Official Media Sponsor of
Quality and
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Focus: Packaging
Using Numerical
Simulations for APIs
Gradation in
Advances Lead to
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Industry Fights Back
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Impact Analytical expands to
meet the growing demands for
its analytical testing services
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■ P H A R MP R O . C O M
■ 4
12 Strategic Outsourcing
Quality and reliability drivers.
14 Packaging Matters
An interview with Almac's David Downey,
Vice-President Commercial Operations.
16 Fighting Back
Pharma takes aim at counterfeit drugs.
20 From Batch to Continuous
How numerical simulations can be applied to
continuous manufacturing of APIs.
24 Improving Lyophilization
Technological advancements lead to higher
quality products.
30 Improving Efficiencies for
Handling Small Parts
New technologies offer manufacturers a better way
of efficiently handling and orientating small parts.
34 Gradation in Pharmaceutical
A look at industry trends and how suppliers help.
36 Tablet Manufacturing
Over-lubrication effect in the force feeder of
a rotary tablet press.
40 Ten Rules for Pharmaceutical
Building an architecture for control documents.
42 Process Validation
A framework for implementing a stage 3 process
validation program.
8 Maximum Impact
Impact Analytical expands to meet the growing
demands for its analytical testing services.
page 28
page 24
page 31
6 From The Editor
28 What’s Hot
44 Blending, Mixing, Drying
48 Coating Equipment
50 Conveying Systems
On the Cover:
Impact Analytical
has moved to a larg-
er 17,000 sf facility
in Midland, Michigan
to provide a wide
range of analytical
services to industry.
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page 48
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There are a lot of things in life that – while I understand why they
are in place – I might not necessarily like.
For example, speed limits are something that I know need to be
in place. Without them people would drive as fast as they were able
to – most without a thought towards safety. Do I think that in some
places speed limits are artificially low? Yes, I do.
Taxes are another topic that fall into this category. Would I love
to not have to pay taxes? Of course, who wouldn’t? But I under-
stand they are necessary to pay for the many services we need
and take for granted. Some would argue that these services
could be provided for a lot less – but that’s a discussion
for another column.
Which leads me to my main point and this one involves healthcare.
Recently, The American Academy of Pediatrics (AAP) released new
guidelines to diagnose and treat bacterial sinus infections in chil-
dren. Sinus infections cause headaches, congestion and pressure. For
adults, sinus infections make us miserable, but we deal with them.
For kids, it makes them just as miserable and depending on their
age, miserable to live with. Sinus infections traditionally have been
treated immediately with a 10-day course of antibiotics. Now, the AAP
has come out with new guidelines that state a doctor can choose to
wait up to 72 hours before writing a prescription for a child’s sinus
infection. The thought behind this is that many infections will resolve
themselves without needing antibiotics and the over-use of antibiot-
ics is causing many types of infections to become antibiotic resistant.
I get this – but I don’t like it.
As a parent you want your child to feel better as soon as possible.
You don’t want to wait three days to see if symptoms start to im-
prove. You want that medicine working immediately, so they can get
back to school and you can get back to work.
Let me know if you get it too - but don't really like it.

■ P H A R MP R O . C O M
I Get It – But I Don’t Like It
Have a comment or question about Pharmaceutical Processing?
My E-mail is: mike.auerbach@advantagemedia.com
Recently The American Academy of
Pediatrics (AAP) released new guidelines
to diagnose and treat bacterial sinus
infections in children …
■Michael Auerbach, Editor in Chief
Phone: 973-920-7793; Fax: 973-607-5682
KY, MA, MI, MO, NH, NJ, NV Madison, WI 52713
NY, OH, PA, SC, TN, VT, WI Tel: 973-920-7793
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QUEBEC, CANADA bill.koenen@advantagemedia.com
DE, ID, SK, LA, MD Madison, WI 52713
ME, MN, MS, MT Tel: 973-920-7706
NC, NE, OK, OR Fax: 973-607-5516
SD, TX, UT, VA, WA david.oleston@advantagemedia.com
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rowth and expansion.
In any industry these two attributes are some-
thing that companies aspire to and are clear evi-
dence of a healthy company. And indeed, these two
fundamental tenants of business are what successful compa-
nies use as the basic building blocks for future success.
For the pharmaceutical industry – the recent past has
been anything but a time of growth and expansion – merg-
ers, acquisitions, and downsizing have all taken their toll on
the industry. For companies to grow and prosper they have
to look toward the future while also keeping a watchful eye
on their current business to provide the quality of services
their customers demand.
In the analytical services portion of the pharmaceutical
industry, Impact Analytical, based in Midland, Michigan has
shown a commitment to quality and to its customers that has
offered it the opportunity to grow and to serve many industries.
Impact Analytical is a division of Michigan Molecular
Institute (MMI) which was started in 1963 as a provider of
contract R&D services to the polymer industry. According
to Eric Hill, Impact Analytical’s Business Manager, the idea
back then was to create a research center in the Midwest to
compete with the big research companies on both coasts.
“The idea,” he says, “was to create a critical mass of poly-
mer technology and research in the Midwest.”
Over the years as the institute developed and grew, a lot
of analytical capability was developed. In 1996 the CEO at the
time decided to take the MMI analytical services group and
turn it into a revenue-generating unit that could stand on its
own. That service started doing external testing and Impact
Analytical was created.
“The first customers were plastic manufacturers doing
plastic testing and then chemical testing grew out of that,”
says Hill. “I came on in 1999 worked in the lab – then in
2004 – started doing marketing and sales. In 2004 a new
president was hired and the plan was to really grow the
company into a true for profit external testing company.”
Hill continues, “We then expanded our testing capabilities
to include other industries such as medical device, specialty
chemicals, consumer products and pharmaceutical – today
pharmaceutical is about 35 to 40 percent of our business.”
All of Impact’s labs are cGMP registered and all equip-
ment is cGMP qualified. “We are now focusing on pharma-
ceuticals but will continue to be diversified across multiple
industries,” says Hill. “Our primary focus in the near future
is medical devices, pharmaceutical and consumer products
– not necessarily in that order, but those are the industries
we are focusing on. Plastic and chemicals will alway be a
big part of our business considering where we are located.”
For an analytical services company like Impact Analytical
the importance of providing the right services with the
most advanced technology is key to their success. In addi-
tion to the technology, the importance of having the best
operational and quality control systems in place goes hand
in hand to provide the best service to their customers.
Regarding the impact of technology on their service offer-
ings, Hill points to the issues of throughput and detection.
“Throughput is very important – there are now larger and faster
Maximum Impact
Impact Analytical expands to meet the growing demands for its
analytical testing services
■ By Mike Auerbach, Editor In Chief
■ P H A R MP R O . C O M

Impact Analytical's new instrument lab features equipment that allows analysts to spend less
time operating instruments and more time analyzing data.

pp1307_coverstory.indd 8 6/24/2013 3:54:19 PM
The instrument lab features all new equipment including the latest UPLC equipment designed
to reduce run times, provide sharper peaks, better detection and use less solvent.
autosamplers. For example, take a look at technology like fast
GC or UPLC. With UPLC you can take an HPLC separation which
typically will take 25 to 40 minutes to run and with broad peaks
and you can now shrink that down to a 5 minute run, with very
sharp peaks and better detection and which uses less solvent
– its all around better. We’ve invested very heavily in this tech-
nology and going forward it will all be UPLC.”
Backing up the state-of the-art equipment are very robust
quality control systems. As Hill explains, “We have a full-time
quality manager and a very robust quality system in place.
Because we operate in various industries our quality systems
need to strong. Our base quality system is ISO 9001. Above
that we offer layers of GLP, GMP and DEA licenses."
"We can have one lab that offers ISO level quality and
right next to it one that offers GMP-level quality.”
“While the testing may be exactly the same as far as what
we are doing in the lab, the documentation behind that is
huge, as are safety controls. We also have to have a very
robust training system for people to operate in both modes
and still ensure quality.”
In addition to compliance scrutiny from agencies like the
FDA, pharmaceutical service companies like Impact Analytical
are also seeing increased scrutiny from the customer side.
“From the customer we see more scrutiny – because they are
outsourcing more,” says Hill. “If a company wants to contract
with us they need to have the confidence that we will deliver
on all the timelines, costs, but most importantly – the quality.”
“Recently, we have been seeing more people coming
to us saying ‘we have developed this drug candidate but
we want you to do all the analytical work from method
development to validation to release testing – all the way
through’. That’s a bigger relationship than we have seen in
the past and it all centers on trust.”
“Outsourcing is a preferred mode for the pharmaceutical
industry and our forecasts show 3 - 4 years of increased
outsourcing,” says Hill.
The success of Impact Analytical has resulted in a happy
problem - they have run out of space in their existing facility.
The company is currently in the process of fitting out its
new facility and expects to have it fully functional in a mat-
ter of weeks.
“Growth is where it's at right now,” says Hill. “In our old fa-
cility we had 7,000 SF and were truly cramped for space.” To
alleviate this problem Hill went before the company’s Board
and explained how, in order to keep growing and to continue
to provide quality services, the company needed more room.
His efforts paid off. “We purchased a building in Midland
- more than double the size of our current facility. It was a
17,000 sf warehouse with just admin areas – an open space.
We gutted the admin areas and built brand new lab areas.”
In addition to the “givens” such as administrative, sales and
■ P H A R MP R O . C O M
pp1307_coverstory.indd 9 6/24/2013 3:54:36 PM
staff as the new capabilities come on-line.”
“Our value proposition is that we are a to-
tal service provider,” says Hill, “that’s where
we try to fit in. Our niche is chemical analy-
sis, but the other niche that we fit is that we
have 25 people - we are going to try and re-
tain the feel of a small and flexible company.
Service is the big differentiator here. When a
company comes through the door we match
them up with our people. It’s literally scien-
tists talking to scientists. We want them to
feel like they are talking to a colleague. This
forms a more efficient relationship and re-
sults in better overall service." ■
lab – this increases safety,
reduce congestion, and
cuts down the number of
computers running instru-
ments - because multiple
instruments can be run
from one computer, saving
costs and also IT process-
Hill goes on to explain
that the facility is also
implementing a new
Microsoft Dynamics CRM/
ERP system which will
run the CRM system, a
LIMS system and their ac-
counting software. “That
software will team all of
our software together and give us tenfold
functionality,” says Hill. “It will do all of our
ordering, invoicing, chemical ordering, chem-
ical tracking and cost analysis.”
“The remote control of instruments is what
we are really looking forward to - to enhance
our service and efficiency for our customers.”
"Next year – we will begin looking at other
opportunities specifically in the pharma
space,” says Hill, “perhaps adding biologicals
capabilities. We need to evaluate those op-
portunities – we will have the space in our
new facility for adding capacity – and we will
also have to evaluate the need for additional
The sample prep lab is separate from the instrument lab to eliminate contami-
nation and any possibility of instrument damage.
meeting areas, the new facility features two
main lab areas – a sample prep lab and an
instrument lab. The basic idea behind this ar-
rangement might seem fairly obvious - put all
the instruments in one area and all the sam-
ple prep in another – but lab design, instru-
ment placement and safety all played a part.
“The idea is, number one, to make the in-
struments tools for the employees versus the
employees owning an “instrument” - we don’t
want that,” says Hill. “We want the instru-
ments to be tools for everyone that is quali-
fied to use them to make everything more ef-
ficient. You can shift resources around based
on the work – eliminating bottlenecks.”
“There is also a safety issue,” he continues.
“The prep lab handles all the sample prep
work and has all the safety equipment in-
stalled such as hoods, sinks, eye showers, etc.
Once samples are prepared – they are put in
vials and brought to the instrument lab. This
procedure keeps the sample prep area away
from the instruments, helping to prevent in-
strument contamination and any damage.”
“The other thing is that it will allow us to
take advantage of all of the latest software
that is available from the instrument manu-
facturers to allow remote access to instru-
ments. We want the analysts out of the lab
once the samples are running and in their
offices interpreting the data and writing
reports," says Hill. “The idea is to let the ana-
lysts control the instrument and download
the data from their office and not from in the
■ P H A R MP R O . C O M
• Actives Quantitation
• Dissolution Testing
• Impurities Identification
• Leachables And Extractables
• Method Development and Validation
• Method Transfer
• Molecular Characterization
• Package Testing
• Problem Solving
• Quality Control Testing
• R&D Support
• Raw Material Characterization
• Release testing
• Stability Testing
• Unknown Component ID
• Microscopy
Polarized light microscope
Transmission electron microscope
Scanning Electron Microscope w/EDS
• Thermal/Mechanical Properties
Differential Scanning Calorimetry
Thermogravimetric Analysis
Thermal Mechanical Analysis
Mechanical Testing
• Molecular Characterization
400 MHz NMR
Carbon13, Proton, Phosphorous/Silicon
GC-MS (EI and CI)
Direct probe MS (EI and CI)
• Elemental Analysis
• Separations
Gas Chromatography (GC)
FID, MS, TCD Detection
CAD, RI, DAD, ELS, UV-Vis, RI Detection
UV Detection
Size Exclusion Chromatography (SEC/GPC)
RI and MALLS Detection
Karl Fischer
pp1307_coverstory.indd 10 6/26/2013 1:53:15 PM
imagination at work
GE Healthcare
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Across the bioprocessing spectrum, our focus is on supporting you from idea to result.
Imaginative minds. Inspiring science.
GE, imagination at work and GE monogram are trademarks of General Electric Company.
Xcellerex and XDR are trademarks of Xcellerex, Inc., now a part of GE Healthcare.
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© 2013 General Electric Company - All rights reserved. First published Feb. 2013
growth potential
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In contrast to cost-driven generic drug development, the market
drivers for innovator drug development and manufacturing for
first-time approval of a New Chemical Entity are significantly dif-
ferent. Despite the fact that CMC requirements for filing an ANDA
and NDA are the same, innovator drug development encom-
passes much greater commercial, financial, and technical risk
than do generic drugs, as well as greater regulatory and sponsor
scrutiny. As a consequence, quality and reliability are the domi-
nant driver attributes for sponsor/CMO partnerships.
Quality and reliability encompass a number of attributes that
include regulatory and environmental compliance, robust quality
systems, innovative problem solving, meeting/exceeding mile-
stones and deliverables, and a commitment, to safety to name
a few. Vince Lombardi once said, “Winning is not a sometime
thing, it is an all-the-time thing.” Similarly, a CMO as an organiza-
tion must be committed to delivering quality and reliable ser-
vices. These attributes cannot be sustained on a transactional
basis; they must be part of the organization’s DNA.
Innovator drug development can take nearly a decade or
longer and cost hundreds of millions of dollars with only a 10%
chance at best of achieving market approval after entering clini-
cal trials.
With so much at stake, strategic outsourcing of drug
substance development and cGMP manufacturing are critical to
the success and cost effectiveness of an innovator drug develop-
ment project. Strategic outsourcing is more than just enlisting the
services of a CMO. Sponsor companies are looking for CMOs that
not only have the appropriate technical expertise and capabilities
for their project, but can also act as an extension of their own
organization, providing an interactive partnership whose exper-
tise can be leveraged to optimize the success of the program and
mutually benefit both organizations. In fact, a highly effective part-
nership that fosters the mutual exchange of information and ideas
can expand core knowledge and expertise, leading to the creation
of new knowledge, competencies, and capabilities.
Today’s dynamic pharmaceutical industry is placing unprec-
edented pressures on sponsor companies to develop high-per-
forming drugs more cost-effectively. Strategic outsourcing allows
drug developers to focus their capital and resources on critical
value-added activities while circumventing huge expenditures on
manufacturing infrastructure. CMOs are also feeling the pressure
■ P H A R MP R O . C O M
Strategic Outsourcing
Quality and reliability drivers
■By Vince Ammoscato, M.Sc., Ash Stevens Inc.
to provide cost-effective high-quality services while remaining
cost-competitive in an increasingly competitive market.
Even though quality and reliability are the main drivers for
innovator drug development and manufacturing, cost is also a
critical consideration for sponsor companies. Quality is expen-
sive and the challenge for CMOs is to cost-effectively deliver
high-quality services. The lure of low-cost offshore development
and manufacturing is attractive to Sponsor companies looking to
reduce development and manufacturing costs.
Over the past several years, however, the trend has been in the
reverse direction, with innovator API development and manufac-
turing moving back to onshore CMOs. The reason for this is the
realization through experience of the “true cost” of offshore drug
development, which encompasses much more than simple cost
savings in lower wage labor markets. Western CMOs located in
North America and Europe cannot compete with Asian pricing,
but they retain a competitive edge on quality, reliability, proximity,
and familiarity with western regulatory requirements. Many early-
stage Biotechs are hesitant to pursue development in Asia given
the complexities and greater risks involved. Small companies
have to get it right the first time and cannot afford compliance or
technical problems that culminate in costly delays.
Only about 8% of foreign manufacturing facilities were in-
spected by the FDA in 2012.
Consequently, the FDA is moving
towards a more proactive strategy to deal with the regulatory
demands of a rapidly changing and expanding global pharma-
ceutical market and supply chain. In the past, the FDA’s focus
has been primarily on regulatory compliance and less on quality.
Observations in the field by investigators, however, have brought
to light the fact that manufacturers who dedicate more resources
to quality, experience fewer compliance issues. Ensuring compli-
ance by manufacturers of the growing number of imported phar-
maceutical products is an onerous task that is rapidly out-pacing
the resources of the FDA. The FDA is moving towards a system
that places more emphasis on quality, enhanced transparency,
and greater stakeholder engagement.
In addition to the US, European nations, Japan, and other
countries are adopting a similar quality approach to API manu-
facturing. In November 2009, Guidance ICH Q8, “Pharmaceutical
Development” was finalized and issued by the International
Conference on Harmonization (ICH) of Technical Requirements
for Registration of Pharmaceuticals for Human Use (Europe,
The lure of low-cost offshore development and manufacturing is attractive to
sponsor companies looking to reduce development and manufacturing costs.
pp1307_outsourcing.indd 12 6/24/2013 3:59:28 PM
Japan and the US).The intent of this Guidance is to define an
approach to drug development that encourages industry to
adopt more modern and innovative manufacturing technologies.
Central to the approach is the concept of “Quality by Design”
or QbD. QbD is a scientific approach that enables an enhanced
understanding of safety and control of chemical drug manufac-
turing processes. The approach is designed to yield more robust
manufacturing processes than that which can be achieved by
traditional approaches to drug substance development.
The EMA has also enacted new legislation to protect the secu-
rity, integrity, and authenticity of drugs marketed in the EU. As
part of the new directive, starting July 2013, all active substances
manufactured outside the EU and imported into the EU must
be accompanied by a written confirmation from the regulatory
authority of the exporting country. The written authorization
statements are to be issued per manufacturing site and per ac-
tive substance. The exporting country also has to ensure that the
standards of cGMP used to manufacture the API are equivalent to
those enforced in the EU.
Given the significant risks and costs associated with the de-
velopment of innovator drugs, it is not surprising that sponsor
companies prioritize quality and reliability over pricing and seek
strategic partnerships over transactional relationships with CMOs.
Since innovator drugs are targeted for approval in established
pharmaceutical markets with strong patent protection, the po-
tential ROI lies in favor of quality over cost. The reason for this
is that even small delays in the development and/or API delivery
schedule of an innovator drug can rapidly wipe out any cost sav-
ings garnered from more risky lower-cost CMOs. Nonetheless,
there is tremendous pricing pressure in the current environment
to reduce the cost of development and manufacturing. Regulatory
compliance represents a significant portion of the cost of an API.
As Western regulatory agencies move to greater emphasis on
quality, transparency, and stakeholder engagement the cost differ-
ential between onshore and offshore manufacturing may narrow
even further. Conversely, as more R&D is conducted offshore and
as demand for innovator pharmaceuticals increases in emerging
markets, there will be greater incentives to develop and manu-
facture innovator drugs regionally. Since strategic outsourcing is
an interactive process, differences in time zones, culture, travel,
communication, and regulations will have to be taken into ac-
count to fully assess the “True Cost” of the outsourcing endeavor.
Experienced CMOs that can provide cost-effective pricing, sus-
tained quality manufacturing services, deliver on schedule, and
foster trusted and valued strategic outsourcing relationships will
prevail in the industry regardless of their global location.
1. BIO and BioMedTracker “Release of BIO/Biomedtracker
Drug Approval Rates Study” BIO International Meeting: Chicago,
Il; April 22-25, 2013.
2. US Accountability Office, GAO-11-936T, Sep. 14, 2011 “Drug
Safety: FDA Faces Challenges Overseeing the Foreign Drug
Manufacturing Supply Chain.” ■
■ P H A R MP R O . C O M
Experience makes a
world of difference.
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pp1307_outsourcing.indd 13 6/25/2013 3:29:48 PM
harmaceutical Processing
spoke with David Downey,
Almac's Vice-President of
Commercial Operations to
get his views on packaging trends in
general and some of the issues facing
contract packagers.
Is there a trend toward more sterile or
cleaner packaging environments?
Sterile environments tend to be exclusively
the purview of filling operations. Thankfully
packaging operations are managed within
a “pharmaceutically clean” environment as
required by GMP. However, Almac Pharma
Services operate our packaging operations
within a Class 100,000/Grade D background.
This exceeds the requirements of GMP
but it's a standard approach within Almac
Pharma Services to control the environ-
ment within which a product is packed.
Are there any new dosage forms that
you see as becoming more popular? If so, what are they and
do they pose any packaging issues?
Yes – lifecycle management, innovation and compliance are
driving numerous “new” types of dosage forms. For example,
combination products such as fixed dose combinations, bi-
and tri-layer tablets and multi-product blister presentations
offer pharmaceutical companies an option to treat multiple
conditions within a single presentation.
Similarly, we have also seen an increasing interest from
our clients in pediatric presentations as a result of recent
regulatory changes. Addressing the challenges of encourag-
ing children to take their medicine has opened up additional
drug formulations such as powder in bottle (for reconstitu-
tion) and flavored powders in sachets.
On the packaging front we see more clients requiring
product packaged in temperature and humidity controlled
environments. All these challenges present opportunities to
Almac Pharma Services as we pride ourselves on our ability
to provide solutions to our clients through dedicated engi-
neering, quality and project teams.
Have you seen an increase in requests from companies for dif-
ferent sizes, form factors or combo packs, etc.?
Again yes – packaging formats do seem to be trending away from
the simple tablets or capsules into bottles. We now package
multiple titration packs, combination products into blisters and
wallets, with the use of complex, yet user
friendly artwork to address patient compli-
The ability of our pack design and art-
work teams to address client needs and
provide mock-ups for marketing assess-
ment or submission purposes means that
expertise and solution provision in this
area is important.
Similarly with our continued focus on
orphan and niche drug launches, kitting
of complex biopharmaceutical packs is
becoming the norm. This can often involve
the design and label/assembly of a patient
pack involving the drug, companion diag-
nostic, plus ancillary items.
Lastly, as we have a dedicated penicillin
packaging facility in the UK we package
multiple combination products for the EU,
US and ROW markets.
Are sponsors asking packagers to provide
other services such as molding, forming,
graphic design, etc?
Yes – our clients are pleased to find that we can provide the
value added services such as tooling and pack design, artwork
management, QP services etc. Simply it means that clients can
leverage these additional services from Almac without having to
outsource further – it makes life easier for our clients. Integrating
project plan elements with a single supplier to ensure on time
launch, mitigate risk, and reduce costs is a “no brainer”.
Are contract packagers being asked to help provide solutions
for drug counterfeiting issues, and supply chain issues?
Yes, with the increasing problem of counterfeit, misbranded,
adulterated and diverted drugs entering the supply chain,
clients are requesting anti-counterfeiting measures to be intro-
duced more and more. Requests range from overt holograms/
watermarks to covert UV and IR reflecting inks to track and
trace solutions of 2D barcodes and full serialization.
Addressing the track and trace requirement, Almac Pharma
Services has developed an internal print and online verifica-
tion system that applies and verifies 2D matrix barcodes to
each carton. Our Overprint Serialisation and Inspection Sys-
tem incorporates the Hapa Red Cube Printer, Cognex Vision
System (confirms data is correct) and LVS Verifier (confirms
quality) and ensures serialisation to GS1 Standards.
How important to a potential client is it for you to demon-
Packaging Matters
An interview with Almac's David Downey, Vice-President Commercial Operations
■ P H A R MP R O . C O M ■

David Downey, VP Commercial Operations, Almac
project plan
with a sin-
gle supplier
to ensure on
time launch,
risk, and
reduce costs
is a “no
pp1307_feature_packaging.indd 14 6/25/2013 11:03:35 AM
■ P H A R MP R O . C O M
strate flexibility in packaging operations?
Telling a client that they can have a packaging slot for a launch
product next month just does not happen in Almac Pharma Ser-
vices. Flexibility is key, particularly when a new product launch
is involved. In our UK operations we have acted as site of
launch for the EU market for more than ten orphan drug prod-
ucts in the last three years. A fully integrated and experienced
project team consisting of Almac and client personnel follow a
well worn launch approach that Almac have refined over many
years. Objectives are defined within this plan with built in flex-
ibility to address the challenges that sometimes arise.
How important is the input and expertise of packaging
equipment vendors to the success of your operation?
Developing a close relationship with your packaging equip-
ment supplier is always advantageous to ensure you are fully
aware of the capabilities/limitations of the technology. Should
technical issues with the packaging equipment arise a solid
partnership with your supplier will also help minimize down-
time through expedited response times.
Have you seen an increase in FDA inspections/audits? Do your
customers inspect your facility now more than in the past?
Our new US commercial packaging operation in PA was recently
inspected by the FDA with no 483s. However allowing for this
milestone, our clients still have an internal audit requirement
to visit and “sign off” the site. With 40 years of commercial
manufacture and packaging experience in the EU we are well
versed in client audits. As we grow the business, specifically
within Almac Pharma Services, we are often seeing two client
audits per week across our various service lines. Similarly, as
we are named in more NDA’s, ANDA’s and MAA’s we see more
oversight from the regulatory agencies, whether they be FDA,
MHRA, ANVISA, JP authorities etc. We welcome these visits as
it illustrates our ongoing growth and success.
Where do you see the biggest growth in contract packaging in
the next five years or so? Will there be more growth in Rx or
OTC products?
That’s a good question and one we thought long and hard about
before opening our US commercial packaging operation. Person-
ally, I believe big pharma will continue to outsource more con-
tract packaging in an effort to reduce internal labor and overhead
costs – this will particularly be true in the OTC space.
Additionally, I believe, and hope, that pharma focuses more
heavily on quality and flexibility within that contracted packag-
ing environment so we avoid the negative headlines of recalls,
mislabeling etc.
For innovative Rx products Almac Pharma Services has seen
more and more smaller companies do business with us on
packaging/3PL of niche and orphan drug products, where all
requirements are fully outsourced. This fits perfectly with the
“one stop shop” model operated by Almac Pharma Services for
this particular type of product. ■
■ P H A R MP R O . C O M

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pp1307_feature_packaging.indd 15 6/25/2013 3:25:34 PM
n the U.S. we are accustomed to trusting that the medica-
tions we take are real and not fake. But incidents of coun-
terfeiting reported by drug makers have increased steadily
over the last decade to more than 1,700 worldwide last
year. Although only six percent of these were in the U.S.,
comes at a time when many of the largest U.S. drug manufac-
turers are mired in serious quality and regulatory issues. The
World Health Organization estimates that the worldwide market
for counterfeit drugs topped 430 billion U.S. dollars a year
Counterfeit drug rings operate across borders and rake
in billions of dollars every year. This is costing legitimate
drug makers a small fortune in lost sales, all the while put-
ting patients at risk of unknowingly taking counterfeit drugs.
Experts estimate hundreds of thousands of people around
the world die because of counterfeit medicines each year.
The USFDA defines counterfeit drugs as a “drug which, or
container or labeling of which, without authorization, bears
the trademark, trade name, or other identifying mark, im-
print, or device, or any likeness thereof, of a manufacturer,
processor, packer,
or distributor other
than the person or
persons who in fact
manufacture, pro-
cessed, packed, or
distributed such drug
and which thereby
falsely purports or
is represented to be
the product, or to
have been packed or
distributed by, such
other drug manufac-
turer, processor, packer, or distributor.”
The definition of counterfeit carries the notion of sub-
standard quality, extending to products without the active
ingredient, with an insufficient or excessive quantity of the
active ingredient, with the wrong active ingredient, or with
fake packaging. This applies to branded and generic drugs
and to bulk ingredients used to make the drug therapy.
Figure 1 shows the escalation of cases the agency is dealing
with. The FDA has not taken the issue lightly and has formed
a new office focused specifically on the issue of counterfeit
drugs. The Office of Drug Security, Integrity and Recalls
(ODSIR), is equipped with resources to address supply chain
threats such as intentional adulteration, cargo theft and diver-
sion. This new division considers the problem through the
entire lifecycle of a product: from drug components through to
the finished dosage for delivery to the patient.
So, too, has industry taken this threat to public safety and
market integrity to heart. Over two dozen of the world’s larg-
est pharmaceutical companies have agreed to provide fund-
ing and other support to Interpol’s battle against counterfeit
prescription drugs.
Interpol’s newly created Pharmaceutical
Crime Program was set up to help health agencies, police and
customs bureaus around the globe stem the supply of bogus
brand-name and generic medicines.
Pharma has pledged nearly $5.9 million over three years to
help Interpol with efforts such as training local law enforce-
ment officials on investigative procedures, evidence handling
and how to work with partners outside their home countries.
Interpol will help local authorities build up their infra-
structure and target enforcement actions against crime
rings who make and sell fake drugs and divert medication
illegally to countries where it’s not approved.
There is no magic bullet that can address the threats to
the supply chain. A framework for a structured risk assess-
ment across each key step of the supply chain is the first
step in identifying risks. Luckily today, the available tech-
nologies are mature and cost effective. The FDA has pub-
lished several guidance’s targeted specifically at Track and
Trace technology; both serialization of drug packaging
the use of physical-chemical identifiers
are well established
anti-counterfeiting measures.
The potential suite of solutions within each of these guid-
ances is broad. From individual dosage form identifiers that
Fighting Back
Pharma takes aim at counterfeit drugs
■ By Bikash Chatterjee, President and CTO, Pharmatech Associates
■ P H A R MP R O . C O M

Figure 2. RFID Technologies
Figure 1. Number of Drug Counterfeit Cases Opened by FDA’s
Office of Criminal Investigations per Fiscal Year
pp1307_feature_bikash1.indd 16 6/24/2013 3:55:37 PM
a tag. Semi-passive
tags use power for
sensors and can
transmit as a pas-
sive platform when
queried by a reader.
Semi-active tags can
initiate transmission
but do not stay on
all the time. Finally,
we come to active
tags. These typical-
ly come equipped
with a lithium battery and can emit a signal periodically. The
sky is the limit for these tags in terms of pricing: they can eas-
ily cost from $20 to $150 per unit. Examples of RFID technol-
ogy are shown in Figure 2.
2. Tamper Evident Labels - Two types of tamper evident
seals are used to indicate tampering; self-destructive labels
and stealth RFID labels. Self-destructive labels are designed
to fall apart if someone tries to remove them; stealth RFID
labels utilize a secondary RFID signature that changes if the
label is moved. This is transparent to the adulterer but can
be flagged upon receipt using a proprietary reader.
3. PUF Technology - PUF stands for Physical Unclonable
Function and is a chip technology that takes advantage of the
fact that every silicon chip has a unique and instantaneous
signature. PUF technology has been used for high value
assets by the military and represents a very highly secure
4. 2D and 3D Bar Coding - By far the most broadly
implemented Track and Trace solution in the pharmaceutical
industry is 2D bar coding. 2D bar codes encode data both
horizontally and vertically: they have limited security and
are easily duplicated. 3D bar codes are engraved or applied
and are much more difficult to duplicate.
5. Holograms - Holograms are used broadly within the
pharmaceutical industry as a sign of authenticity. Unfor-
tunately, in many of the emerging markets counterfeiters
create packaging that is superior to the branded drug and
use holograms as their label of quality. Holograms use alight
signature to authenticate. Hologram technology has evolved
rapidly to the point that QR codes and even other holograms
can be placed within a hologram, making duplication very
difficult if not impossible. Examples of holographic security
labels that include secondary verification technology are
shown in Figure 6.
6. Bar Code within an Image - One of the most innovative
track and trace solutions is to use a bar code embedded within
a label or image. Pharma companies in many high risk markets
have successfully deployed this technology in combination
with a decoy barcode. Counterfeiters duplicate the diversion-
ary barcode without realizing that the true identifier bar code
is embedded in the logo or other image on the label. Serializa-
tion technology can easily be employed for this application.
Figure 7. Example of Synthetic DNA Illuminated
by a Custom Reader
immediately flag
a counterfeit drug
at the dosage form
level, to track and
trace sensor solu-
tions that surrepti-
tiously indicate they
have been tampered
with are available
in the marketplace.
The following technologies are mature and represent tan-
gible deterrents to drug counterfeiting:
1. RFID - The promise of RFID is undeniable, but it is impor-
tant to understand its technological limitations before launch-
ing into an RFID implementation. RFID tags can be grouped
into four basic categories: passive tags, semi-passive tags,
semi-active tags and active tags. Passive tags are by far the
mostly broadly implemented and span several market sectors.
They are designed to simply store data that can be read by a
reader and are the lowest priced technology - costing pennies
Figure 6. Examples of Holographic Security Labels
Figure 5. 2D and 3D Bar Code Technology
Figure 4. PUF Technology
Figure 3.Tamper Evident Label Technologies

■ P H A R MP R O . C O M
pp1307_feature_bikash1.indd 17 6/24/2013 3:55:55 PM
■ P H A R MP R O . C O M
7. Synthetic DNA Signature - Another
effective and broadly used track and trace
solution is synthetic DNA. This is custom
fabricated to be invisible to the naked eye
but visible by a specific light frequency. The
readers are inexpensive and easy to use.
Synthetic DNA solutions are inexpensive and
limitless in terms of their combinations.
8. Serialization - In March of 2010 the FDA
issued its guidance on serialization defining
the concept of a Standardized Numerical
Identifier (SNI). Europe has been requir-
ing SNIs for years now. The decision by
California’s pharmacy board to push back
its e-pedigree requirement provides the
industry the chance to implement the neces-
sary systems to comply. SNI solutions go far
beyond the technology itself. Subsumed with
the decision to implement a SNI scheme are
the following activities:
• Establishing a security framework for data
• Record retention policies,
• Implementation of SNIs at the pallet and
case level,
• Standardized chain-of-custody data to be
tracked by logistical units,
• Standardized electronic data exchange
• Data carriers with specific encoding for-
mats identified,
• Guidelines for reporting exceptions noted
by supply chain participants, and
• Hierarchy of the SNIs expected in a shipment.
Mandatory serialization will be here
sooner rather than later and developing the
necessary support systems as part of an
anti-counterfeiting strategy will position an
organization to meet the impending e-pedi-
gree requirements in 2015.
As the pharmaceutical supply chain contin-
ues to expand across the globe, the risks to
supply chain will continue to escalate. Simple
risk management approaches are highly ef-
fective in identifying weak links in the supply
chain that represent a risk to product safety,
quality, integrity, purity and potency. Track
and trace solutions have matured to a point
where they can cost-effectively address coun-
terfeiting, adulteration and drug diversion
risks across the global drug substance and
drug product supply chain.
1. M. Perrone, AP, USA Today, Counterfeit
Drugs Becoming Big Business Worldwide,
Feb. 2012
2. AP, Pharmaceutical Companies Fund
Interpol Fight Against Fake Prescription
Drugs, March 2013
3. I. Bergeman, FDA Effrts: Counterfeit Drugs
, CDER, FDA, Apha Annual Meeting ,
March 2013
4. FDA Guidance for Industry Standards
for Securing the Drug Supply Chain -
Standardized Numerical Identification for
Prescription Drug Packages, March 2010
5. FDA “Guidance for Industry Incorporation
of Physical-Chemical Identifiers into Solid
Oral Dosage Form Drug Products for
Anticounterfeiting”, October 2011. ■
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Figure 3: DEM simulation for tablet coating with
STAR-CCM+ showing pill coating thickness in a
fluidized bed.
■ By Sabine Goodwin, Senior Engineer, Technical Marketing, CD-adapco and Dr. Kristian Debus, Director,
Life Sciences, CD-adapco
ith unprecedented economic pressures and
increased global competition, pharmaceuti-
cal manufacturing companies are continu-
ously looking to gain a competitive advantage
through improving the efficiency of their processes and the
quality of their products. Traditional manufacturing processes,
which are batch processes, are no longer sustainable and
there is no question that continuous manufacturing is the clear
path forward towards leaner processes. Multi-physics numeri-
cal simulation is emerging as game-changing technology to
help continuous manufacturing for Active Pharmaceutical
Ingredients (APIs) become a reality through virtual prototyp-
ing, optimization and modeling of the complete system.
The pharmaceutical industry is encountering a decline in
productivity, and outdated “tried-and-true” batch processes are
at the root of the problem. The batch-based systems currently
in place are inefficient due to segmented steps involving multiple
facilities and requiring start-and-stop of the batch, site-to-site
transfer and warehouse storage. Performed through sampling
and in post-production, quality assessment of the product is
also cumbersome, causing long lead times and waste.
Continuous manufacturing, a non-stop end-to-end manu-
facturing process, could modernize the industry and solve its
productivity crisis. At a recent MIT conference, Josef Jimenez,
CEO of Novartis, stated that changing production from batch
to continuous will transform the way medicines are made
around the world and could cut the time from development
to market-entry in half [1]. Implementation of these processes
will result in smaller production plants, lower inventory costs,
reduction in carbon footprint and higher quality products [2].
The regulatory agencies are also starting to lay the
groundwork for continuous manufacturing with several ini-
tiatives [3,4] and regulatory frameworks such as the Process
Analytical Technology (PAT) and Quality by Design (QbD).
Each of these encourages the development of new manufac-
turing technologies by building quality into the process and
using a science-based quantified risk approach.
Both the chemical and food processing industries have
been improving their productivity by successfully integrating
continuous manufacturing into their plants. It is clear that
regulatory hurdles and conservative thinking by the pharma-
ceutical industry can no longer be used as an excuse to avoid
taking pharmaceutical manufacturing into the 21st century.
Before continuous manufacturing can become main-
stream, potentially suitable candidate processes must be
From Batch To Continuous
How numerical simulations can be applied to continuous manufacturing of APIs
■ P H A R MP R O . C O M
Figure 1: Ultra-lean manufacturing, from start of chemical synthesis to
final pharmaceutical dosage form. (courtesy of Novartis-MIT Center for
Continuous Manufacturing)
Figure 2: DEM simulation with STAR-
CCM+ showing tablet velocity magni-
tude as they tumble in a coating pan.
pp1307_feature_continuousprocess20 20 6/25/2013 11:04:43 AM
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■ P H A R MP R O . C O M
identified and designed, and risks must be
analyzed and mitigated. This will help man-
age regulatory compliance and make a busi-
ness case for implementation. Multi-physics
Computational Fluid Dynamics (CFD), a
numerical method for predicting the coupled
behavior of fluid, gas and particulate flows
including heat and mass transport, offers a
solution for the enhanced understanding and
design of these novel processes.
Virtual Prototyping
Traditional manufacturing processes are
based on the “design-build-test” principle
in which the effects of design changes are
quantified by experimental tests on physi-
cal prototypes. There are currently very few
suppliers who are developing integrated sys-
tems for continuous manufacturing and, as a
result, physical prototyping is anticipated to
be very costly. Numerical simulations enable
the engineer to build a virtual laboratory,
providing insight into the performance of a
product before tests are carried out. This
means that the uncertainty resulting from
major process and equipment changes can
be evaluated up front, leading to a significant
risk reduction and cost savings.
Multi-physics CFD and state-of-the-art
visualization tools also offer a wealth of
detailed information, not always readily
available from laboratory or experimental
tests. This not only results in an increased
level of insight into the details of what is go-
ing on inside the processes, it also enables
innovation. For example, multi-physics CFD
can help explore new reactions and mol-
ecules for drugs manufactured with a con-
tinuous process.
Design Exploration and Optimization
In recent years, the phenomenal increase
in computing power and the maturing of
robust simulation tools have paved the way
for using numerical design optimization in
production environments. Parameter studies
and optimization will be vitally important
for designing and tuning of the new (often
smaller) equipment required for continu-
ous manufacturing while ensuring that the
operation can efficiently handle fast reac-
tions and remains flexible. In addition, the
CFD-generated responses -obtained through
design of experiments over a range of op-
erating conditions and equipment design
parameters -can be combined with statisti-
cal models to identify risk and implement
robust real-time process control. This will
ultimately result in reduced variability and
consistent, repeatable processes.
Optimate (a module in STAR-CCM+ using
Red Cedar Technology’s HEEDS software)
is an example of a tool that enables intel-
ligent design exploration to easily consider
“what if” scenarios and identify the critical
manufacturing points that define quality.
For example, feeding devices for continuous
manufacturing influence all downstream op-
erations and designexploration of parame-
ters such as feed rate will help identify their
impact on final blend uniformity.
Solving complex real-world problems
demands an accurate, easy-to-use, multi-dis-
ciplinary approach to simulating complete
systems. CFD-focused multi-physics engineer-
ing simulation tools such as STAR-CCM+ can
accurately deliver full spectrum engineering
results and the pharmaceutical industry
should fully leverage these tools in support
of the development of continuous manufac-
turing processes.
Up until now, inte-
gration of numerical
simulations in a pro-
duction environment
has required a great
deal of specialized
knowledge, but this
is no longer a show-
stopper. Automation
and ease-of-use are
enabling the deploy-
ment of CFD for
complex multi-phys-
ics applications. For example, STAR-CCM+
offers state-of-the–art meshing, seamless
integration with CAD and easy modeling of
complex moving parts, all in a single inte-
grated environment. The net result is more
time for an engineer to analyze data instead
of preparing and setting up the simulations,
resulting in engineering success.
Seeing the “big picture” for continuous
manufacturing will require a multi-phys-
ics approach to solving problems. Be it
mixing, coating or drying, multi-phase
flows lie at the core of the pharmaceutical
processing industry. Capabilities such as
Discrete Element Modeling (DEM), a nu-
merical method for computing the interac-
tion of a large number of small particles,
and Eulerian Multiphase Modeling (EMP),
a numerical method for simulating several
phases in a system, will be invaluable for
implementing continuous manufacturing of
APIs. Two case studies are presented next
to demonstrate these capabilities.
DEM simulates the motion of a large num-
ber of interacting particles and tracks them
in a numerically efficient manner, modeling
contact forces and energy transfer due to
collision and heat transfer between par-
ticles. DEM will be particularly important
in the design and optimization of continu-
ous coating processes to help identify the
important factors for equipment design (e.g.
number of spray guns) and to determine op-
timal equipment operation conditions (e.g.
inlet temperature).
Figures 2 and 3 show STAR-CCM+ gener-
ated solutions for two types of equipment
Figure 4 : Mixer model showing the effects of increasing gas injection rate using STAR-CCM+
pp1307_feature_continuousprocess22 22 6/25/2013 11:04:58 AM
■ P H A R MP R O . C O M
currently used for real-world tablet coating:
coating pan (rotating drum) and fluidized
bed. In these simulations, DEM is used
to analyze the random movement of the
particles as layers of coating are applied.
Parameters such as particle velocities,
residence time and coating thickness are
tracked to assess and improve tablet coat-
ing uniformity. In addition to tablet coating,
DEM can also be used to simulate other
steps in manufacturing such as filling, filter-
ing and conveyer processes.
EMP modeling provides an effective means
for studying the interacting streams and
randomly dispersed phases in multiphase
flows. The EMP model in STAR-CCM+ includes
an extensive range of sub-models including
break-up and coalescence models for bubbles
and droplets and a granular flow model for
particles. Figure 4 demonstrates an EMP
simulation of a gas-liquid mixer with three
rotating impellers. Shown are the effects of
increasing gas injection rates on gas. The
ability to predict gas hold-up, a parameter
that governs mass transfer across the phases
and consequently rates of reaction, is a key
enabler in the design of such reactors. This
approach adds valuable scientific insight into
the decision-making criteria to develop practi-
cal solutions for mixing and other processes
in continuous manufacturing.
In today’s competitive climate, manufac-
turing must become leaner with a focus on
building quality into the process. Continuous
manufacturing for the pharmaceutical indus-
try will change the way drugs are made and
multi-physics CFD simulations offer a cost-
effective way to perform rapid prototyping
for design of new equipment and processes.
In particular, design optimization tools and
powerful multiphase models such as DEM
and EMP will play an important role, and the
pharmaceutical industry should fully lever-
age these state-to-the-art technologies for
the design and implementation of continuous
manufacturing processes.
1. “A Defining Moment: The Future of
Manufacturing in the US”, Presented at
The Future of Manufacturing in the US
Conference, MIT, May 8-9, 2012
2. Plumb, K. Continuous Processing in the
Pharmaceutical Industry : Changing the
Mindset, Chemical Engineering Research
and Design, 2005, 83, 730-738
3. “The FDA Critical Path Initiative and its
Influence on New Drug Development”,
Woodcock J., Woosley, R. ,Annu. Rev. Med.
2008. 59:1–12
4. “Pharmaceutical cGMPS for the 21st
century” - A Risk Based Approach
Pharmaceutical%20cGMPs.pdf) ■
pp1307_feature_continuousprocess23 23 6/25/2013 11:05:11 AM
■ By
■ P H A R MP R O . C O M
s the freeze drying/lyophilization process has
progressed over the past few years, the industry
has encountered advancements in technology
that can improve the process. Whether it is
exploring alternatives to glass vials or utilizing the latest
control systems ensuring quality and reducing waste, the
freeze drying/lyophilization process offers users technologi-
cal advancements to produce quality products.
Processors can see advancement in the use of isolators
and barrier equipment. With the ever increasing regula-
tory requirements, processors are encountering the use of
isolators or barrier equipment to reduce contamination.
“LSNE performs a risk assessment and acquires a toxicol-
ogy review of all incoming compounds so we can be sure
that we are using the proper level of containment to mini-
mize personnel exposure and cross-contamination,” says
Christine Palus, vice president of sales and marketing for
Lyophilization Services of New England.
Additional safe handling efforts are required as the need
for smaller and more sophisticated freeze dryers continues
to grow. “As technology progresses, drug potency increases
and the amount of product in the vial is reduced,” says T.N.
Thompson, president of Millrock Technology, Inc. “Smaller
vials are being used and the value of the product is increas-
ing…The higher potency drugs also drive the need for safer
handling and the need for isolators and sterilization.”
In order to optimize lyophilization cycles while minimiz-
ing risks, DSM Pharmaceuticals, Inc. looked toward freeze
dryers with oversized condenser capacity and liquid ni-
trogen cooling where isolators and barriers minimize risks
from operator intervention or contamination.
While traditional glass vials have remained a mainstay in
the lyophilization process, some people in the industry note
the potential use for other materials. Utilizing other materi-
als would offer several benefits. Lars Waldmann, process de-
velopment manager at Pharmalucence, Inc., recognizes that
one benefit to a glass vial alternative is the possibility to
reduce the number of broken vials. However, he also notes
the concern about the age and viscosity of plastics.
According to Jeremy Griffin, with Grand River Aseptic
Manufacturing, glass vial alternatives include container sys-
tems manufactured from plastic or with a special coating.
“The technology looks pretty promising, but it is still wait-
ing to be scrutinized by regulatory agencies,” he says.
Palus has seen some movement away from traditional
glass vials, specifically towards the Crystal Zenith resin vi-
als. “They are a good alternative since their dimensions are
similar to the standard glass vials, and they can be filled on
Industry Progress Improves
Freeze Drying/Lyophilization
Technological advancements lead to higher quality products.
■ By Kimberley Schmitt, Associate Editor
■ P H A R MP R O . C O M
LSNE (above) utilizes the proper level of containment to minimize person-
nel exposure and cross-contamination. DSM Pharmaceuticals, Inc. (left)
looked toward freeze dryers with an oversized condenser capacity.
pp1307_feature_lyophilization.in24 24 6/25/2013 2:36:35 PM
pp1307_ads.indd 25 6/27/2013 8:26:20 AM
Millrock Technology's Revo Series features
Freezebooster, Accuflux and Auto-Dry technologies.
■ P H A R MP R O . C O M
our automated vial filling line,” she says.
“Since the vials are made out of break-
resistant materials it can help reduce the
risk of vial breakage during shipping.”
Another option available for vials is a sys-
tem incorporating the stopper in the caps.
“Typically, the stoppers and caps come
separately,” says Joe Redford, formulation
and preparation team lead at Grand River
Aseptic Manufacturing. “However, systems
are coming out with the stopper in the cap.
So, during the lyophilization process the
capping takes place at the same time—eliminating risk.”
Griffin notes that this system saves in production time because
the material does not have to be processed twice. However, one
drawback is that it requires custom equipment.
While non-glass vials limit breakage, processors may encounter
a few drawbacks to using the product. “The biggest drawback to us-
ing a non-glass vial is that additional material capability studies are
required and there is a risk of extractables and leachables,” Palus
says. “Additionally, because the vials arrive pre-sterilized, there are
some different handling procedures.”
The industry has seen several new control systems emerge over
the past few years resulting in a significant impact on processing.
These control systems ensure that the safest and most effective
product is delivered to the market. One area processors have seen
improvement is in controlled nucleation.
“The freezing process has always been considered the foundation
of the freeze drying process, yet it has never been properly con-
trolled,” Thompson says. “Simply placing vials on a shelf and lower-
ing the shelf temperature leads to heterogeneous nucleation and
non-uniform crystal growth.”
Millrock Technologies has improved nucleation with its
FreezeBooster, a controlled nucleation that nucleates all the vials at
the same time, temperature and rate to produce a consistent point
for freeze control across the entire batch. It also has AccuFlux, a
heat flow control for controlled crystal growth.
Providing the highest yield for customers has led DSM to develop
new systems. “We have developed new systems and process flows
designed to detect and eliminate quality issues to prevent impact on
the product,” says Wayne Edgerton, director of manufacturing and
packaging production at DSM Pharmaceuticals, Inc. “We use auto-
mation when applicable to control and monitor our process to help
maintain the highest quality standards.”
Patheon has encountered process analytical technologies that
have been developed mainly for lyo pilot units where the devel-
opment of lyophilization parameters is preformed. It includes in-
process monitoring, NIR/FTIR, micro-gravimetric, thermocouples,
lyophilizer headspace monitoring pressure rise testing/MTM, and
pirani vs. chamber pressure.
Another area where controls have seen advancements is in the push
to streamline lyophilization cycles exposing the product to lyophiliza-
tion for specific times. “Basically they are exposed only for the time
they need to be rather than the old mentality of it needs to this much
time to freeze and add an hour,” Griffin says. “The cycles that are run
with products will be very specific, and there won’t be slack in that.
This technology will allow users to reduce waste and increase quality.”
Wireless technology for temperature mapping is another control
system Griffin has encountered and hopes to see accepted for pro-
duction within the next few years.
As the demand for freeze drying/lyophilization continues to
grow, the future of the service will result in possible technological
changes to adjust and meet the industry standards. From creating
systems that conserve energy to improving temperature distribu-
tion, processors will find the freeze drying/lyophilization process
improved in various areas.
Waldmann predicts the next five years will lead to a greater focus
on energy and utility conserving systems in the market. “Currently,
control systems follow the architecture of PLC system for actuation
of the mechanical components of the lyophilizer or loading systems,
which connects to a PC or HMI,” he says. “With microcontrollers
becoming more powerful and capable to drive HMIs we may see an
elimination of the PC and instead control the whole system by a mi-
Representatives from Patheon, Inc. also believe that new process
technologies for fast, continuous freeze-drying will move forward
in the next five years. They believe the rationale is behind the need
for economic drying processes for large scale production, mass pro-
duction of MABs and the need for bulk storage as an alternative to
frozen solution.
The addition of fully automated loading systems in isolator or
RABS is another possible option in the future of freeze drying.
“Cycle optimization will be a key component to our success to open
up additional capacity in the freeze dryers,” Edgerton says. “As tech-
nology improves with thermal transfer and cooling capabilities the
Some systems are incorporating the stopper in the caps during lyophilization - elimi-
nating risk and reducing production time. (Photo courtesy: Pharmalucence)
pp1307_feature_lyophilization.in26 26 6/25/2013 2:36:53 PM
Above: Consistent temperature distribu-
tion within shelves is a design consider-
ation for lyophilizers in order to ensure
quality products. Right: Despite available
alternatives, glass vials remain a main-
stay in the freeze dry process.
(Photos courtesy: Grand River Aseptic
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■ P H A R MP R O . C O M
trol for the freeze drying process. “With the ability to measure and
control the heat flow, the product can be properly and consistently
frozen,” he says. “The shelf temperature can be optimized during pri-
mary drying to shorten the cycle while maintaining product quality.”
While the demand for lyophilization continues to grow, Palus an-
ticipates a continued shortage of lyophilization capacity at CMOs.
“Due to the increased demand for lyophilization against a backdrop
of some capacity being removed from the market due to regulatory
considerations, we anticipate that there will most likely continue
to be a shortage of lyophilization capacity at CMOs,” she says.
“Lyophilization is a complicated science and not every company
with a lyophyilizer can successfully develop or execute the process
so we believe we will see certain companies emerge as lyophiliza-
tion experts.” ■
newer freeze dryers should be
able to handle more aggressive
cycles that will help with im-
proving cycle times.”
Waldmann also expects to see
more manufacturers of lyophiliz-
ers to offer loading systems for
barrier applications. “Right now there are still a significant number
of manufacturers that do not offer automated loading systems for
lyophilizers,” he says.
Thompson foresees the next five years resulting in process control
and PAT as the major considerations for freeze dryers. “Today, the
freeze drying process is an open loop control with very little monitor-
ing in-situ,” he says. “Processing companies may not know there is a
faulty run until the freeze drying run is completed. New technologies
will enable complete control of the freeze drying process including:
Controlled Nucleation, Controlled Crystal Growth during freezing,
Product Temperature Control instead of shelf temperature control, the
ability to determine the end of freezing and the end of primary drying,
and the ability to verify that the process has executed properly.”
With changes made to freeze dry technologies, Griffin notes that
there is always room for improvement with temperature distribution
within shelves. “Temperature distribution within shelves is a constant
design consideration when they are building lyophilizers that is huge
for product quality,” he says. “If shelf stability and uniformity with ly-
ophilizers can be nailed down that would be huge for the product.”
Thompson also notes that FreezeBooster controlled nucleation and
AccuFlux heat flow control will become the preferred method of con-
pp1307_feature_lyophilization.in27 27 6/25/2013 2:37:22 PM
Vented Enclosures
Series of vented enclosures provide effective containment of
airborne particulates during manipulation and transfer of
potent compounds. In-house research suggests that even slight
modifications of enclosures can result in containment
factors from the microgram down to the nanogram.
The turbulent-free design utilizes environmen-
tally friendly, ductless technology in combination
with carbon/HEPA filtration to provide precise,
safe containment in all applications. Ductless
technology also makes installation of dedicated
workstations easy, as no additional HVAC design
is required. Features include turbulent-free airflow pattern,
custom sizes to meet every need, specialized HEPA-filter technology for
increased safety, and a ductless design that increases location possibilities. ■ Air Science USA,
Fort Myers, FL 33906. www.airscience.com or call 800-306-0677
Filtration Plant
M embrane-filtration pilot unit is ideal for investigational and process-development
projects in the pharmaceutical industry. With correct membrane selection, the
filtration process can produce a purified or more concentrated end-product, not only
removing particulates, but also separating dissolved species of specific sizes while al-
lowing other dissolved components to permeate through the membrane. The lab-scale
integrated test platform is caster-mounted for portability. It is designed to accommo-
date a broad range of membrane geometries, including tubular, spiral, hollow fibre and
ceramic, and can attain the flows and pressures required for reverse osmosis, nanofil-
tration, ultrafiltration and microfiltration operation. The units are supplied with all the
instrumentation necessary to automatically collect data on pressures, temperatures and
flows to enable process modelling for full system scale up. ■ Membrane Specialists, LLC
Hamilton, OH 45015. www.membranespecialists.com or call 513-860-9490
■ P H A R MP R O . C O M
Industrial Vacuums
White Line vacuums are ideal for facility
maintenance and continuous-duty process
integration within applications where hygiene is
essential. The VHW321, VHW310 and VHW311
feature advanced safety solutions, easy-to-clean
design and new application-special features.
The VHW321 portable unit is engineered to
make daily cleaning in production areas and
process manufacturing fast and hassle-free. This
premium model is equipped with new conical
cartridge filters that provide more surface area,
extended filter life and resistance to clogging. To
reduce production downtime, users can clean
the new filtration system with the vacuum in
use. A Bag-In Bag-Out system is also available
for safe replacement of the HEPA filter, eliminat-
ing the possibility of contact with any collected
toxic materials. ■ Nilfisk CFM , Morgantown,
PA 19543. www.pharmaceuticalvacuum.com or
call 800-645-3475
Cleanroom or Containment
PODs are self-contained, autonomous clean-
room or containment systems for biopharma-
ceutical product processes. PODs are flexible,
rapidly deployed, scalable, and mobile due to
integrated air bearings. The POD is typically
positioned in grey space. The maintenance
area of the POD is easily accessible via the grey
space. PODs provide ultimate flexibility and can
be used in multi-product or patient scenarios,
as the PODs can be easily decontaminated via VHP. ■ G-CON, College Station, TX 77841.
www.gconbio.com or call 979-314-7473

pp1307_whatshot.indd 28 6/25/2013 10:39:57 AM
Fully Integrated Drive for OEM Pumps
DriveSure™ is a new panel-mount OEM brushless DC
gear motor with fully integrated speed controller.
The highly adaptable drive is an ideal solution for
biopharmaceutical, medical device, and process
analysis equipment. DriveSure features a 51:1
control ratio and a 408-8rpm speed range. The
drive is offered in 24V and 48V DC options, and
directly accepts market-standard analogue
control signals. DriveSure features a range of
panel-mount brushless DC motor gearboxes
and controllers as a package, ideal for OEMs wishing
to panel-mount Watson-Marlow’s proven pumpheads,
including the 102R, 114, 313D, 501RL and 520R series, for
a flow range from 0.1 to 6100 ml/min. The compact, light-
weight and well-balanced design provides a ‘plug-in and forget’ solution. The
use of the company’s own gearbox provides the user with excellent torque and silent running,
making it ideal for the life science and biopharmaceutical sectors. The comprehensive control
and flow rate capability also meets the requirements of bioreactors, bench-top cross-flow filtra-
tion and chromatography equipment. ■ Watson-Marlow Pumps Group, Wilmington, MA 01887.
www.watson-marlow.com/us/ or call 800-282-8823

Filling and Closing Equip-
ment for Containers
This liquid filling system was designed to
fill, insert a pump, crimp, and cap contain-
ers at rates greater than 50 cpm. The diffi-
culty of accurately placing a dip tube/pump
into a small neck opening and crimping the
closure onto a glass bottle is the challenge
that is solved with this system. It positions
the containers in pairs below the fill nozzles
while the nozzles are inserted to a point
just inside the necks of the containers. By
lowering the nozzles into the necks of the
containers, product splashing is eliminated and foaming is minimized. The dip tube/pump is sorted
and positioned in a discharge nest where two axis-servo driven arms move over the filled bottle
and a funnel mechanism guides the tube/pump into the glass bottle. During the crimping process,
the tubes are guided into the mouths of the container by the funnel mechanisms which open to
allow the pump to rest on the container openings. The containers then are indexed to the crimping
process where the crimping devices firmly attach the pump assemblies to the containers. The heavy
gauge aluminum closure requires both downward force for proper seating and a two-step crimping
process to form and finish each closure. The capping technique allows for the actuator/dust cap as-
semblies to be loaded into the feed bowl via the chute. The pick and place mechanism then transfers
two actuator/dust cap assemblies onto the containers held in position by the turret. ■ Filamatic, a
Division of National Instrument, LLC, Baltimore, MD 21215. www.filamatic.com or call 866-258-1914
High Purity Ball Valves
CleanFlow ball valves are BPE-compliant and
designed for service in a range of pharmaceuti-
cal applications. Materials chemistry, delta
ferrite and surface finish are all controlled to
ensure high purity service. CleanFlow is avail-
able with Nickel infused (NiEX) and Stainless
Steel actuators for use in caustic cleaning envi-
ronments and the hermetically sealed position
sensor is corrosion resistant and submersible.
■ SVF Flow Controls, Inc. Santa Fe Springs, CA
90670. www.svf.net or call 800-783-2255
Protection System
The Needle-Trap system is
designed to protect healthcare
providers from accidental needlestick inju-
ries from disposable syringes. The Needle-
Trap system features a safety mechanism in-
tegrated as a component of the self-adhesive
syringe label. This compact design allows
the blood-contaminated needle to be simply
and safely secured following its use, and can
be easily operated by healthcare personnel
in a controlled, single-handed fashion. After
the needle has locked into the plastic trap
- an action clearly perceptible by a clicking
sound - it is irreversibly protected. It can be
easily integrated into conventional packaging
and labeling systems, since it is processed
and dispensed like a single-layer label.
Needle-Trap requires no additional storage
space and is housed in common secondary
packaging. ■ Schreiner Medipharm, Blauvelt,
NY 10913. www.schreiner-medipharm.com or
call 845-848-9000

pp1307_whatshot.indd 29 6/25/2013 3:22:48 PM
■ By Mike Hosch, P.E. Director of Product Development – Dorner Mfg. Corp.
andling small components, such as drugs and diag-
nostic devices during manufacturing has tradition-
ally been a challenge for the pharmaceutical indus-
try. That’s because their miniature size and uncon-
ventional shapes make it difficult to properly orientate and
move from one process to another. However, new advances in
conveying systems aimed specifically at the pharmaceutical
industries are aiming to improve the process of small part han-
dling and eliminate those problematic issues that have plagued
companies in their manufacturing processes.
When engineers draw up plans for designing machinery
and equipment, the supporting conveyor system isn’t given
much thought. The machine’s functionality almost always
takes precedence, and suffice to say that conveyors have
generally been viewed as an afterthought in the in the de-
sign process. This backward thinking is at the root of the
problem when it comes to conveying handling small parts
and impedes the overall manufacturing process.
Machines that don’t properly account for conveyors often
leave little space for them. And since there haven’t been
many commercially built conveyors small enough to fit into
tight places, a common practice is for end users to build
their own. But this brings along its own set of problems.
For starters, the task is taking an employee away from
their core competencies and asking them to build a conveyor.
That’s not their job and they don’t have the expertise to
properly build one. If a company is a manufacturer of fluid
management devices, why would they be wasting their time
building conveyors? And once is it built, what is the company
going to do about spare parts? Who is the company going
to call if it’s not running properly? What happens if the em-
ployee who built it is on vacation, or no longer works for the
company, then who’s in charge of maintaining the conveyor?
The main problem with conveyors serving the pharma-
ceutical industries is their size. The locations of in-feed/out-
feed applications within a machine that conveyors generally
serve are extremely tight, and for years there haven’t been
many manufacturers that offer a viable small platform to
fill this need. A reason for the dearth of availability is the
low ROI manufacturers felt in comparison to the amount of
research and development needed to develop material han-
dling solutions for this industry. That left pharmaceutical
companies scrambling to develop their own solution.
Anyone involved in the manufacturing or handling of
small pharmaceutical parts knows the complexity of that
Improving Efficiencies for
Handling Small Parts
New technologies offer pharmaceutical manufacturers a better way of
efficiently handling and orientating small parts.
■ P H A R MP R O . C O M

Above: Small parts can become stuck or damaged when transferring between two conveyors if
the gap is too wide.
Top Right: With miniature conveyors having 5/8” diameter roller bearings, small parts can easily
transfer from one conveyor to the next.
Bottom Right: A waterfall transfer involves parts from one conveyor falling onto the second
pp1307_feature_dornerconveying.i30 30 6/24/2013 3:56:55 PM
task. Their small, lightweight and fragile design can make
them difficult to handle, orientate and move on a conveyor
from one processing area to the next. When designing a
conveyor system to best work within a pharmaceutical ap-
plication, the engineer has several challenges to consider in
moving, orientating and transferring of parts.
Part end transfer – Since the items are so small, the abil-
ity to transfer them from one conveyor to the next can be
problematic. Parts are often less than 1” in size, therefore
requiring a roller diameter much less than 1”. Typical con-
veyors have rollers 1 ¼” or larger, a size that is simply too
large to be practical as a viable transfer mechanism. Small
parts attempting to transfer over a 1 ¼” or larger roller
could fall between the two adjoining rollers of the convey-
ors and become damaged. Another transfer option can be
the waterfall transfer, which is accomplished by placing the
roller of one conveyor over the next and letting parts fall
onto the lower conveyor. While this solves the transfer issue
with the larger rollers, it does not maintain product orienta-
tion, and parts can become damaged due to the fall.
Part side transfer – If a part cannot be transferred off the
end of a conveyor, the alternative method is to transfer it off
the side to an adjoining parallel conveyor. The problem with
this type of transfer is that bearing housings typically are
on the outside of the conveyor, preventing a flush meeting
between the top conveyors. This causes a gap in which very
small parts can fall through.
Conveyor belt flatness – Typical operations performed in pharmaceutical applications include vision inspection, filling,
robotic pickup, etc – all of which require the part be flat on
the conveyor belt. Since the part itself is so lightweight, it
does not have the weight to force the conveyor belt flat, and
thus will simply follow the surface flatness of the belt. Belting
used for small end rollers needs to be very thin, and these
thin belts have a tendency to curl when placed under tension.
Think of a rubber band expanded – it becomes thin and the
edges curl – this same principle occurs with conveyor belts.
This belt curl causes the light part to not lay flat, hence caus-
ing problems for the automation process.
Size of the conveyor – The floor space an engineer is
given for an assembly machine is relative to the product be-
ing assemble. Since the parts manufactured are small, the
room and engineer is given to accomplish the tasks likely
won’t be very large. There is simply no room in the machine
for oversized conveyors and the associated motors and
drives that go with them. This compact size also creates a
new challenge for an engineer. Because the machine isn’t
big, the distance between operations is short. Therefore,
the conveyor transporting the product from one operation
to the next is short, often less than 12” long.
So what is the best way to design a conveyor system to
move and handle tiny pharmaceutical parts? Some of the
design challenges include reduced bearing life due to small
bearings, small component strength and durability, consis-
■ P H A R MP R O . C O M
Top- Parts can lose their orientation when being transferred on a side-by-
side conveyor if the gap between the belts is too large.
Below - Miniature conveyors with the end roller support completely flush
allows parts to maintain their orientation in side product transfers.
Miniature conveyor showing mid-drive gearbox detail and
location. Modern pinch drive mechanisms allow the conveyor
to run with almost no belt tension.
pp1307_feature_dornerconveying.i31 31 6/24/2013 3:57:09 PM
■ P H A R MP R O . C O M
tent short belt fabrication and effective use
of product space. Additionally, conveyor
manufacturers need to take into account
the handling and orientation of parts during
movement, as well as the overall environ-
ment they’re operating in.
To build a miniature conveyor, end roll-
ers have been reduced to 5/8”. This profile
enables it to fit into tight spaces within a
machine, but also when positioned together
end-to-end, can successful transfer products
as small as 7/8” in diameter. The bearing
housings are fully encapsulated within the
conveyor frame. The advantage this affords
an end user is that two conveyors can be
positioned side-by-side and be nearly flush
with one another with only a 1/4” gap from
belt edge to belt edge.
Another challenge in building a miniature
conveyor with a low profile was developing
a mechanism to drive the belt – and that
mechanism proved to be a pinch drive, a
new engineering trend that allows the con-
veyor to run with almost no belt tension.
Typical belt conveyors run under high ten-
sion, which is needed for the drive roller
to have enough traction to drive the belt.
However, it is this tension that causes bear-
ings and conveyor rollers to be oversized
– and that’s something that wouldn’t be fea-
sible in a miniature conveyor.
The purpose of the pinch drive is to force
the conveyor belt against the drive roller,
giving it driving traction without the use of
tension. Conveyors have two pinch drive
mechanisms, each spring loaded against the
drive roller. This design allows the belt to
be run in either direction and only requires
enough belt tension to lay the conveyor belt
flat. Since over-tensioning the belt is not re-
quired, the belt lays flatter, which is needed
for lightweight components.
Miniature conveyors give engineers more
options in designing their applications, such
as allowing them to integrate the right-sized
conveyor into their machine. Miniature con-
veyors with new technologies are addressing
product handling issues by expanding the
available options to position and orientate
parts as the move through production. Bot-
tom line is that miniature conveyors provide
added flexibility to design engineers in han-
dling small parts for medical and pharma-
ceutical applications – a small design that’s a
big leap forward.
Mike Hosch is the Director of Engineering
at Dorner Mfg. Corp. Since 1985, Hosch
has held many titles at Dorner, including
mechanical engineer, chief engineer and
manager of new product development.
Hosch has a bachelor’s degree in mechani-
cal engineering from Milwaukee School of
Engineering, where he graduated on the
Dean’s List. Hosch holds multiple patents in
conveyor design and is a licensed engineer
in the state of Wisconsin. He can be reached
at mike.hosch@dorner.com. ■
pp1307_feature_dornerconveying.i32 32 6/24/2013 3:57:24 PM
. . . Insight
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■ By Brigitte Mangiarotti, SAFC Manager of Quality Services - EMEA
rug development is a lengthy process, some-
times taking up to 15 years to get to the final
commercial manufacturing phase. Whether
biologics or small molecules, all medicines have
to meet strict regulatory and quality standards to ensure
patient safety and product integrity. Within these standards
there are different ranges of quality for the raw materials
used in biopharmaceutical manufacturing depending on
where manufacturers are at in the development process.
Often times, the quality of raw materials used in discovery
and pre-clinical phases can be very different than those in
the clinical trial phases and through to review and commer-
cial manufacturing.
As drug manufacturers are increasingly looking to mini-
mize costs in the research and development phases of a
product, they may choose a lower-quality version of the
regulated raw material, not wishing to pay for full traceabil-
ity or GMP-standard manufacture when it is not necessary.
When looking at the right level of quality to use through the
different phases of manufacturing, it is important to take all
factors into consideration. In this paper, we take a look at
raw materials, why grade matters, the responsibilities of a
supplier, and the importance of a clear remediation policy.
While the regulatory demands are clear for commercial-
ized drug products, they tend to be much less specific dur-
ing development phases. It is true that many potential medi-
cines will go through the scale-up process only to fail in
Phase III trials. In other cases, they may successfully make
it through clinical trials, only to have regulatory authorities
reject them when a market authorization application has
been made. Yet a biopharmaceutical manufacturer should
be looking to the final manufacturing process even at this
early, uncertain stage of the development process.
As the product moves through the pipeline, from the me-
dicinal chemist’s lab bench to the commercial product, the
approach should change. Ideally, the raw materials being
used are subject to a grading system to determine whether
they comply with industry regulations at each point.
To save costs during scale-up, a company may be willing
to accept non-critical raw materials that do not meet all the
stringent requirements for items of GMP or other high quality
standards. However, pursuing supply chain transparency and
demanding extensive documentation earlier should minimize
risks and help to avoid problems further down the line.
Undocumented materials introduce the risk that unde-
fined or unquantified contaminants might be introduced
into the process, which could impact the final product.
Those may also affect the manufacturing process itself, al-
tering the yield or even the product of a chemical reaction,
or the composition of a peptide for a biologic.
As the quality level of a raw material increases, the risks
it poses decrease. The most difficult decision for a manufac-
turer is frequently balancing cost and risk in the early stage
of development in terms of raw material choices. While
those higher-quality products do increase costs, there are
other advantages on top of the reduced risk – should the
product advance into clinical trials, the necessary supply
chain transparency documentation will already be in place-
with certificates of origin for those raw materials.
Consequently, biopharmaceutical manufacturers have
become increasingly reliant on their suppliers to assist with
product compliance. They are looking to meet all the neces-
sary standards without engendering excessive cost and will
consult on what grades are appropriate. Raw materials must
Gradation in Pharmaceutical
A look at industry trends and how suppliers help
■ P H A R MP R O . C O M

Involving quality raw material suppliers from the beginning of drug development can reduce
many risk factors.
pp1307_feature_rawmaterials.indd34 34 6/25/2013 11:06:31 AM
Ensuring the quality of raw materials at every stage of manufacturing development helps to
shorten timelines.
meet the regulators’ quality requirements for each stage of
the process – so here, the real consultation is looking into
the end product itself, learning actual details and staying
in line with the precise requirements (which can also vary
from one region to another).
The simplest – and safest – solution is to work with a sup-
plier who is capable of providing raw materials of different
grades. This will make the transition between the different
phases of manufacturing development more straightforward,
and it will also shorten the timelines, as new suppliers will not
have to be qualified every time the project advances through
the pipeline. The supplier should have a clear understanding
of what, in quality terms, is acceptable at each stage of the
development process and whether the raw materials are non-
regulated, non-GMP quality or highly regulated materials man-
ufactured to the exact criteria laid down in GMP regulations.
Perhaps the most important thing a supplier can provide
is insight into precisely what regulatory requirements are de-
manded by the agencies in each region where the biopharma-
ceutical manufacturer may want to sell their products. These
regulations are complex and subject to updating, and a good
supplier will remain on top of the regulations at all times,
helping ensure their customers will, too. Impartial advice re-
lating to the quality standards required for raw materials for
any particular application should also be available.
This will constitute a strong supply chain – one that is
validatedwith full documentation and transparency of all
the ingredients they supply, and one possessing an under-
standing of the necessary product quality for each step of
the development process. Any changes in their supply chain
should be passed on to the customer in a timely fashion.
A secured supply chain is equally important. However
good that supplier may be at manufacturing and document-
ing the raw materials they provide, if disaster strikes this
can cause enormous problems for the manufacturers who
rely on them. This is where the importance of redundancy
comes to the fore. If a manufacturing facility has a major
fireor is hit by a natural disaster, it may be out of commis-
sion for some time. While such occurrences are rare, they
do happen. If that supplier manufactures its raw materials in
more than one location, it will be able to mitigate the prob-
lems in the stricken facilityand ensure continuity of supply.
They should also be competent at dealing with any qual-
ity issues that do arise – in the real world, problems do
happenand speedy, effective resolution is essential if the
manufacturer’s business is not to be adversely impacted in
the long term.
Process control is also a key factor; a qualified supplier
will have up-to-date facilities and control technology. Not
only will this assist in providing clear documentation and
full disclosure to the customer, perhaps more importantly
it helps them manufacture contaminant-free products that
meet all quality standards.
Even when supply chains are carefully planned, devel-
oped and monitored, the occasional quality control error
can still occur. As it is impossible to remove all risks from
the supply chain, it is essential that there is a remedia-
tion plan in place. Routine regulatory inspections should
reveal deficienciesand enable problems to be isolated and
addressed. Complete transparency in the supply chain is a
crucial factor, as it makes it easier to take up technical or
regulatory issues at the outset, and it facilitates the creation
and revision of guidance documents.
At its heart, remediation recognizes problems, fixes them
and then closes any gaps to ensure regulations are met in
the future. Regulators are not so much looking for perfec-
tion as they are looking to ensure that the manufacturer is
well versed in its own processes and their optimal opera-
tion; it is imperative to understand how data is stored, man-
aged and analysed. Proactive involvement can help predict
issues that might occur before they cause recalls and warn-
ing letters. Often, the best person to do this is a remedia-
tion expert who has experience and expertise in managing
such situations.
It is no secret that biopharmaceutical manufacturers
have a great amount of choices to make when investing
time and money into the development of a new product.
When looking at what raw materials to source, and in what
grade, it can be hard to know what the right answer is. In
many cases, involving quality raw materials from the start
addresses and removes the risk factor that a manufacturer
may have. However, there is no such thing as a perfect situ-
ation. Each case brings its own individual implications, so it
is important to work with a knowledgeable supplier who can
offer piece of mind with a back-up plan to keep things on
track. ■
■ P H A R MP R O . C O M
pp1307_feature_rawmaterials.indd35 35 6/25/2013 11:06:46 AM
■ By Manuel Hervas Patheon Inc., Pharmaceutical Development Services
with support from Anush Mehta, Jasmine Ramsuran, Akaash Singh, Radu Balint, and Austin Freedman.
ubricants play a vital role in solid dose manufac-
turing, preventing materials from sticking to punch
faces, decreasing friction at the interface between
the tablet surface and the die wall during ejection,
and reducing wear on punches and dies. However, over-
lubrication of the powder blend is a well-recognized issue,
adversely affecting many of the properties of the finished
tablets (1, 2).
Traditionally, over-lubrication has been associated with
overmixing in the blender, but new evidence suggests that
other parts of the manufacturing process may contribute to
the overall effect. This study confirms that the force feeder
of the rotary tablet press may play an important role in the
over-lubrication effect.
This study was prompted by earlier work by Feng Li and
John C. Cunningham (5), which looked at the mixing/shear-
ing effect of the force feeder. They concluded that, by acting
as a second ‘paddle blender’, the feeder could cause over-lu-
brication of a blend prior to compression.
The Patheon team set out to further investigate the poten-
tial of the feeder to cause over-lubrication and its effects on
the physical properties and dissolution performance of the
tablets produced. Folic acid was selected as several reports
suggested that it was very sensitive to a number of formula-
tion and processing factors (3, 4). The lubricant magnesium
stearate was also selected
as its potential for over-
lubrication is well recog-
nized. Finally, two filler
materials were selected:
microcrystalline cellulose (MCC), which undergoes plastic
deformation during compaction, and anhydrous dibasic
calcium phosphate (DCP), where the primary consolidation
mechanism is fragmentation.

Tablet Preparation
Two direct compression blends were prepared for each
model formulation consisting of 0.4 % folic acid (400 µg/tab-
let), 2.0% croscarmellose sodium, 1.0% magnesium stearate
and 96.6% of filler (MCC or DCP respectively). Folic acid
was de-lumped and geometrically blended with either MCC
or DCP and with croscarmellose for 20 minutes; afterwards,
it was lubricated with magnesium stearate for 3 minutes.
Each blend was split into twelve portions for separate com-
pression runs during which the powder was compressed
into 100 mg tablets. An instrumented 16 station Manesty
Betapress equipped with a variable speed paddle feed frame
was used for compression.
Experimental Design
Twelve runs were performed for each formulation accord-
ing to the experimental design detailed in Table I. Three key
factors were monitored – blend residence time (the time spent
inside the feeder), paddle speed and compression force.
All other factors that could affect the responses were kept
at a fixed level: compression dwell time was kept invariable
by maintaining constant the tablet press turret speed (St).
As dictated by equation No.1 which estimates the residence
time of powders in the feed frame of a tablet press (5), if
the turret speed (St) is fixed and since both the feed frame
Tablet Manufacturing
Over-lubrication effect in the force feeder of a rotary tablet press
■ P H A R MP R O . C O M


Figure 1. - left,
Dissolution of
0.4 mg Folic Acid
Tablets. Note: For
clarity only a subset
of dissolution
profiles are present-
ed in this figure.
Figure 2. - right,
pp1307_feature_pantheon.indd 36 6/24/2013 3:58:06 PM

volume (Vff) and die fill volume (Vd) are constants the only
possible way to vary residence time is by varying the num-
ber of active stations; therefore, ten and two active stations
were used for the low and high residence time respectively.
The non-active stations were blocked with blank dies.
Residence Time =
= Volume of feed frame (mm
= Volume of die fill (mm
= Turret speed (RPM).
= Number of stations.
Tablet Testing
A dissolution profile was obtained for each run by deter-
mining the dissolution at 5, 10, 15, 30, 45 and 60 minutes
according to the USP dissolution method for folic acid tab-
lets (7). Tablet hardness was determined on a sample of 10
tablets from each run, while disintegration testing was per-
formed on a sample of 6 tablets from each run.
Dissolution Profiles
Tablet weight was carefully monitored during compression to
minimize the impact of tablet weight variability on the dissolu-
tion results. For MCC runs, individual tablet weight maintained
within range 97-103 mg, and for DCP between 96-104 mg.
Figure 1 (a and b) presents the dissolution profiles of folic
acid tablets obtained from the twelve runs using MCC and
DCP formulations respectively. For clarity only a subset of
dissolution profiles is presented. The 60 minute time point
is not included in the graphs.
For the formulation containing MCC there is a pattern in the
dissolution profiles (Figure 1, a), noticeable especially at the
early dissolution time points. The material subjected to longer
residence time in the feed frame resulted in tablets that pre-
sented a slower dissolution of folic acid while the tablets from
the low residence time had faster dissolution. This observation
was confirmed using a least squares multiple regression analy-
sis (6), which showed that increased residence time negatively
affected the dissolution of the active. In addition, this factor
consistently showed statistical significance (p < 0.05) for all
the dissolution time points from 5 to 45 minutes. Compression
force seemed to be also important; although, not consistently
significant for all the dissolution time points. The paddle speed
factor and the two factor interactions of the experimental
variables were rather small and non-significant (except for the
early time points).
The least squares multiple regression analysis for the
dissolution profiles from the folic acid DCP formulation
revealed a statistically significant interaction between
residence time and compression force at each dissolution
time point, which indicates that the compression force
has a different effect on a blend with a low residence time
than it does on a blend with high residence time. Since it
is generally accepted that DCP is not normally affected by
over-lubrication because of its tendency to fragment during
compression, this result is surprising and warrants further
confirmation. Residence time and compression force alone
did not show statistical significance except for the first dis-
solution time point. It was also observed that tablets from
most of the experimental runs failed the USP dissolution
standard for folic acid (in contrast to those that used MCC
in the formula which all pass the USP test). This is not sur-
prising since it has been reported that DCP can impede dis-
solution (4). This phenomenon possibly masked or influence
the effects under evaluation.
Looking at tablet hardness, the MCC formulation was af-
fected by residence time, paddle speed and compression
force, while compression force was the most important fac-
tor for the DCP formulation. Figure 2 (a and b) shows the
compression profiles for the 12 runs of the MCC and DCP
based formulations respectively.
All tablets from both MCC and DCP formulations and from
all the runs presented a very rapid disintegration time (less
that 2 minutes); therefore, this response was not analysed.
Results from the study allowed the team at Patheon to
make several conclusions. Firstly, that over-lubrication does
occur in the force feeder of a rotary tablet press. Secondly,
that the residence time of a powder blend in the feeder is
an important parameter influencing the dissolution and
mechanical properties of a pharmaceutical tablet, where for-
mulations are sensitive to magnesium stearate. Finally, that
■ P H A R MP R O . C O M
Table I. Experimental Factors
Residence Time (1) Paddle Speed (setting) Compression Force
(kN) (2) RT PS CF
1 Low 3 Low
2 Low 3 Middle
3 Low 3 High
4 Low 9 Low
5 Low 9 Middle
6 Low 9 High
7 High 3 Low
8 High 3 Middle
9 High 3 High
10 High 9 Low
11 High 9 Middle
12 High 9 High
(1) The actual residence time was not calculated as the feed frame volume was not determined.
(2) For MCC formulation: Low = 5-6 kN, Middle = 9-10 kN and High = 14-15 kN (5.5, 10 and
14.5 kN values used for Figure 2 a)
For DCP formulation: Low = 4-5 kN, Middle = 7-8 kN and High = 12-13 kN (4, 8 and 12 kN
values used for Figure 2 b)
pp1307_feature_pantheon.indd 37 6/24/2013 3:58:22 PM
■ P H A R MP R O . C O M
the impact of residence time is both drug and excipient-dependent.
Moving forwards, it is clear that pharmaceutical scientists need
to look beyond the blender when considering the impact of over-
lubrication and seeking to optimize the blend process. They must
look to minimize both the time a blend is kept in the feeder and the
speed of rotation of the paddles (to avoid overblending).
While folic acid was known to be sensitive to processing factors, the
extent to which the force feeder may affect the properties of other ac-
tive ingredients is currently unknown, yet worthy of further investiga-
tion. It is also possible that the feeder may not be the only part of the
manufacturing process that contributes to the over-lubrication effect.
The author thanks the following team members for their contribu-
tions to this research: Anush Mehta, Jasmine Ramsuran, Akaash
Singh, Radu Balint, and Austin Freedman.
1. B.B. Sheth, F.J. Bandelin and R.F. Shangraw, “Compressed Tablets,”
in Pharmaceutical Dosage Forms: Tablets Volume 1, H.A. Lieberman
and L. Lachman, Eds. (Marcel Dekker, Inc. New York, 1980), p. 164.
2. G.K. Bolhuis and A.W. Hölzer, “Lubricant Sensitivity,” in
Pharmaceutical Powder Compaction Technology (Drugs and the
Pharmaceutical Sciences, Vol. 71), G. Alderborn and C. Nyström,
Eds. (Marcel Dekker, Inc. New York, 1996), pp. 517-560.
3. S.W. Hoag, H. Ramachandruni, and R.F. Shangraw, “Failure of
Prescription Prenatal Vitamin Products to Meet USP Standards for
Folic Acid Dissolution,” J. Am. Pharm. Assoc. NS37 (4), 397-400 (1997).
4. J. Du, and S.W. Hoag, “Characterization of Excipient and Tableting
Factors That Influence Folic Acid Dissolution, Friability, and
Breaking Strength of Oil- and Water-Soluble Multivitamin with
Minerals Tablets,” Drug Dev. Ind. Pharm. 29 (10), 1137-1147 (2003).
5. F. Li, and J.C. Cunningham, “Effect of Feed Frame Paddle Speed, Powder
Residence Time Inside the Feed Frame, Pre-compression and Strain
Rate on Tablet Strength,” poster presented at the 2003 AAPS Annual
Meeting and Exposition, Salt Lake City, UT, October 26-30, 2003.
6. JMP, Version 5.1. SAS Institute Inc., Cary, NC, 2002.
7.Folic Acid Tablets, Official Monograph in USP 29-NF 24 (United
States Pharmacopeial Convention, Rockville, MD, 2006).
Manuel Hervas, Senior Technical Project Leader
Anush Mehta, Technical Project Leader
Jasmine Ramsuran, Project Manager
Akaash Singh, Technical Project Leader
Radu Balint, Senior Research Chemist
Austin Freedman, Former Director at Patheon
Patheon Inc.,Pharmaceutical Development Services
Toronto Region Operations, 2100 Syntex Court,
Mississauga, Ontario L5N 7N9
Visit us at AACC Booth No. 3062
pp1307_feature_pantheon.indd 38 6/24/2013 3:58:37 PM
Mass Flow Controllers
The I-Series of mass flow controllers is
designed for use in harsh environments
where resistance to liquid or dust ingress
(IP66 rated) is essential. Typical applications
include Biotech, Pharmaceutical, Food and
Beverage production where hose down may
be required. The I-Series mass flow control-
lers are general purpose, metal or elasto-
mer-sealed instruments available with either
analog (0 to 5 VDC or 4 to 20 mA) or digital
I/O. The devices incorporate the latest digital
flow control electronics and a thermal sensor
and mechanical design to provide 1% of Set
Point accuracy and precise control for full
scale flow rates from 5 sccm to 50 slm (I50)
and from 100 to 250 slm (I250). Multi-gas/
multi-range capability, enabled through the
device’s on board Ethernet interface, allows
the user to change device gas and range
reducing inventory requirements. ■ MKS
Instruments, Inc., Andover, MA 01810. www.
mksinst.com or call 978-645-5500
errors during weighing. If errors occur, the
balance identifies the uncertain weighing re-
sults in the display and blocks their transmis-
sion. Secura can therefore increase process
reliability and decrease error rates in the lab.
■ Sartorius Group, Goettingen, Germany.
www.sartorius.us or call +49(0)551 308 3615
Laboratory Balance
The Secura laboratory balance was devel-
oped for applications in regulated areas such
as pharmaceutical labs and fulfills particular-
ly high reliability requirements. The balance
monitors its ambient conditions automatical-
ly, thereby preventing handling errors. This
increases the reliability of weighing proce-
dures in pharmaceutical labs and helps users
to achieve even better measurement results.
Nine different models of the Secura balance
are available, covering a range of weighing
capacities from 120 grams to 5,100 grams,
and a readability of 0.1 to 10 milligrams. The
balance is also equipped with various as-
sistance systems designed to prevent further
processing of uncertain weighing results,
which frequently occur through operating
Bottle Filling and Closing Equipment
The Macofar LF 200 FD is used for high-speed
filling of pharmaceutical sprays, nose and ear
drops as well as ophthalmics and syrups. The
machine boasts a maximum output of 12,000
bottles an hour with a filling volume of up
to 100 millilitres. The LF 200 FD is equipped
with two closing stations and is capable of
handling a wide range of closure types includ-
ing pipettes, droppers, dosing cups, spray
pumps, plugs, plungers and screw caps. The
dual closure system is extremely flexible
and facilitates many different combinations.
The bottles are filled continuously, speed-
ing up the filling process. The movement of
the swivelling dosing systems is synchro-
nised with the bottle transport through the
machine. The LF 200 FD is suitable for glass
and plastic containers 16 to 80 millimetres in
diameter and 35 to 200 millimetres in height
with a filling volume of 0.5 to 500 millilitres. ■
Ramaco, Karlsruhe, Germany. www.romaco.
com or call +49 (0) 721 4804 0
■ P H A R MP R O . C O M
Benchtop Chillers
Designed to maximize bench space, LS-Series
/ LM-Series / MM-Series Chillers provide up
to 1290 watts of cooling at 20°C, making them
ideal for use with rotary evaporators, jacketed
incubators, small reaction vessels, spectropho-
tometers, chromatography columns, condens-
ers, and other devices that require robust
heat removal. The LS-Series, which has a
working temperature range of -20° to +40°C and
provides 475 watts of cooling at -10°C; the LM-
Series, with a working temperature range of
-10° to +30°C and a 230 watt cooling capacity at
-10°C; and the MM-Series, which has a working
temperature range of -5° to +50°C and provides
129 watts of cooling at -5°C. ■ PolyScience,
Niles, Illinois 60714. www.polyscience.com or
call 1-800-229-7569
Laboratory Exhaust Fan
Vektor®-MH mixed flow, high plume labora-
tory exhaust fan features a mixed flow wheel
and high plume discharge with capacities
up to 60,000 cfm and 8 in. wg. The plume’s
conical discharge nozzle, with multiple nozzle
sections per fan size for increased efficiency,
utilizes a bifurcated opening allowing easy
access to belts and motors. ■ Greenheck ,
Schofield, WI 54476. www.greenheck.com or
call 715-359-6171
pp1307_newproducts.indd 39 6/24/2013 4:00:33 PM
■ By Craig Wylie, PA Consulting Group
he pharmaceutical industry is overloaded with
regulatory documents, such as policies, standard
operating procedures (SOP) and working prac-
tices, and needs a robust, understandable and
effective architecture model to drive compliance. Once the
architecture is clearly defined, it’s important that the docu-
ments themselves should be easy to use and lead to compli-
ance. Remember, compliance is achieved through simplicity
and clarity, not complexity or extensive detail.
The pharmaceutical industry could not function without
all of its regulated documents, and there is nowhere where
this is truer than in a manufacturing site. The globalization
of manufacturing has led to a situation where a single site
maybe releasing product to tens of different markets, and
it needs policies and procedures that are sufficient to the
task. Therefore, there are three fundamental requirements
for the For the successful management of the control docu-
ments in a manufacturing environment, there are fundamen-
tal requirements: you need a clear architecture to define
what does and does not go into different documents with a
set of rules to keep the documents easily understood, and
there needs to be a robust change control process to keep
it all in line. Since change control is something usually cov-
ered at manufacturing locations, let’s focus on the rules.
In writing the control documents, there are ten rules to
guide the creation and management of controlling docu-
ments. Ultimately, the guidance is that the documents them-
selves should be clear, easy to use and lead to compliance.
1. Aim for simplicity and clarity, avoiding complex-
ity and the drive to cover all eventualities. Organizations
must seek opportunities to reduce complexity as this will
enhance the likelihood that people will comply, and result
in fewer errors. When organizations try to cover every pos-
sible situation, the documentation becomes so complex it
becomes practically impossible to remain compliant with it.
2. Be outcome oriented. Building on the first rule, it is im-
portant to define the outcome required, not the input expected.
When organizations define the input, or activity, then the pro-
cess can be adhered to without meeting the regulatory obliga-
tions set by the regulator. When the outcome is defined, then
the tasks become those that are required to meet the outcome,
and compliance is not achieved unless the outcome is right.
3. Don’t aim for perfection; use a risk-based model. The
goal is to develop a good system that is fit for the purpose with-
out a lot of complexity. Inevitably there will be circumstances
that are not catered for within the documents; do not expect
every possible eventuality to be covered. High frequency risks
must be covered but low frequency high-impact risks are better
managed by people reacting to the crisis rather than trying to
mandate behavior a priori for every possible event. Good con-
trolled document architecture requires a risk based approach.
4. Make processes role based, not job title based. While
organizational restructuring happens frequently, organiza-
tions must build processes around roles, which will expe-
Ten Rules for Pharmaceutical
An introduction to building an architecture for control documents
■ P H A R MP R O . C O M

Document type Definition
Policy The policy lays out the commitment of the business to compliance;
it is an essential part of any QMS and it demonstrates the com-
mitment of the senior executive management to delivery of high
quality. It is not in itself a regulated document, but it is a critical
component of the control document architecture
Core Processes
There are so many SOPs in a typical pharma company environment
that there is a need for a very limited number of driving SOPs. Each
of the critical business processes (as defined by the QMS) has a driv-
ing SOP that lays out the end to end process and then references
any supporting material (including other SOPs). As an example the
core processes for a QA group might be Audit, CAPA and Knowledge
Non-core processes include processes that drive administration, rather
than the operations, of the function. In our hypothetical QA group
non-core processes might include, on boarding, document archival
and retrieval, access to computer systems.
Guidance Guidance documents generally cover the way in which certain activities
are to be carried out and recorded. They do not necessarily cover every
aspect of the process but focus on those that are complex or where a
specific approach is needed. Good examples include the way in which
complex products might be encoded in a license management system,
standard language to be used in particular circumstances or the master
data to be used in entering a record in a computer system
How to execute a specific task, detailed step by step directions on
how to execute a particular task. Useful for complex systems.
pp1307_feature_PAconsulting.indd40 40 6/25/2013 11:07:27 AM
dite redevelopment or integration of documents.
This also allows for the organization to align to
local requirements without needing to rewrite
SOPs. For a role-based model to be success-
ful, individuals need to have their roles
recorded in the learning management
system and these roles need to be main-
tained as responsibilities change.
5. Ensure different document types
have clear guidelines for the dif-
ferent content required. It has to be
clear whether a specific document mandates process or sim-
ply provides guidance; the selected document type must also
reflect this intent. For example, policy documents set the
ambition, a quality management system (QMS) lays out the
scope, SOPs define how the scope is to be met and work in-
structions and other documents cover specific needs without
covering all eventualities.
6. Remember that regulatory documents should not take
the place of job descriptions and operational training; they
are there to create regulatory compliance. We often find that
many of the tasks laid out in SOPs are there to help people
do their job; they do not address regulatory need. This
means that any situation that is not completely aligned with
the way things were operationally when the SOP was written,
now run the risk of causing unnecessary compliance failure.
7. Manage all regulated documents in the same repository.
Having multiple systems or, worse, no system at all, makes
it difficult to view the entire portfolio. If documents are in
different locations then employees run the risk of not know-
ing where to look for the definitive version of documents. It
becomes difficult to quickly assess the impact of a change and
there is a significant risk of personally held (and therefore un-
controlled) versions being used to execute critical processes.
8. Manage local variations locally. Local organizations
are accountable for ensuring that they meet the obligations
put on them by the global organization and by their lo-
cal regulator. When there is a conflict between these two
then the local wins, if there is no conflict then global takes
precedence. Trying to incorporate local requirements into
higher level documents often leads to increased complexity.
Organizations should allow local variations to be managed
locally rather than globally.
9. Ensure vital training is proportionate to the level of
involvement. If a role is central to the execution of a process
then organizations need to make sure that the right people have
received training. If, however, a role is involved only occasion-
ally in the process, or influences only a small section of it, then
the training for that role needs to be appropriate for the level
of involvement. This requires on-demand training and training
courses that target sub-components of the process. Training
everyone on everything is neither popular nor effective.
10. Make sure that creating and deploying new docu-
mentation and processes is not a “once and done” activ-
ity. Organizations must enable the business to support
continuous improvement and monitoring of the
document portfolio. They must also establish
robust governance processes and infrastruc-
ture to provide effective oversight of the
portfolio and enable rigorous monitoring
to identify areas of weakness and oppor-
tunities in the portfolio.
Craig Wylie is a life sciences and
healthcare industry expert at PA
Consulting Group. You can contact him via www.pacon-
sulting.com/us. Follow PA Consulting Group on twitter @
PA_Consulting. ■
■ P H A R MP R O . C O M
T: (208) 376-7008
Excellent design and
manufacture of filter
dryers for over 24 years.
From small-scale synthesis
to full scale production.
World renowned
Tray Dryers
o Proven Heating Uniformity with Maximum
Recorded Temperature Variation of +/- 1
o Direct Tray Heating
o High Containment Discharge Option
o Enhanced Ergonomics
o Easy Clean Open Shelves
PSL’s agitated nutsche filter dryers are
innovatively designed and engineered to
a highly ergonomic and efficient standard,
and can be fully contained within
a PSL Glovebox.
pp1307_feature_PAconsulting.indd41 41 6/25/2013 11:07:41 AM
Figure 1 – The Three Stages of Process Validation
■ By Michele Levenson and Bikash Chatterjee, Pharmatech Associates
n January 2011 the FDA issued the New Process
Validation Guidance. The modern definition of
Process Validation has abandoned the concept
of a one-off activity where success consists
of obtaining three commercial batches of prod-
uct. Instead, the new guidance describes
Process Validation as a continuous life-
cycle founded upon the principles
of scientific understanding, and
divides it into three stages.
Stage 1 tackles product and
process development by identi-
fying critical process parameters
and critical material attributes, to
establish the Processes Proven
Acceptable range (PAR) and
Normal Operating Range (NOR).
Stage 2 is the closest thing to the
old concept: demonstrating process predictability.
But it is Stage 3 that introduces the most significant
departure from the 1987 concept: that is, Continuous
Process Verification throughout a product’s lifecycle. This
article will examine the components of a successful Stage
3 Continuous Process Verification program and discuss a
framework for integrating this new activity as part of an
organization’s current Quality Management System (QMS).
To understand the Stage 3 methodology, it is important
to understand the activities that comprise the total PV life-
cycle. Figure 1 summarizes the major tasks that constitute
the three stages.
All pharmaceutical Quality Management Systems include an
Annual Product Review (APR) process. The GMPs require an
annual evaluation of the quality standards of a drug product to
determine the need for adjustments in drug product specifica-
tions, manufacturing and control procedures. Subpart J of 21
CFR 211.180 mandates establishing a written procedure for the
APR process and recommends review of a representative num-
ber of approved as well as rejected batches.
The concept behind the APR process is a regular periodic
analysis exercise to evaluate the overall performance of a
product based upon its Critical to Quality Attributes (CQAs).
The concept behind the Stage 3 Continuous Monitoring pro-
cess is to extend the same phi-
losophy to those factors within
a process that affects product
performance. The challenge
with the Stage 3 portion of the
new process validation guidance
is two-fold; how to acquire the
data from the shop floor and
what rules to apply in terms
of adjustments to the process.
The four activities of establish-
ing a continuous verification sys-
tem will be discussed as follows.
Implementing an effective veri-
fication and control strategy to ensure process and
product performance is the heart of the new Process
Validation Guidance. Prior to Stage 2, the CPPs that drive
product performance variability and the control strategy for
those parameters that affect process predictability should
be clearly identified. Similarly, critical material attributes
(CMAs) should have been identified and measurement tools
implemented in Stage 1 to capture the appropriate attri-
butes. The goal of Stage 3 is to ensure the validated process
remains in a state of control that translates to analyzing the
behavior of any CPPs and CMAs identified against the pro-
cess understanding derived from Stages 1 and 2.
Specifically, for new products and processes, Stage 3 builds
upon the process knowledge gained in Stage 1 and Stage 2.
For legacy products, process understanding is a hybrid of
historical control and performance data and Stage 2 confirma-
tion data. The APR process is a good place to obtain historical
product performance data as well as any discussion regarding
Out of Specification( OOS) and Out of Trend (OOT) results.
When designing the sampling and testing approach for
the control strategy it is important to consider the Stage
3 data acquisition component. Many organizations have
limited or no Statistical Process Control (SPC) programs in
place. Capturing documentation within the batch record is
typical. However, the systems for extracting that data for
use as part of a Continuous Verification Program do not
typically exist.
Beyond the Stage 3 compliance component of this activ-
Process Validation
A framework for implementing a stage 3 process validation program
■ P H A R MP R O . C O M

pp1307_feature_bikash2.indd 42 6/25/2013 11:08:52 AM
ity, the benefits of enhanced visibility to in-process data
are many for most manufacturing operations. SPC allows
manufacturing to identify and address potential sources of
variability within a particular step, unit operation, phase,
etc., of the manufacturing process. Another advantage of
SPC is that it helps to prioritize sources of variability within
a process so that efforts are put toward controlling the cor-
rect process inputs.
Several critical pieces to SPC:
• Setting up a variables and an attributes control chart
• Stabilizing an out-of-control process
• Process improvement and control charts
• Identification of key unit operations and products
• Preparing for a capability study
• Determining the process output
• Comparing the process output to the specification
• Taking action to improve the process
• Identification of area to display data on the factory floor by
each unit operation
Through the evaluation process, the control limits can
serve to provide immediate feedback to the operators if the
process begins to stray.
Defining the roles and responsibilities within the orga-
nization is essential to ensuring that the designated data
is captured so it can be analyzed and reported. When de-
veloping the process for data capture a cross-functional
team with representatives from Manufacturing, Quality
Assurance, Technical Services and Engineering should
convene to define how data is to be captured and communi-
cated without adding additional burden to the organization.
Considerations for establishing an effective process start
with identifying where in the process the designated data
will be generated, then establishing the following:
- A GMP record that is consistent with the current or pro-
posed in-process control program
- Procedure for reviewing the data for accuracy
- Process for communicating data to the appropriate qual-
ity function
- The statistical tests to be applied to the data and defin-
ing how the data can be used. Possible applications include
troubleshooting, complaints support and continuous im-
provement activities through Change Control.
Finally, if an organization is going to reap the maximum ben-
efit from this activity, the data must be used by all functions
in charge of product performance. The Continuous Process
Verification program is not solely the responsibility of the PV
or Quality organization. There are responsibilities required
from a cross-functional team. Up front costs to establish the
program and training for the organization may initially seem
steep but these costs can be modulated depending on the
maturity of the organization, the process knowledge and his-
torical performance of the products, and the maturity level of
other established QMS programs at the site.
The new guidance departs significantly from the 1987
guidance specifically in terms of the concept of revalidation.
Since the 1987 guidance was issued the industry has viewed
validation as the end of the development process, i.e. the
last step to commercial introduction. If a significant change
were introduced into the process the result would typically
trigger a revalidation of the process. As a result, the threat of
having to revalidate a process was the excuse for not imple-
menting improvements that could affect the process predict-
ability, yield or efficiency. The new guidance considers that
the purpose of Stage 3 is to allow quality and manufacturing
organizations to leverage process understanding as a basis
for calibrating the risk of process variation. As data are gath-
ered and analyzed, it becomes possible to understand the
natural process variation based upon the identified CPPs and
CMAs. Six Sigma professionals call this the common cause
variation, which is intrinsic to the process. After sufficient
data are captured it will be possible to establish alert and
action limits that can be used to diagnose process drift or
variability caused by factors that are no longer in control in
the process.
The new guidance allows adjustments to be made to the pro-
cess based upon the process understanding derived in Stages 1
and 2. However, the new guidance does not give carte blanche
to the manufacturing or engineering organization to make
changes as it sees fit. The most important component of the
Continuous Verification program is defining how adjustments
can be made to the process before it is no longer in control.
The biggest benefit to manufacturing operations is the abil-
ity to improve the process via the change control process.
Organizations with an established Operational Excellence pro-
gram can now take advantage of process and operational im-
provements by defining their impact based upon the process
understanding derived in Stages 1 and 2. Highlighting statisti-
cally justified sampling plans and acceptance criteria within
the guise of historical performance will provide the framework
for implementing improvement. This reduces the quality risk
associated with process improvements and provides a sound
basis for evaluating any potential regulatory impact.
There is no doubt that the concept of Continuous Verification
of critical process parameters is a significant departure from
the classical requirements defined in the 1987 FDA guidance. If
properly designed, the program can provide significant benefits
to an organization by providing the ability to intervene in a
process before it drifts out of a state of control. In addition, the
investment in time and money made in establishing process
understanding in Stages 1 and 2 can be recouped by allowing
process and operational improvements to be made without the
need to revalidate, thus achieving the end result of enhanced
process predictability and product performance. ■
■ P H A R MP R O . C O M
pp1307_feature_bikash2.indd 43 6/25/2013 11:09:08 AM
᭣ Mixer/Dryer/Cooler
The Bella Series 543 mixer/dryer/cooler offers an improved
method for drying or cooling powders, granulates and filter
cakes. The Bella dryer can be used for drying, mixing, spray-
ing, agglomerating and cooling in the same unit without
additional equipment or costs. Operation is efficient because
air flows around material while it is suspended in the weight-
less zone of the mixer. This maximizes the total surface
which is exposed to the air, increasing the desired effect. The
drying process will go through an adiabatic evaporation with
thermal efficiency at about 80%. Only small air volumes are
required compared with other fluidizing dryers. Benefits include better air
distribution which increases drying/cooling efficiency; homogeneous mixing
during drying/cooling process; low air volume reduces filter requirements, rotat-
ing paddles prevent material lumping and air channels; increased air contact creates better thermal
efficiency; random material/air movement reduces drying/cooling time; gentle paddle motion cre-
ates low shear and low energy usage due to high thermal efficiency. ■ Dynamic Air Inc., St. Paul, MN
55110. www.dynamicair.com or call 651-484-2900
᭣ High Shear Blender
The FSH high shear blender for emulsifications and par-
ticle size reduction applications is designed to achieve
submicron droplet sizes at one-third the cost of similar
technology. It is designed to provide intense shear-
ing of products with dispersed/emulsified oils. The FSH
operates at tip speeds up to 55 m/s, shear rates in excess
of 100,000 1/s seconds, and flow rates to 80 gpm. It is CIP'able and fea-
tures a front-loading seal for simple routine maintenance. ■ Fristam Pumps
USA, Middleton, WI 53562. www.fristam.com/mix or call 800-841-5001
᭣ Benchtop
Nutsche Filter
Pharmaceutical inter-
mediates are efficiently
filtered, washed, reslur-
ried and dried in these
portable nutsche filter
units, minimizing
contamination and
exposure. Its design
allows withdrawal
of filter cake utiliz-
ing removable
top head, bottom
head and filter
support as-
sembly. It may
be pressurized
to increase rate
of solvent removal,
and drying is aided
by vacuum and
heating capabil-
ity. It is available
in 0.2 to 5 liters, with
larger floor models up to 400 liters. It is available
with ASME and optional CE/PED certification
for full vacuum to 100 psi, -80 to 250° C. The
unit is offered in stainless steel, Hastelloy, or
alternate metals with optional pharmaceutical
grade mechanical and electropolish finishes.
Custom design features include manual or mo-
torized raising/lowering cake agitators, mixers,
temperature control options, jacketing, valving,
special porting, sight glasses, instrumentation
and pumps. ■ Pope Scientific, Inc., Saukville, WI
53080. www.popeinc.com or call 262-268-9300
■ P H A R MP R O . C O M
᭣ Dry Powder Blending System
The blending system allows homogeneous blending of dry powder batches with its patented
blending elements mounted to the inside of the container lid. The blending procedure can be
scaled up from 4 – 12,000 liters. For full flexibility the blending containers can be exchanged
to use different volumes. Due to the patented blending system each blending container can be
used for effective mixing between 20 – 85 % of the total container volume for densities between
0.2 – 1.2 kg/dm³. The Pharma Blender is a stationary blending device, consisting of PM machine
body with load suspension device, an electrical switch cabinet integrated in machine
body (separate installation optional upon request), separate operator panel, and safety
light barrier or laser scanner (optional). The blending operation is a fully contained and
closed process. Each container has an inner lid for filling procedures. An extended hoist
allows the blender to also be used as a milling station for bin to bin transfer. ■ L.B. Bohle
Maschinen + Verfahren GmbH Ennigerloh, Germany. www.lbbohle.de/de/ or call +49 (0)
2524 93 23 150


pp1307_Innovations_Mixers.indd 44 6/25/2013 10:38:00 AM
Rotary Vane Vacuum Pumps ᭤
This line of dry running and oil-lubri-
cated rotary vane vacuum pumps are
geared towards mixing, blending
and drying machines that manu-
facture various types of pharma-
ceutical products. The central
vacuum system can operate
the entire plant with a PLC. This
allows the company to control the
vacuum usage for all of the machines
becoming more energy efficient. The dry running rotary
vane compressor is a continuous duty pump that is maintenance
friendly, easy to operate, encompasses a low noise level and is environmentally friendly. The
process is also extremely safe and reliable. The oil lubricated rotary vane compressor, also
ideally for higher vacuum pharmaceutical machines, is cost-effective and can handle pro-
cess streams containing residue, high toxic vapors and gases flawlessly. ■ Republic Vacuum
Pumps , Dallas, TX 75247. www.republicsales.com or call 800-847-0380
High-shear Mixers ᭤
High-shear mixers that can be quickly and cost-effectively custom-
ized to meet unique processing challenges. Mixing processes vary
from each application but having a flexible bowl configuration
offers greater efficiency and permits working volumes
from 30 – 90% of full capacity. Here are a few key
functions to look for in all mixers: auto-cleaning and
liftable tool systems for easy clean-up and inspec-
tions, saving much time in cleaning while
reducing set-up time, but most importantly
reducing downtime between batches. Having
a hydraulic drive system permits torque down
to ¼ RPM providing plenty of break-out torque at
slow speeds for additional mixing after inspec-
tion and continuous discharging to wet milling
systems. Another tip is to check to see where
the impeller and chopper are located, the best
performance is if the impeller is bottom-driven
and a side mounted chopper, having a consis-
tent impeller tip speed for all models ensures
scale-up. Lastly look for an elliptical or dome shaped lid to permit the product to perform a com-
plete roll over, ensuring a homogeneous mix. Mixers come with a variety of options and features that
can include vacuum loading, vacuum drying, nitrogen inerting system, and bowl water jackets just to
name a few, each companies needs vary depending on the end results needed. ■ Fluid Air, a division
of Spraying Systems Co., Aurora, IL 60502. www.fluidairinc.com or call 630-665-5001
᭡ Vacuum Processing Unit
With its enclosed design, the FrymaKoruma
Frymix II vacuum processing unit is the sys-
tem of choice for manufacturers of high-qual-
ity pharmaceuticals. The machine complies
with all cGMP/GAMP specifications for sterile
suspensions and emulsions. The products are
processed utilizing the rotor-rotor principle
by a powerful homogenizer, which was explic-
itly developed for temperature and shear-sen-
sitive formulations. The efficient deaeration,
continuous heat exchange and removal of all
external piping guarantee absolutely reliable
processes and superior product quality. ■
Romaco Karlsruhe, Germany. www.romaco.
com or call +49 (0) 721 4804 0
᭡ Microwave Mixer
Custom-designed, microwave-mixers are
capable of maintaining long-term drug stability
with stringent granule characteristics. It offers
several advantages including rapid and uniform
volumetric heating and better process control
with no overheating at the product surface.
Other benefits include no environmental heat
loss with elimination of greenhouse gas emis-
sions, energy savings and low operating costs.
The 3A-sanitary certified horizontal designs
provide superior hygienic processing with easy
cleanout. Systems range in size from lab-scale
systems less than 5 cubic feet to high power
vessels up to 200 cubic feet. ■ Marion Mixers
Marion, IA 52302. www.marionmixers.com or
call 319-377-6371
pp1307_Innovations_Mixers.indd 45 6/25/2013 3:20:20 PM
Conveying and Pre-Mixing Dry Solids into a Slurry ᭤
The powder and liquid delivery system automatically and precisely
delivers dry bulk ingredients into a motive liquid stream to convey
slurries, solutions or suspensions into users mix tank, blender or
other process equipment. In addition to dramatically reducing mix
times, the Solidquid instantly creates non-viscous mixtures, which
eliminates the need for additional conveyors, saves maintenance and
energy costs, creates less dust, uses less floor space and offers more
flexibility in equipment layout. Material is discharged from a bulk bag
unloader frame into a feeder, which volumetrically or gravimetrically
measures it into a solids eductor. Motive process liquid supplied to
the eductor inlet creates a vacuum, pulling the dry material into sus-
pension and disperses them evenly into the effluent flow. ■ Hapman,
Kalamazoo, MI 49048. www.hapman.com or call 800-427-6260
■ P H A R MP R O . C O M
EZ-Down System ᭡
The EZ-Down System is a simple yet highly
innovative and effective tool that improves
yield while reducing the potential for layering
or segregation. The EZ-Down system consists
of a rubber bladder inside a clear tube. When
inflated, the bladder pinches off the flow of
product within the tube. By slowly allowing the
air to deflate from the bladder, the weight of the
material causes the blend to flow gently from
point A to point B without any free fall, which
would likely lead to de-blending. It was recently
installed on the line of a large pharmaceutical
company that was dealing with bad segregation.
The result was a gentle, controlled decelerated
transfer from the hopper to the tablet press
that improved yields from less than 75% to over
98%. ■ Custom Powder Systems, Springfield,
MO 65803. www.custom-powder.com or call
Sterile Microsphere Filter Dryer ᭤
Suspended microspheres obtained from various micro encapsulation
processes require unique handling that differ from a typical filtration
and drying operation. Microspheres are random in size and need to
be filtered and classified into the micron size desired before dry-
ing. Once the range of microspheres, have been dried, they are then
ready to be made into a free flowing injectable product. Sterile Filter
Dryers are designed to meet the process criteria from small scale
processes up to production. ■ Powder Systems Limited, Boise, ID
83704. www.powdersystems.com or call 208-376-7008
Kilo-lab Size Conical Vacuum Dryer/Mixer ᭤
Kilo-lab size conical vacuum dryer/mixer machine matches
the special requirements in the lab with regard to the soft-
ware program data recording, measurement points, outfit
and use, and offers modular design, maximum flexibility and
mobility, applications can be carried out on drying processes
under vacuum and other procedures such as mixing and
homogenizing, degassing, moistening and so forth. All process
data points can be evaluated, re-appraised and available for
the necessary scale-up calculations. All necessary PAT instru-
ments and measuring elements are available so that the
lab dryer-mixer is configured to a production machine in
every way. Other key benefits of this design include 150ml
to 1500ml small scale volume; interchangeable mixing systems of
either orbiting arm or central shaft for evaluation/comparison of different mix-
ing technologies; plastic vessel option to view mixing; proven conical design guarantees a
free unobstructed, complete discharge of the valuable products; and direct scale up. ■ Heinkel
USA, Swedesboro, NJ 08085. www.heinkelusa.com or call 856-467-3399
Stainless Steel
Homogenizer ᭤
The PRO400 SS model is
constructed entirely of 316
stainless steel. With its
1-3/4 hp, 1305 watt, high-
torque motor, the PRO400
stainless steel homog-
enizer is the most powerful
homogenizers in the PRO line. A
closed-loop speed control with
digital LED display allows for
accurately setting the blade
or generator speed from 0
to 23,000 rpm. While the ho-
mogenizer can handle samples
as small as 0.03 ml, it is engineered to
efficiently process tough samples in volumes
as large as 40 L. It features a variety of acces-
sories to custom fit your lab, and it is available
with the standard height stand of 24 inches or
an extra long stand of 38 inches. The PRO400
stainless steel homogenizer is also available
as a “P” programmable or computer interfaced
PRO “PC” homogenizers for verification of
processing and documentation maintenance.
■ PRO Scientific Inc., Oxford, CT 06478.
www.proscientific.com or call 203-267-4600

pp1307_Innovations_Mixers.indd 46 6/25/2013 10:38:35 AM
᭣ Double Planetary Mixers
The new agitator blade is designed for the line of double
planetary mixers. The 100-gallon model is equipped with
two identical rectangular stirrers with upward rake fin-
gers. Designed to rotate on their own axes while orbiting
the vessel on a common axis, these style blades are ideal for
batching dry powder blends, wet granulations and similar
formulations in the double planetary mixers. Interchange-
able helical blades are available as options and allow the
mixer to be utilized for viscous pastes and putty-like materi-
als. The NEMA 4X control panel includes a 6-inch color touch
screen linked to a 30HP Variable Frequency Drive. Speed,
power load and cycle time are all controlled and displayed
from this screen. Two-hand raise/lower controls for the
air/oil hydraulic lift are also located on the panel for opening
and closing the mixer. With the blades in the fully raised
position, they are completely accessible for easy clean-
ing while the portable mix can is removed from under the
mixer and rolled into the discharging area. The vessel is
supplied with lift trunnions so it can be raised and tilted for
fast transfer of the finished product. ■ Charles Ross & Son Company ,
Hauppauge, NY 11788. www.mixers.com or call 631-234-0500
Resodyn Acoustic Mixers ᭤
Studying 32 various API samples with excipients, resodyn
acoustic mixers perform below/well below the 4% "read-
ily pass" FDA threshold. Using a patented, high-intensity,
low-frequency process, RAM generates acoustic
energy. These acoustic fields generate accelera-
tion up to 100g’s, at ~60 Hz, mixing
uniformly and simultaneously,
throughout the mix vessel. The
system’s fast and efficient, but
non-invasive, non-destructive
performance meets stringent FDA
and GMP requirements. In times
ranging from 2 to 6 minutes, RAM
produced RSD figures from ~0% to
<4%. Careful monitoring of times
at intensities of 70 g’s or less illus-
trates the efficiency, speed, and
quality RAM delivers. Moreover, RAM
scales directly — R&D lab to production
level. ■ Resodyn Acoustic Mixers, Butte, MT 59701.
www.resodynmixers.com or call 406-497-5333
Dynamic Batching Station ᭡
The Dynamic Batching Station (DBS) is a skid-
ded process module for batching dry powders
into liquids. It can be fed dry powders or
granular sugar from bulk trucks, bulk bags or
other feed options. The fully automated process
can operate as a “batch and pump” or “continu-
ous steady state” and other operating modes.
Process guarantees unparalleled throughput
volumes and precise solids control. The unit
employs the company’s patented Vacucam
Dynamic Dispersion
technology that conveys
dry materials via a powerful naturally created
vacuum. Design assures total and complete
dispersion of any dry ingredient into any flow
able liquid. ■ Semi-Bulk Systems, Inc., St. Louis,
Missouri 63026. www.semi-bulk.com or call
Continuous Blender ᭡
The Model 350 is a versatile, multi-purpose
continuous blender utilizing a modification of
company’s unique, dissimilar speed, Double
Concentric Auger Mechanism for the highly ef-
ficient mixing of dry solids with dry solids and,
in certain applications, dry solids with liquids.
The action imparted to the material within the
blender by the dissimilar parallel motion of the
dual concentric augers operating at different
speeds produces a gentle, homogeneous blend
of the ingredients. ■ Acrison Inc., Moonachie, NJ
07074. www.acrison.com or call 201-440-8300
pp1307_Innovations_Mixers.indd 47 6/25/2013 3:20:36 PM
Multi-Particulate Forming and
Coating System ᭤
The Granurex
Conical Rotor allows for the economical produc-
tion of very small, very high API content beads. The conical rotor
process easily switches from agglomeration, to film coating, to
powder layering modes with simple parametric changes. A
spherically agglomerated active core can be quickly given a
barrier film coating to separate incompatible APIs and then
seamlessly powder layer a different API, creating a multi-
layered multi-particulate bead product. The conical rotor
design generates dynamic particle movement improving
product yields. Uniform slit air distribution prevents granule
agglomeration during the coating process and generates
excellent coating uniformity. Product drying is achieved using a duct system to introduce process
air directly into the drying zone. There are seven models of the Granurex
available. ■ Freund-
Vector Corporation, Marion, IA 52302. www.freund-vector.com or call 319-377-8263
᭣ Continuous Coater
The Driaconti-T pharma Lab operates on the same principal as the company’s continuous pro-
duction unit and represents the company’s response to requests from potential customers for
smaller continuous coating equipment for scale up and lab testing. The perforated drum of
the unit is divided into three chambers. One third of the entire film coating is applied in each
chamber at the same time. Once an application is finished, all mini batches are moved by
flaps to the next chamber, discharging the contents of the last chamber into a discharge con-
tainer. This process allows to infinitely expose the contents of the drum to the spray media.
Charging of the first chamber is accomplished by means of a loading hopper. The machine
can be operated in a cycled continuous mode resulting in high quality coated products but
can also be used as a batch process by activating the transport flaps only at the end of the
process. ■ Driam USA, Inc., Spartanburg, SC 29303. www.driamusa.com or call 864-579-7850
■ P H A R MP R O . C O M
᭡ Tablet Coater for Production
The ManestyXL Cota 150 was developed for
batches up to 230 liters. Designed for use with
aqueous, organic solvent or sugar coating
media, optional control and cleaning systems
provide a comprehensive solution for tablet
coating.Fully reproducible results using either
manual or automatic versions of the m-tec
control system ensure high product quality
and quick availability for the next batch. Tab-
lets are loaded using a simple chute and un-
loaded by reversing the direction of the drum
for fast and gentle removal. Manesty tablet
coating systems are suited for small, medium
and large scale production. All coaters use
fully perforated pan technology, delivering ef-
ficient and controllable processes. They also
feature patented spray gun and mixing baffle
technologies. Tailored air treatment handling
systems ensure fast processing of production
batches. ■ Robert Bosch Packaging Technol-
ogy, Inc., Minneapolis, MN 55445. www.
boschpackaging.com or call 763 424-4700
᭣ Tablet Coater
Innovative processing and cleaning concepts im-
prove the coater functionality and deliver outstand-
ing results. The type of air system utilized provides
significant process-related advantages eliminating
the risk of suspension spray drying. This reduces
spray losses and improves coating structure. Tab-
lets are handled with less mechanical stress thanks
to the geometry of the pan and the mixing and conveying
elements. By changing the rotating direction of the pan, tablets
can be discharged completely and without additional fixtures. ■ LB Bohle
LLC, Warminster, PA 18974. www.lbbohle.de or call 215-957-1240
pp1307_Innovations_coating.indd 48 6/24/2013 4:02:04 PM
www. l oadtransfer. net
Prevent contamination from
entering production areas; use a
Columbia Load Transfer Station
- Category 3 safety compliant
- Safer, cleaner & faster than other load transfer
* Transfers from one
pallet type to another
- Enhance safety for warehouse personnel
■ P H A R MP R O . C O M
High Speed Dispersers for
Large Scale Production
A full range of high speed dispersers
are suitable for high-volume mixing in
vessels up to 6,000 gallons or larger.
These production-scale high speed
dispersers are either tank-mounted or
supplied with an air/oil hydraulic lift.
In the latter configuration, a height
limit switch enables the mixer to
operate from the fully down position
to a safe raised height. This allows the
operator to adjust blade position as
necessary to eliminate any potential
stratification within a large batch as
well as agitate smaller liquid volumes
during the initial stages of mixing. Used for wetting out powders,
creating a uniform suspension and general liquid-liquid mixing, the
classic saw-tooth open disc blade of the high speed disperser turns at
tip speeds up to around 5000 feet per minute. It generates a vortex on
the liquid surface into which solids and other minor components are
added for quick incorporation. Satisfactory flow patterns and rapid
turnovers are achieved in dispersions and solutions with a viscosity
of >50,000 centipoise. ■ Charles Ross & Son Company, Hauppauge, NY
11788 . www.mixers.com or call 1-800-243-ROSS
Chemical Storage Cabinets
The Safestore™ Vented Chemical
Storage Cabinets are ideal for stor-
age of noxious or odorous chemi-
cals. These cabinets minimize health
and environmental risks in handling
chemical vapors and residues, VOCs
and general laboratory functions.
The filtration system protects the
safety of personnel during use,
maintenance and decontamination.
Advanced carbon filtration technol-
ogy offers a safe, high performance
alternative to ducted cabinets for
a broad range of applications. The
Safestore cabinets are available in three capacities, 25 liters, 1,000
liters and 2,000 liters. ■ Air Science USA, Fort Meyers, FL 33906. www.
airscience.com or call 239-489-0024
Combination Filler
Combination fillers allow users the
benefit of filling two or more differ-
ent elements, such as dry powder
products and particulates, into
one container at the same time
on an automatic pouch machine
— saving time and valuable space
in plants. Using a combination filler
on an automatic pouch machine
greatly speeds up the process, filling
pouches as fast as 120 per minute.
For added flexibility, the combination
fillers are available in formats such
as two augers, two cups, auger/cup,
and multi-lanes; they are designed to specific application. ■ Spee-Dee
Packaging Machinery, Inc., Sturtevant, WI 53177. www.spee-dee.com
or call 877-375-2121
Manifold Connections
Leak-proof molded manifold connec-
tions for single use process systems
are custom made from platinum-cured,
USP Class VI silicone tubing and molded
fittings in Class7 (Class 10,000) ISO-cer-
tified clean rooms under the highest
quality controls. The single use system
components eliminate many barbed fit-
ting junctions and the potential for leaks
and contamination, reduce the risk of a
wasted batch of costly pharmaceutical
product, and provide a smooth inner
surface for even, unrestricted flow. ■ AdvantaPure, Southampton, PA
18966. www.advantapure.com or call 888-755-4370
pp1307_newproducts.indd 49 6/25/2013 3:19:15 PM
᭣ Tablet Conveyor
Tablet conveyors are an
economical way to efficiently
convey tablets horizontally or up
to a 40 degree incline utilizing
a very small foot-
print. GMP-compliant
design that is easy to
disassemble for cleaning,
fabricated from stainless steel, with FDA ap-
proved belt materials. Conveying lengths from 1
to 2.5 meters, and various stand heights to meet
specific requirements. Conveyors are very flex-
ible and easy to adjust inlet and outlet orienta-
tions to meet numerous applications. ■ Kraemer
U.S., Allendale, NJ 07401. www.kraemerus.com or
call 201-962-8200
᭣ Vacuum Conveyors
p conveyors are designed for robust-
ness and cleanability. The vacuum generated by
p is produced in an energy efficient way
through the use of COAX
cartridges. The COAX

cartridges are smaller, more efficient and more reliable
than conventional ejectors, which allows for the design
of a flexible, modular and efficient vacuum system.
A vacuum system based on COAX
technology provide
the user with three times more vacuum flow than conventional systems, while reducing energy
consumption. piFLOW
p is designed according to USDA and GMP guidelines. All materials are FDA
approved and all configurations can be delivered with an ATEX Dust certificate. ■ Piab, Hingham,
MA 02043. www.piab.com or call 800-321-7422
᭣ Pneumatic Conveyors
Each system has it’s own unique set of operating characteristics for pres-
sure, conveying line velocity, efficiency and performance. Because each
and every material to be conveyed reacts differently under a given set of
operating conditions, it is extremely critical to match the system operat-
ing characteristics to the material to be conveyed in order to achieve
the most desired conveying performance and to provide the best value.
Pneumatic conveying concepts have the ability to convey at almost any
conveying velocity desired to suit a given material to be conveyed. Units
can convey many materials with conveying velocities as low as 50 feet
per minute using the HDP 6000 dense phase pneumatic conveying system
and, using the LDP 2000 dilute phase pneumatic conveying system, units
can convey at velocities well over 7000 feet per minute. ■ Dynamic
Air Inc., St. Paul, MN 55110. www.dynamicair.com or call 651-484-2900
■ P H A R MP R O . C O M
Tilt-Down Conveyors ᭤
S anitary tilt-down flexible screw conveyor on
a caster-mounted frame can be maneuvered
through narrow aisles and around corners. With
the hopper, support boom and conveyor assem-
bly tilted down, the unit fits through standard
doorways and orients the conveyor tube horizon-
tally, allowing the flexible screw to be removed
easily for thorough cleaning and inspection. The
conveyor’s surge hopper, which is configured for
dust-tight connection to the outlet of upstream
equipment, includes an air displacement vent
with cartridge filter that is equipped with a re-
verse pulse cleaning system that dislodges accumulated dust with short bursts of compressed air.
■ Flexicon Corp., Bethlehem, PA 18020. www.flexicon.com or call 888-353-9426
᭡ Reactor Loaders Safely
Convey Dry or Wet Powder
and Granules Into Hazardous/
Explosion Risk Areas
The company’s ATEX-approved INEX vacuum
conveying system takes vacuum transfer of
dry or wet powder and granules into poten-
tially hazardous conditions to a new level. By
using a sophisticated, patent-pending nitro-
gen purging function, INEX reduces oxygen
content within the unloaded batch to below
7% (or lowerwhen required), maintaining the
material’s inert safety while providing dust-
free transport. The INEX features a closed
station which can be flushed from within by
sucking in the washing liquid or through WIP/
CIP. Standard lightweight and pressure-rated
systems are available with INEX functionality.
■ VOLKMANN, Inc., Hainesport, NJ 08036. www.
volkmannUSA.com or call 609-265-0101
pp1307_innovations_conveyors.ind50 50 6/24/2013 4:03:04 PM
■ P H A R MP R O . C O M
Slide Gate Valves
A new range of pneumatic and manually actu-
ated double flanged in-line slide gate valves
are now available. Features and benefits of
the SD-P Slide Gate Valve include: a robust,
complete, shut-off solution that is ideal for
powders, granules and pellets. A durable self-
compensating polymer seal that ensures the
blade is completely dust tight which prevents
material leaking into the environment. It also
offers total unobstructed full bore opening
for smooth, non-jamming operation. The SD-P
Slide Gate Valve is self-cleaning, low main-
tenance and economical. ■ Mucon, Bristol,
PA, 19007. www.KemutecUSA.com or call
Jet Mill
The Micronizer® utilizes a unique fluid energy
grinding system to generate particle-on-particle
impact. The jet mill grinds and classifies pow-
ders to micron and sub-micron sizes in a single
grinding chamber using compressed air or gas.
It is engineered to meet sanitary demands and
is designed for easy access and cleaning. Inside
the Micronizer®, precisely aligned jets create
a vortex. Material is fed into this vortex along
an engineered tangent circle which accelerates.
High-speed rotation subjects the material to
particle-on-particle impact, creating increasingly
smaller fines. While centrifugal force drives
large particles toward the perimeter, fine par-
ticles move toward the center where they exit
through the vortex finder. ■ Sturtevant, Inc. ,
Hanover, MA 02339. www.sturtevantinc.com
or call 1-800-992-0209
Rotary Airlock Valves
Designed specifically for sanitary applica-
tions such as pharmaceutical processing or
medical device manufacturing, the Quick-
Clean Series of rotary airlock valves aids in
regulatory standards and practices compli-
ance, reduces cleaning and sanitizing time,
and simplifies inspection. ACS Quick-Clean
Series rotary airlock valves are available
in 304 or 316 stainless steel, in sizes from 6
inches to 18 inches, with pressure differen-
tials up to 20 PSIG, and temperature toler-
ance up to 750ºF. It features the ACS Rotor-
Rail™ design that enables full validation
access to the rotor and all internal surfaces
of the housing without disassembly of the
endplate or the concern for accurate rotor re-
alignment during re-assembly. The stainless
steel housings are CNC-machined to precise
tolerances. With internal surfaces polished
to a No. 4 finish, the ACS Valves CIP-ready
design eliminates internal crevices and joints
where contaminants can accumulate. The
optimal inlet/outlet seal produced by the
ACS Quick-Clean Series rotary airlock valve
is achieved using the standard, ACS Valves,
8-vane rotor design. The 8-vane rotor design
eliminates excess pressure loss through
the system, ensures cost-efficient upstream
and downstream material management, and
reduces process energy consumption. ■ ACS
Valves, Ontario, Canada. www.acsvalves.com
or call 800-655-3447
Tablet Coating Solution
The Tablet Coating System can be custom
designed and optimized for flexibility and a
variety of tablet coating requirements. The
system consists of a modular air atomizing
manifold, liquid delivery skid and Batch Archi-
tect™ process controls. The removable spray
bar provides cleaning advantages and features
anti-bearding nozzles, internal recirculating
guns, a shut-off valve that keeps liquid mov-
ing, reducing product build-up and a mounting
design which prevents tablet entrapment. The
liquid delivery skid can perform manually and
automatic operation with closed-loop solution/
liquid delivery metering using loss-in-weight,
mass flow sensing, and totalizing, ultimately
saving time in costly trial and error efforts. ■
Fluid Air, a division of Spraying Systems Co.,
Aurora, IL 60502. www.fluidairinc.com or call
Electric Drum and Tote Heaters
The Sahara Hot Box Model E8 Electric Drum
and Tote Heaters provide precise tempera-
ture control and trouble-free service. Each
heater features steel construction, including
304 stainless steel as an option, to withstand
the harshest environments. The exterior for
each unit features an acrylic enamel while the
interior is finished with heat-resistant silver. A
1,020 cfm air circulation blower with controls
is also included. Another feature is state-of-
the-art digital controls with independent over-
temperature protection helping ensure precise
temperature control. ■ Benko Products, Inc. ,
Sheffield Village, OH 44054 . www.benko-
products.com or call 440-934-2180
pp1307_newproducts.indd 51 6/24/2013 4:01:02 PM
If you purchased Vitamin C since December 1, 2001
A Class Action Lawsuit and Settlements Could Affect You
What is this case about?
Plaintiffs have brought a class action lawsuit claiming that
vitamin C manufacturers conspired to fix and raise prices. A jury
has awarded a verdict in favor of Plaintiffs and against certain
Defendants. This judgment is not yet final, and does not apply to
all class members. Some Defendants agreed to settle to avoid the
cost and risk of a trial.
The Defendants are Hebei Welcome Pharmaceutical Company,
Ltd., Weisheng Pharmaceutical Company Ltd. (“Weisheng”),
Aland (Jiangsu) Nutraceutical Co., Ltd. (“Aland”), Northeast
Pharmaceutical Group Co., Ltd. (“NEPG”) and certain of
their affiliated companies. NEPG is a Defendant for only the
Injunction Class and the Indirect Purchaser Damages Class
described below.
Are you included?
The case seeks to recover money (damages) for Class Members
and an order from the Court (an injunction) that the Defendants
not engage in any price-fixing activities.
You are included in the Direct Purchaser Damages Class if
you: 1) purchased vitamin C, 2) for delivery in the U.S., 3)
directly from a Defendant (except NEPG) or another Chinese
manufacturer of vitamin C, 4) between December 1, 2001 and
June 30, 2006, 5) without a contract, or with a contract that did
not include an arbitration clause.
You are included in the Indirect Purchaser Damages Class if you:
1) currently live in and purchased capsules or tablets containing
vitamin C in Arizona, California, District of Columbia, Florida,
Iowa, Kansas, Maine, Massachusetts, Michigan, Minnesota,
Nebraska, Nevada, New Mexico, New York, North Carolina,
North Dakota, South Dakota, Tennessee, Vermont, West Virginia,
or Wisconsin, 2) between December 1, 2001 and June 30, 2006,
3) for use or consumption and not for resale.
You are included in the Injunction Class if you: 1) purchased
vitamin C manufactured by a Defendant, or products from any
company containing vitamin C manufactured by a Defendant,
2) directly from a Defendant or from any other company, 3) for
delivery in the U.S., 4) from December 1, 2001 to now, 5) without
a contract, or under a contract without an arbitration clause.
What is the status of the lawsuit?
Weisheng Pharmaceutical Company Ltd., China Pharmaceutical
Group, Ltd. (“CPG”), and NEPG (“Settling Defendants”) have
For more information: 1-866-684-9673 www.vitaminCantitrust.com
recently agreed to Settlements with some or all of the Classes.
(Aland previously agreed to Settlements with all three Classes.)
Weisheng and CPG agreed to settle the claims of the Direct
Purchaser Damages Class for $22.5 million. NEPG will pay a
total of $1 million to settle the claims of the Injunction Class
and the Indirect Purchaser Damages Class. In settling the claims
of the Injunction Class, all three Settling Defendants promised
to comply with any injunction the Court may enter against any
other Defendant. See the Detailed Notice for information about
how the Settlement proceeds will be distributed.
A jury has awarded the Direct Purchaser Damages Class $54.1
million against the Non-Settling Defendants; the Court entered
a judgment of $162.3 million for the Class. This money will not
be distributed until all appeals are resolved.
What are your options?
If you want to stay in the lawsuit or Settlements, you do not need
to do anything. You will be bound by the lawsuit and Settlements
and give up certain rights to bring separate lawsuits about the
claims in the lawsuit.
If you stay in the Settlements, you may object to one or more of
them by August 9, 2013.
Members of the Direct Purchaser Damages Class may submit a
claim for a cash payment.
If you do not want to be legally bound by the Indirect Purchaser
Damages Class lawsuit or its Settlement with NEPG, you must
exclude yourself in writing by July 12, 2013. You will not receive
any money. You cannot exclude yourself from the Injunction
Class or the Direct Purchaser Damages Class. The lawsuit and
Settlements do not cover damages incurred after June 30, 2006.
If you are an indirect purchaser and you want to keep the right to
sue for damages after June 30, 2006, you must exclude yourself.
The Court has appointed Class Counsel to represent you. You
don’t have to pay them, or anyone else, to participate. You can
hire your own lawyer, at your own expense, to appear or speak
for you at the hearing.
The Court will hold a hearing on August 29, 2013 at 2:30 p.m.
at the U.S. District Court for the Eastern District of New York
to consider approval of the Settlements, including a request
for attorneys’ fees of up to 35% of the Settlement funds, plus
Legal Notice
pp1307_ads.indd 52 6/21/2013 9:12:43 AM
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Costs With
DeltaV Batch is based
on the ISA 88.01 batch
standard providing the flexibility needed for today’s agile man-
ufacturing. Whether it’s the physical model, procedural model,
or easy-to-use class-based model, the DeltaV system is built
for batch from the ground up. The DeltaV system reduces vali-
dation costs by eliminating the need to configure and interface
different software packages to each other. Advantages can be
realized in the HMI interface which shares a common data-
base with IO and in the Continuous and Batch History which
requires no configuration- providing less engineering, less
configuration, less documentation and, hence, less validation.
Emerson Process Management;
www.emersonprocess.com/DeltaV; 512-418-7534
MegaShear Ultra-High Shear Mixer
The MegaShear Ultra-High Shear Mixer is a patented inline
rotor/stator designed
for high-volume and
high-throughput deag-
glomeration, emulsifica-
tion, and homogeniza-
tion requirements. The
MegaShear is capable
of producing very fine
emulsions and dispersions at a fraction of the cycle time.
Just as important, it is not susceptible to common milling
and homogenization issues such as clogging, sensitivity to
viscosity changes, time-consuming clean-up, and intensive
maintenance. The MegaShear is ideal for processing a wide
range of applications including pharmaceutical emulsions,
creams and ointments, gels, pastes, nutraceuticals and
supplements, biosuspensions, active ingredient dispersions,
additive formulations, medical coatings and adhesives.
Charles Ross & Son Co., www.mixers.com;
Veltek’s Easy2Gown System
Easy2Gown disposable garments are packaged using a
patented fold which was developed to minimize operator error
and personal contact from the outside of the gown during the
gowning process. The soft, comfortable material is double-
stitched with bound edges to reduce particulate shedding
and has excellent chemical resistance. Sewn thumb loops,
elastic at the wrists and ankles, make the gowns easy to wear,
eliminating the cumbersome shifting typical of other gowns
Veltek Associates, Inc., www.sterile.com
pp1307_AdShowcase.indd 53 6/25/2013 1:26:22 PM
■ 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.
Ash Stevens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Baldor Electric Company . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
CD-adapco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Columbia Machine Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
EMD Millipore Corporation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Emerson Process Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3, 53
Finesse Solutions LLC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53, 56
Fluid Metering Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
General Electric Company - Energy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Impact Analytical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
International Products Corporation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38, 53
Kinsella Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Lyophilization Services of New England . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Millrock Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
OPTIMA packaging group GmbH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21, 53
Petro Canada-Suncor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Powder Systems Limited . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Ross, Charles & Son Company . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .7, 53, 54
Siftex Equipment Company . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15, 54
Vac-U-Max . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32, 53
Value Plastics Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18, 53
Veltek Associates Inc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5, 53
Xcellerex. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11, 53
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On the surface
all white mineral oils appear
to be the same.
With PURETOL white mineral oils, your money goes farther because it’s buying much more than
just another ingredient. You’re buying supply (we’re the world’s largest producer of white mineral oils).
You’re buying quality (every PURETOL product is produced by us from start to USP/NF-certifed fnish).
You’re buying support (world-class R&D and a dedicated team that knows its business – and yours).
Want to go deeper?
call: 1-866-335-3369 | e-mail: sales@suncor.com | visit: lubricants.petro-canada.ca/puretol
Petro-Canada is a Suncor Energy business
™Trademark of Suncor Energy Inc. Used under licence.
Purity You Can Count On
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USA Toll Free +1 800 598 9515 | Europe +41 81 641 2000 Asia +65 8322 8128 | Finesse.com
Dependable software
for cGMP production
Comply with cGMP regulations and mitigate risk
Scalable Accelerate scale-up and scale-down
Modular Configure, customize, or expand with ease
Adaptable Connect with many bioreactor sizes and brands
Reliable Entrust your production to the DeltaV
control platform
Total Unify upstream processes: one common user interface
Make your process excellent.
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