equipment Mix of stainless steel and single-use or all single-use equipment
Less focus on cost control and process improvement Focus on lean process improvement and bottom line impact
Vertically integrated with minimal need for technology transfer Increasingly complex technology and knowledge transfer between R&D,
pilot, and commercial manufacturing sites
Table 3 – Sources of Process Inefficiencies with
Single-Use Systems
Multiple single-use components from multiple vendors
Long vendor lead times
Excessive item number set-ups, costly maintenance of multiple item
numbers in material master
High inventory and scrap levels
Inefficient use of warehouse storage space
Inefficient use of operator time, EHS issues
Complicated assembly design and long set-up periods
Difficulties in handling single-use assemblies
pp1107_feature_millipore.indd 31 7/1/2011 11:14:50 AM
■ P H A R MP R O . C O M
■ S I NGL E - US E
■ 32 JULY 2011 | PHARMACEUTICAL PROCESSING
single-use systems can accelerate produc-
tion, improve flexibility, reduce costs and
waste – benefits that are well-aligned with
lean process initiatives.
What can prevent a company from fully
realizing these benefits, however, is the
manner in which single-use systems are
sometimes employed – on an ad hoc basis
without a cohesive plan for applying the
technology across all process scales. Lack of
an overarching single-use strategy can actu-
ally increase process inefficiencies (Table 3).
When single-use assemblies are sourced
from different vendors, inefficiencies can be
amplified as operators must become famil-
iar with multiple systems, and components
are likely to have different expiration dates
and lack compatibility. Further, a smooth
and seamless technology transfer process
may be much more challenging when differ-
ent materials are used at various manufac-
turing scales.
Consideration of the principles of lean
process improvement during implementation
of single-use systems can help ensure that
maximum value is achieved.
DELIVERING VALUE WITH
SINGLE-USE FILTRATION
In order to deliver lean process benefits,
single-use systems must be able to speed
production processes, reduce the risk of
deviations, maintain consistency, and have
an immediate and favorable impact on the
bottom line through improved efficiency.
Assemblies must effectively keep pace with
changing product, scale and site require-
ments via a modular structure that is repli-
cable and scalable across geographies.
To fully support lean initiatives, the
single-use filtration system should offer fully
optimized, customized and integrated assem-
blies, and reduce waste.
Single-use storage and filtration systems
based on Mobius® Flexible Filtration ap-
proach (EMD Millipore) are designed to
target the wastes identified by lean process
initiatives: overproduction, defects, excess
inventory, overprocessing, unnecessary
transportation and motion, waiting, and un-
derutilized talent (Table 4).
Most critical to the successful implemen-
tation of single-use systems and delivery
of the full array of benefits, however, is the
applications support process. This prac-
tice brings together users, applications
engineers and lean process improvement
experts. Through observation of existing
process and direct interface with operators,
performance gaps and opportunities for im-
provement are identified.
The team then works in a collaborative
fashion to develop the new process designed
on Flexible Filtration principles.
REDUCING PROCESS
PRODUCTION TIME
We have found that single-use filration as-
semblies can reduce processing time by as
much as 50% through decreased preparation
and set-up time. A number of innovative ele-
ments are the drivers of this reduction. A
modular manifold design allows a manifold
to be built on site, to scale as needed. The
easy filling bag design eliminates the need
for operator handling during bag filling. A
universal bag design and scalable sterile
filtration assemblies facilitate technology
transfer between early development, late
development and commercial manufacturing.
Unique disconnection technology reduces
the time required for sterile disconnection to
less than a minute as compared to five to ten
minutes required by a tube sealer.
IMPROVING PROCESS CONSISTENCY
As with any lean process initiative, the
ability of single-use technologies to con-
sistently deliver the full range of expected
benefits depends on a thorough assessment
of the current processes, opportunities for
improvement, and a clear definition of ob-
jectives.
To this end, EMD Millipore mimics the
customer’s pilot manufacturing setup in our
Biomanufacturing Sciences and Training
Center (BSTC, Figure 1). The center enables
prototyping of solutions and performance
testing in a laboratory setting before the
definitive solution is finalized and delivered.
Consultants review process parameters
such as flow rate and pressure drop re-
quirements, and recommend appropriate
filter membrane and size when designing
filtration sub-assemblies.
As many as ten to fifteen operators can
gather at the training center to see, touch,
and use the prototypes in the training
center. Hands-on testing gives operators a
greater degree of confidence than a typi-
cal new processing setup might foster. In
addition, operators can provide real-time
feedback, allowing the solution to be better
adapted to their actual process.
FACILITATING TECH TRANSFER
The effectiveness of the technology trans-
fer process is critical to maintaining product
quality and speeding time-to-market. Use of
different systems from different vendors can
impede an efficient and accurate transfer
and force processes developed at one scale
to be recreated and re-optimized at other
scales.
Use of replicable, modular single-use sys-
tems help facilitate cost-effective and timely
Table 3 – Sources of Process Inefficiencies with Single-Use Systems
Multiple single-use components from multiple vendors
Long vendor lead times
Excessive item number set-ups, costly maintenance of multiple item numbers in material master
High inventory and scrap levels
Inefficient use of warehouse storage space
Inefficient use of operator time, EHS issues
Complicated assembly design and long set-up periods
Difficulties in handling single-use assemblies
P
pp1107_feature_millipore.indd 32 7/1/2011 11:15:03 AM
Table 4. Reduction of Waste Using Mobius Flexible Filtration
TYPE OF WASTE BENEFITS OF SINGLE-USE SYSTEM
Overproduction Based on the manufacturing requirements of the day, the operators can develop a Flexible Filtration-based solution by choosing
the right-size and right quantity of modular components such as a storage bag sub-assembly and a filtration sub-assembly and
connect them using a sterile connector sub-assembly, thereby preventing over-use of single-use components.
Defects A limited, yet prudent selection of modular components that can be easily connected to each other reduces the risk of excessive
handling related product defects, a very common occurrence with complex and custom designed single-use solutions.
Inventory Flexible Filtration-based solutions can result in as much as 75% reduction in single-use catalog numbers with the added benefit
of product consistency from a single vendor. This significantly reduces warehouse storage space, produces far less scrap, and
results in shorter ordering lead times. Item master maintenance is reduced and synchronized expirations dates are ensured. A
smaller set of catalog numbers and increased standardization also helps ensure security of supply.
Overprocessing A modular approach reduces unnecessary handling of supplies as well as time needed for data input and recordkeeping tasks.
Transportation The risk of damage associated with transporting assemblies, as well as the difficulty in moving complex assembly manifolds, is
reduced with modular solutions.
Waiting Flexible Filtration based modular solutions can result in as much as 50% reduction in single-use assembly set-up and handling
time. Easy connection of modular components using Lynx S2S sterile connector devices and easy filling bag designs requiring
minimal operator intervention during filling contribute to significant time savings and improve operator productivity.
Motion The traditionally designed custom single-use assembly manifolds can result in excessive motion related waste. Operators are not
only forced to design jury rigged hardware systems to support “spaghetti-like” assembly manifolds, they also have to spend a lot
of wasted effort and deal with EHS issues while maneuvering and using these assemblies. Flexible Filtration-based modular solu-
tions address this problem and make the assembly set-up and use a really simple step in the manufacturing process.
Underutilized People Flexible Filtration-based single-use systems incorporate extensive collaboration with and input from users. This process creates
engaged stakeholders with a clear understanding of how the system and processes work.
technology transfer across multiple sites and different scales.
IMPACTING THE BOTTOM LINE
Table 4 summarizes the reduction in waste that can be achieved
through proper incorporation of single-use systems. Properly estab-
lished single-use systems can deliver as much as a 20% reduction in
materials usage.
In addition to significant reductions in processing time and waste,
Flexible Filtration based single-use systems can significantly reduce
the number of part numbers needed to be maintained. One customer
has reported to us a 70% reduction in material master maintenance
when the number of single-use vendors was consolidated; with each
new catalog number requiring an investment of up to $1200 to main-
tain it annually in an ERP system, this reduction represents an im-
pressive cost savings.
PERSPECTIVE
Drug developers are actively exploring and leveraging single-use
operations to deliver lean process improvements. When incorporated
as part of an overall strategy to reduce waste and process time, im-
prove process consistency, and facilitate technology transfer, single-
use systems designed with lean process improvement principles can
deliver measureable benefits to the bottom line.
Critical success factors include consolidation of single-use vendors
and equipment to minimize variability and create consistency across
processes, and a collaborative approach with applications support
engineers and lean process improvement experts to assess current
process and identify opportunities for improvement. ■
■ P H A R MP R O . C O M
■ S I NGL E - US E
PHARMACEUTICAL PROCESSING | JULY 2011 33 ■
pp1107_feature_millipore.indd 33 7/1/2011 11:15:14 AM
■ 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
■ 34 JULY 2011 | PHARMACEUTICAL PROCESSING
Advanced Scientifics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21
Cook Pharmica LLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13
Heinkel Filtering Systems Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34
IMA North America Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .28, 35
Mettler-Toledo Safeline. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
Mettler-Toledo Hi-Speed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17
Millrock Technology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36
Natoli Engineering Company Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1, 7
OCS Checkweighers Inc. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23
Pall Life Sciences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Reed Exhibition Companies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16
Ropack Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25
Ross, Charles & Son Company . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .34
Scilog Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Sensient Pharmaceutical Coating Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Veltek Associates Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Western States Machine Co. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .33
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