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February 2012
Volume 36
Number 2
Optimizing
Adjuvant Filtration
Regulatory
Scientists’ Future
Expanding
the Cold Chain
Outsourcing Outlook: Biomanufacturing on the Rise
PEER-REVIEWED: Evaluating Impurities

Applying QbD
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Professor, Department of
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University of Maryland
David H. Bergstrom, PhD
COO, NovaDel Pharma Inc.
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GlaxoSmithKline
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Director, Quality Systems Audit,
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t Sterile
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Phar mTech. com
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On PharmTech.com
February 2012 Volume 36 Number 2
cover Story
34 Drug-Substance Devel-
opment and manufacture
by angie Drakulich
FDA and industry members of the ICH Q11
expert working group discuss the pending
guideline’s goals and impact.
Compositing by Dan Ward.
Images: Ian Sanderson/Getty Images
Pharmaceutical Technology is the authoritative source of peer-reviewed research and
expert analyses for scientists, engineers, and managers engaged in process devel-
opment, manufacturing, formulation and drug delivery, API synthesis, analytical
technology and testing, packaging, IT, outsourcing, and regulatory compliance in the
pharmaceutical and biotechnology industries.
Features
technical forum
38 optimizing
adjuvant Filtration
a technical forum
Experts discuss solutions for filter bac-
terial retention and related challenges.
pharma ingredients
42 expanding
capabilities in the
Pharmaceutical cold chain
Patricia Van arnum
As biopharmaceutical development and
commercialization increases, companies
are expanding their cold-chain capabilities.
Plus: Formulation Development Forum
Peer-reviewed research
impurities
46 evaluating impurities in
Drugs (Part i of iii)
Kashyap r. Wadekar, mitali Bhalme,
S. Srinivasa rao, K. Vigneshwar reddy,
l. Sampath Kumar, and e. Balasubrahmanyam
In Part I of a three-part article, the
authors discuss what constitutes an
impurity and the potential sources
of impurities in APIs and finished
drug products.
Departments/Products
16 in the Field
22 in the Spotlight
58 industry Pipeline
62 Showcase/markeplace
64 ad index
Continued on page 8
issue extras

In correlation with this
month’s cover story, FDA ad-
dresses regulatory and manufac-
turing flexibility when using a
QbD approach.

Read more of this month’s
filtration technical forum online,
with additional information on
oil-in-water emulsions and lipo-
some adjuvants.
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2012 Supplement to the February 2012 Issue of
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Continued from page 6
columns
from the editor
10 Sustainable investment
angie Drakulich
Pharma announces plans for year
ahead at annual JPMorgan Global
Healthcare conference.
pharmtech talk
12 FDa’s Social
media insight
Stephanie Sutton
Guidance offered on how to deal with
off-label information requests.
agentinplace
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control, a Senior compliance officer
A nickel’s worth of free advice to
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bio forum
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Debottlenecking downstream
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statistical solutions
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Where is the variability coming from
and what have we done to minimize it?
inside ich
52 ich implementation
Support
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ICH Q8, Q9, and Q10 support and
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Industry optimism is on the rise for 2012.
Viewpoint
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New educational programs are
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FROM THE EDITOR
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PharmTech.com/forum
E
very year, industry leaders gather at
the JPMorgan Global Healthcare con-
ference to discuss key opportunities
for investment during the months ahead.
About 9000 people attended this year’s
event in January, in San Francisco. Several
key themes emerged from the presenta-
tions given by the pharmaceutical industry
C-suite executives about their upcoming
initiatives and focus, with the most preva-
lent being sustainability and innovation.
As part of these plans, several large
companies highlighted the need to reboost
R&D pipelines that have diminished dur-
ing the past several years. Targets include
not only new products (whether innovator
or generic), many in the oncology area, but
also personalized medicine and biosimi-
lars. Threaded throughout most of the pre-
sentations was the importance of emerg-
ing markets as a critical factor to success in
pipeline growth and sustainability.
While the talks did not unveil any big
surprises for investors looking at pharma-
ceutical development and manufacturing,
the conference made it clear that the same
hot growth areas (e.g., biosimilars, sustain-
able R&D, emerging markets) that have
been on chief executives’ minds for the
past few years are not going away. In fact,
these areas are becoming more cemented
into the industry’s future. Below are a few
highlights from the show regarding how
industry is thinking—and rethinking—
about these targets.
Approaching the R&D pipeline with
an eye on sustainability was a large com-
ponent of the talk given by Pfizer CEO
and Chairman Ian Read, who noted that
the company has several products at vari-
ous stages of development. And although
Pfizer reduced its R&D spending in 2011
by $1 billion, Read says he has “no illusions
that we need to have an engine that can
produce sustainable pipeline growth.” As
a result, the company “stopped spending
where we didn’t believe we had a competi-
tive advantage, or we believe that we would
be producing me-too products.” This strat-
egy involves looking at proof-of-concepts
more from a business perspective and
deciding whether or not to pursue certain
projects in the value chain. It sounds as
though the company is being more strin-
gent in such decisions in order to save time
and money in the long run.
Merck & Co is also expanding its think-
ing around scientific innovation, according
to CEO and President Kenneth Frazier’s
talk. “Many first-in-class medicines pro-
vide high return on investment, but they
also come with some of the highest risks
of failure. So to succeed, we have to have a
balance between first-in-class investments
and risks and drugs that can be consid-
ered best-in-class. Also, we must get the
full value of discoveries through effective
life cycle management for products….” He
mentioned, like many other speakers, bi-
osimilars as an area of innovation and how
Merck plans to compete in this space.
Bristol-Myers Squibb (BMS) CEO Lam-
berto Andreotti focused on what he called
the “next generation biopharma.” He pre-
sented this term as a combination of the
best of biotech and the best of pharma, in-
corporating innovation, selective integra-
tion, and continuous improvement. BMS
also noted R&D sustainability with a nod
towards creative partnerships as well as
integration of research, development, and
regulatory issues.
Amgen President, COO, and CEO-Elect
Robert Bradway (he takes over as CEO in
May) spoke about pipeline plans for 2012,
with a strong focus on biosimilars. “We
think in order to be successful in biosimi-
lars, a company will have to have strong
biologics manufacturing, regulatory, and
commercial capabilities,” he said. “…We
think we have that and we expect that these
biosimilar molecules will enable us to grow
not just in the US but in international mar-
kets as well.”
Generic-drug leader Teva Pharmaceuti-
cal Industries focused on the fast-changing
world of the generics sector, describing it as
a new era for the pharmaceutical industry.
CFO Eyal Desheh and CEO and President
of Teva-Americas William Marth pointed
to the growing markets in South America,
such as Chile and Peru, as well as the pre-
dictable ones in America and Western Eu-
rope. They noted as many as 40 potential
product launches for Teva in 2012.
Many more companies of diverse sizes
and investment opportunities presented at
the JPMorgan healthcare conference, set-
ting off a whirlwind of investment discus-
sions. It will be interesting to watch where
funds end up in the months ahead based
on the renewed push to plump up pipelines
while also keeping costs and resources at a
sustainable level.PT
Sustainable Investment
Pharma announces plans for year ahead at
annual JPMorgan Global Healthcare conference.
Angie Drakulich
Angie Drakulich
is editorial director of
Pharmaceutical Technology.
Send your thoughts
and story ideas to
adrakulich@advanstar.com.
PharmTech.com/forum
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12 Pharmaceutical Technology FEBRUARY 2012 Phar mTech. com
PHARMTECH TALK
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FDA’s Social Media Insight
Stephanie Sutton
D
edicated social media recom-
mendations from FDA may not
yet have materialized, but the
agency is beginning to address some
of the industry’s questions in this
area. At the end of 2011, FDA released
a draft guidance titled Responding
to Unsolicited Requests for Off-Label
Information About Prescription Drugs
and Medical Devices, which includes
recommendations on responding
through online channels such as fo-
rums and chat rooms.
According to the guidance, many
firms encounter requests for off-la-
bel information about their products
through websites, discussion boards,
and other electronic forums, and
FDA recognizes that firms are ca-
pable of responding to such requests
in a “truthful, non-misleading, and
accurate manner.” Indeed, FDA ac-
knowledges that it can be in the best
interest of public health for compa-
nies to reply to these requests because
other participants in the discussion
may not be able to provide accurate
information.
The guidance discusses responses
to both non-public information re-
quests, such as a one-on-one email or
telephone call, and public requests,
such as a request on an online forum.
The latter type is more complicated
because firms must ensure that their
response does not communicate unap-
proved information to those who have
not asked for it.
If a firm responds to unsolicited re-
quests for off-label information in the
manner described in the draft guid-
ance, FDA said it will not use such re-
sponses as evidence of a firm’s intent
that the product be used for unap-
proved or cleared uses. PT
Guidance offered on how to deal
with off-label information requests.
Stephanie Sutton
is an associate editor of
Pharmaceutical Technology.
»
Read Stephanie’s blogs at
blog.PharmTech.com.
14 Pharmaceutical Technology February 2012 Phar mTech. com
Agent-in-PlAce
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Cautionary Tales from the Files of “Control,”
a Senior Compliance Officer
correlation may be causation
“I thought it was merely coincidence,
but the head of marketing thought it
was the problem,” our GMP Agent-
In-Place began. “I work in a small
specialized subset of the pharmaceu-
tical industry, and I received a call
from a former colleague. It turns out
he had recently joined a competitor
company. He had a question regard-
ing shipment of our common raw ma-
terial across the ocean. His company
was missing a temperature monitor,
and wondered how we would rectify
such a situation. Because this was
a generic regulatory question, and
didn’t relate to any trade secrets, I
provided the information.
“A week later, the head of our mar-
keting organization called me regard-
ing one of our products,” chuckled
our Agent. “Apparently our main
competitor in this product area was
no longer supplying the market and
she wondered whether there was a
way we could get batch approval faster
for our product to prevent shortages.
It turns out that the competitor was
the one I talked to the previous week!
I mentioned this, and my marketing
colleague immediately grasped this as
the reason for the competitor’s appar-
ent production issues.”
Double-duty filter redux
“In last mont h’s column, I noted
that we discovered that a filter could
perform a secondary task,” our GMP
Agent-In-Place gri maced. “Guess
what, we’ve got another one. In this
case, it is a viral-removal filter. It
operates by having such small holes
that viruses must stay behind and
let the product pass through. After
we tried to change it, we found out
it also removed some heavyweight
polymers. The product failed release
testing, so we had to perform further
work on the process before we could
change the filter.”
Ask forgiveness, not permission
“We instituted an intensive change-
control program,” boasted our GMP
Agent-In-Place. “We educated the
staf f, especial ly the mai ntenance
shop staff, to run any change to a
product contact material through the
change-control process for evalua-
tion. We thought things were running
smoothly when the maintenance su-
pervisor said that the production staff
wanted to change a tank gasket from
Tef lon to silicone. When we looked
into this, we discovered that the gas-
kets were traditionally purchased by
the production staff for replacement
by contractors during shutdowns, and
they had already made the switch.
They wanted maintenance to carry
the gaskets for emergency replace-
ments and the next shutdown.
“After initiating a deviation for the
failure to follow the proper change-
control system, we performed a post
implementation evaluation, includ-
ing a risk analysis and extractables
studies,” noted our Agent. “The risk
was minimal because these particu-
lar gaskets are placed above the liquid
level and rarely have product contact.
Any product contact is f leeting, and
seen as little risk. The extractables
and leachables were well within al-
lowable limits, but they should have
been checked first.”
Audit the auditor
“I’ve been in quality my whole career,”
our GMP Agent-In-Place said. “This
past year, I was asked to work on a
quality system for a US-based mar-
keting organization. We have a global
policy about this, so it wasn’t hard to
do. A year later, we were audited. Our
standard agreements specify that the
manufacturing sites could audit us an-
nually, but in my 35 years they never
had, until now. I really made the au-
ditor mad when I told her that I had
no intention of changing practices,
and that any observation she gave
me would get the answer; ‘We shall
continue our current practice.’ As a
result, she took this minor issue and
cited it as a major failing, needing a
higher level oversight and correction.
It was funny at the time, now it’s an
irritation.” PT
A nickel’s worth of free advice to the competition
could come at the expense of your bottom line.
Shipping with the enemy?
Pharmaceutical Technology’s
monthly “Agent-in-Place” column
distills true industry tales from the
files of Control, a senior compli-
ance officer. If you have a story to
share, please email it to Control at
AgentinPlace@advanstar.com. We
won’t use any names, but if we do
use your experience in the column,
you’ll receive a Pharmaceutical
Technology T-shirt.
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16 Pharmaceutical Technology February 2012 Phar mTech. com
In the Field
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IN THE FIELD
contin. from page 16
Plans to increase pharmaceutical exports
“The idea is to double pharmaceutical exports to $25 billion by
2013–2014,’’ says India’s Health Minister Ghulam Nabi Azad.
The Indian pharmaceutical sector has already emerged as one
of the major contributors to the country’s overall exports, with
earnings rising from a negligible amount in the early 1990s to a
value near the $12-billion mark. With generic-drug exports to the
United States and Europe likely to increase, Azad says the time
has come for India to be recognized as a global pharmaceutical
manufacturing leader.
India’s Department of Commerce has advised its Pharmaceu-
ticals Export Promotion Council (Pharmexcil) to undertake a
Brand Pharma India campaign to improve the sector’s global
positioning. The campaign will raise awareness of the Indian
pharmaceutical-sector success story and acquaint international
audiences with India’s growing expertise in generic-drug manu-
facturing. A component of the campaign will focus on improv-
ing the global perception of quality standards in India; much
attention has been paid to counterfeit drugs in the region of
late and the country is working to put an end to such practice.
“We need to establish India firmly as the first choice partner
for the entire global pharma fraternity and with regards to the
entire spectrum of pharma services. If aggressive growth drivers
kick in, the domestic market is primed to reach $74 billion at a
CAGR of 20% within no time,’’ says P.V. Appaji, executive direc-
tor of Pharmexcil.
In 2010, India exported $10.3 billion worth of pharmaceuti-
cal products, registering 17.5% growth since 2009. By March
2012, exports are likely to record a growth of 19%, says Ap-
paji. India’s largest export destination is still the US, followed
by the United Kingdom, Germany, South Africa, and Russia.
Segment-wise, generic drugs account
for 58% of total exports, APIs account
for 40%, and traditional medicines ac-
count for the remaining 2%.
“We need to aggressively promote ex-
port growth of high value products that
have a strong domestic manufacturing
base. This will be the lynchpin of our over-
all export growth strategy,’’ says Union
Minister of Science and Technology and
Earth Sciences Vilasrao Deshmukh. He
added that, with help from the govern-
ment, India could easily take a large share
of the API market from Europe.
India is currently at par with Europe
in terms of the number of type II drug
master file (DMF) applications submit-
ted. In the second quarter of 2011, Europe
filed 3150 DMFs and India filed 3084 to
their respective authorities. “Moreover,
the quarter-on-quarter DMF filing rate
of India is slightly higher than Europe.
The rate is continuously increasing,’’
says Tarun Shah of MP Advisors, a spe-
cialized healthcare investment advisory
firm based in Vadodara, Gujarat.
Glen Saldanha, chairman of Glen-
mark Pharmaceuticals based in Mumbai,
agrees. “Today, many Indian firms have
US Pharmacopeia Proposes
Supply-Chain Guidelines

The US Pharmacopeia (USP) has released proposed guidelines on
ensuring the integrity of the pharmaceutical supply chain. The
guidelines cover five main areas: good importation practices,
counterfeit drugs and medical devices, best practices to combat
counterfeit drug and medical devices, diversion and theft, and natural
disasters. The guideline is open for public comment through May 31,
2012, and will appear in the Pharmacopeial Forum 38(2). A May 2012
USP workshop will address the comments received and the draft
chapter.
ABB Inc.
Analytical Measurement
Phone: +1 418-877-2944
1 800 858-3847 (North America)
Email: ftir@ca.abb.com
MB-Rx. Reaction Monitoring Made Easy
See our latest analyzer, the MB-Rx Reaction Monitor, at PITTCON 2012.
The MB-Rx is a plug-and-play solution designed for research laboratories
and pilot plants. It provides chemists with direct access to real-time
experiment data via a rugged insertion probe and an intuitive software interface.
The MB-Rx is maintenance-free and offers analytical performance, reliability
and simplicity. www.abb.com/analytical
Visit us at PITTCON in booth #2559
20 Pharmaceutical Technology February 2012 Phar mTech. com
IN THE FIELD IN THE FIELD
already established themselves as leading API manufacturers and
generic players in the US and other western markets. Indian firms
have made their presence felt in developed markets and if we
continue to do quality work, then gaining market share in these
markets should not be difficult. Government impetus is bound
to boost the process.’’
Incidentally, Glenmark has transitioned from supplying APIs
to semi-regulated markets to servicing the regulated markets.
The company claims it has the unique distinction of servicing
nearly all the leading generic-drug manufacturers in the US.
Already making gains
Generic-drug companies have historically sourced APIs from
European manufacturers, explains Y.K. Hamied, chairman
of Cipla. He says that several API producers based in China
and India are posing a threat to the future of European API
manufacturers, particularly those in Italy. He was referring
to a January 2012 generics and API intelligence report by
Thomson Reuters, which stated that, during the past four
years, the number of Italian producers capable of supplying
APIs to regulated markets has decreased. The report added
that generic-drugs companies’ willingness to source APIs
from India and China was particularly damaging to their
counterparts in Italy.
“The total market share in the world generic API market held
by Italy and Spain, which are traditionally the two leading pro-
ducers of generic APIs, has fallen and is forecast to further de-
crease. China and India could capitalize,’’ says Hamied, who is
quick to add that China and India are not taking over the branded
API market. “European API producers still score on patent non-
infringing process,’’ he said.
With pharmaceuticals valued at more than $30 billion set to
lose patent protection this year, Indian firms are waiting to grab
the opportunity, including by teaming up with competitors in
China and Japan.
Asian power
Although the Indian government has set a global export target of
$25 billion by 2013–2014, intense competition closer to home as
well as outside of Europe could derail the process. In a statement
to the Indian Parliament on Dec. 19, 2011, India’s Commerce
Minister Jyotiraditya Scindia said that Indian pharmaceutical
exporters were facing intense competition from China, particu-
larly in the bulk-drugs sector and in formulations.
Double-digit growth propelled Indian bulk-drug exports past
$1 billion in 2010, but China continues to hold the lead with bulk-
drug exports valued at $6 billion. To close the gap, the Indian
government has decided to increase sales to China and Japan.
“China is not the only threat. Japan is the second largest
pharmaceutical market in the world, predicted to be worth
$87 billion by 2014. The Japanese government is also encour-
aging generics and expects [that sector] to account for 30% of
its market share by 2012. We will have to explore new markets
other than the US and Europe to meet the $25 billion export
target,’’ says N.R. Munjal, president of the Indian Drug Manu-
facturers’ Association.
At the association’s golden jubilee celebration held in Mum-
bai on Jan. 7, 2012, Rajeev Kher, a secretary in the Ministry
of Commerce, said that Japan had opened its generic-drug
market to the Indian drug industry. “The Indian industry
needs to draw a plan based on regulatory mechanisms to tap
that market efficiently.’’ He added that India is set to enhance
its global image at the forthcoming CPhI–Japan conference
taking place in March in Tokyo.
Deepak Chander, business director at DSM Anti-Infec-
tives India, is of the opinion that competition need not be
labeled a threat. DSM has three plants in China that are
manufacturing intermediates and antibiotic APIs, and has
sales of $1.5 billion in China. The company has a plant in
Toansa, Punjab, as well.
“Big Pharma trusts Indian firms to make the intermedi-
ates and APIs for even their most sensitive new products. We
should think of this as an opportunity,’’ says Chander. Pursu-
ing this course would ensure an accelerated growth path for
India, thereby enabling it to break into the top tier of the global
pharmaceutical market.
A. Nair is a freelance writer based in Mumbai.
22 Pharmaceutical Technology FEBRUARY 2012 Phar mTech. com
New Product Announcements
may be sent to New Products Editor,
Pharmaceutical Technology,
485 Route One South, Building F,
First Floor, Iselin, NJ 08830,
fax 732.647.1235,
ptpress@advanstar.com.
IN THE SPOTLIGHT: TABLETING AND GRANULATION
Particle-size analyzer facilitates
dry-powder measurement
Malvern Instruments’s Mastersizer
3000 particle-size analyzer is designed
to extend dry measurements to a wide
range of sample types. It provides a
10-KHz data-acquisition rate, and all
parameters for dry-powder measure-
ment (i.e., sample feed rate, dispersion
pressure, and system cleaning) are
controlled through the software by its
SOP interface. Its real-time feedback
capability helps streamline method de-
velopment and routine measurement.
The analyzer’s Aero S dry-powder
disperser enables users to measure
materials from 0.01 to 3500 µm. It
disperses dry samples by accelerating
particles through a venturi mechanism,
using compressed air at a user-defined
pressure. The particles then pass
through the Mastersizer 3000’s laser
for measurement and are collected
using a vacuum source. The sample
feed rate through the Aero S is closely
controlled using a vibrating feeder,
which maintains a suitable sample con-
centration for laser measurement. It is
fitted with an interchangeable sample
tray that can be configured to ensure
the measurement of enough material
to quantify the entire size distribution
reproducibly.
Image analyzer features
particle characterization
The ShapeSizer image analyzer from
Whitehouse Scientific can characterize
particles in the size range of 1–5000 µm.
The analyzer integrates a charge-coupled
device camera with its software system,
which is designed to provide a cost-effec-
tive solution for a variety of industrial par-
ticulate applications where size and shape
are important parameters.
Some key features of the ShapeSizer
include automatic cluster recognition and
elimination, a particle-separation and
editing facility, and a sieve calibration
option. In addition, it contains a Miles-
Lantuejoul option to maximize its field of
view without eliminating particles.
Mastersizer 3000
Malvern Instruments
www.malvern.com
ShapeSizer image analyzer
Whitehouse Scientific
www.whitehousescientific.com
To ensure that a tableting process will be predictable, active ingredients
and excipients in powder form must undergo granulation. This process
results in granules, which comprise several particles each, and helps per-
sonnel produce tablets within the desired specifications. This month’s
products aid the granulation process in various ways. A particle-size ana-
lyzer from Malvern Instruments helps streamline particle measurement.
Whitehouse Scientific’s image analyzer provides powder characterization.
Bosch’s extrusion line helps to form tablets accurately.
Extrusion and calendering line
forms tablets accurately
Bosch Packaging Technology’s integrated
melt-extrusion and calendering line fea-
tures a continuous production process for
pharmaceutical substances, and meets
all GMP standards. Its modular structure
enables manufacturers to customize
extrusion and forming equipment. Its ca-
pabilities feature direct shaping of pills or
oblong shapes, in addition to pelletizing
with its granulation-head technology. The products can be used for customized
scale-ups and are designed for contained or noncontained environments.
The line includes the Pharma Extruder WCF 0040PH, which continually pro-
cesses the substrate with active ingredients through the melting, mixing, knead-
ing, aerating, tempering, and forming stages. Also included is the Pharma Calen-
der BPK 0050, which is designed to ensure accurate forming of tablets by using
dual rollers with forming cavities.
Melt-extrusion and calendering
line Bosch Packaging Technology
www.bosch.com
Editors’ Picks of Pharmaceutical
Science & Technology Innovations
Zeta Plus™ Activated Carbon
Cartridges and Capsules

Zeta Plus Activated Carbon media incorporates our latest activated carbon
technology to meet the needs of pharmaceutical manufacturers by
decolorizing and reducing contaminants from the process stream. It can be
used in any application where bulk activated carbon is used.
Zeta Plus Activated Carbon cartridges and capsules are available in a range
of sizes from laboratory-scale to process development through to full scale
production.
3M Purification Inc.
3M Purification Inc.,
400 Research Parkway,
Meriden, CT 06450 U.S.A.
3M is a trademark of 3M Company.
Zeta Plus is a trademark of
3M Company used under license
© 3M 2010. All rights reserved.
Applications
Pharmaceuticals

Decolorization in production
of active pharmaceutical
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Parenterals


Blood fractionation


Catalyst reduction from API
To learn more about how 3M Purification Inc. filtration products
can improve process efficiency and save costs, contact us at:
www.3Mpurification.com or call 1-203-630-4574.
24 Pharmaceutical Technology February 2012 Phar mTech. com
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T
he Department of Justice cele-
brated the end of 2011 by announc-
ing billions of dollars in recoveries
from False Claims Act cases, most of it
from pharmaceutical companies. Of the
more than $3 billion in settlements col-
lected during the fiscal year that ended
Sept. 30, 2011, nearly $2.2 billion came
from pharma. At the top of the list was
the $750 million paid by GlaxoSmith-
Kline (GSK) to settle charges involving
adulterated drugs and failure to meet
strength, purity, or quality requirements
at its Puerto Rico facility, evidently the
first FCA settlement involving GMP
violations reported by a whistleblower.
These civil fraud cases represent only
the tip of the iceberg in pharmaceutical
industry compliance battles. The Justice
Department also collected $1.3 billion in
criminal fines and forfeitures for viola-
tions of FDA regulations. Some of that
money may come from GSK, which
also is negotiating with the feds to settle
several investigations into marketing
and pricing practices. Amgen agreed
to pay $780 million in October 2011,
related to promotion of its anemia drug
Aranesp (darbepoetin). Merck recently
announced a $1-billion settlement to re-
solve allegations about Vioxx (rofecoxib)
marketing. And in January 2012, John-
son & Johnson said it would pay more
than $1 billion to resolve state and federal
lawsuits involving off-label marketing of
its antipsychotic Risperdal (risperdone).
While most of the high-profile cases
involve illegal marketing and pricing al-
legations, the government is also step-
ping up enforcement actions for failure
to meet quality standards. In addition
to the GSK Puerto Rican case, Indian
drugmaker Ranbaxy Laboratories
signed a consent decree with FDA in
December, and agreed to pay up to $500
million to settle a three-year investiga-
tion into falsifying records and GMP
violations, which shut down imports
into the US.
“We demand accountability when
companies’ failures in drug manufac-
turing lead to products that materially
differ from the strength, purity, or qual-
ity of what was required,” stated De-
partment of Justice Assistant Attorney
General Tony West at the Pharmaceu-
tical Regulatory and Compliance Con-
gress in November 2011. He noted that
the Obama administration’s broader
campaign against healthcare fraud,
which was strengthened by the Afford-
able Care Act (ACA), has led to more
than $8 billion in settlements, penalties,
and fines since 2009.
Promoting compliance
West also emphasized the government’s
intent to prosecute individual industry
executives, under the controversial Park
legal doctrine, a policy that can hold
corporate officers liable for company vi-
olations of FDA and other federal laws.
Another enforcement strategy is to “ex-
clude” company executives from doing
business with government health pro-
grams such as Medicare and Medicaid,
which basically prevents the targeted of-
ficer from holding any responsible drug
industry position. Taking action against
individual executives aims “to promote
a culture of compliance by emphasizing
deterrence,” said West. The goverment
wants to dispel the notion among man-
ufacturers, he explained, that dealing
with enforcement is “simply the cost of
doing business.” Instead, the govern-
ment will levy judgments and penalties
that “eliminate any benefit that may be
WASHINGTON REPORT
Jill Wechsler
is Pharmaceutical
Technology’s Washington
editor, 7715 Rocton Ave.,
Chevy Chase, MD 20815,
tel. 301.656.4634,
jwechsler@advanstar.
com.
More collaboration and expanded oversight aim
to compel manufacturers to follow GMPs.
Jill Wechsler
FDA and Justice Department
Address Drug Quality Concerns
FDA may defer
or waive routine
GMP inspections
of previously
inspected European
facilities.
In Washington this month
• FDA is ramping up foreign
inspections and boosting
Warning Letters.
• EMA–FDA joint inspections
reduce duplicative oversight.
• FDA works with PIC/S to
standardize global inspections
and inspection teams.
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Very high performance
Pharmaceutical
Metal Detection Systems
Available Versions
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26 Pharmaceutical Technology February 2012 Phar mTech. com
Washington Report
obtained from engaging in unlawful
conduct in the first place.”
West and others similarly urge
medical-products companies to estab-
lish effective safeguards against eco-
nomic fraud, negligent production, and
theft. He acknowledged that the govern-
ment will never have enough resources
to tackle every fraud and abuse case or
to inspect every drug-production fa-
cility, especially the growing number
of foreign operators that ship medical
products to the US.
FDA officials agree. At the Decem-
ber enforcement conference sponsored
by the Food and Drug Law Institute
(FDLI), Howard Sklamberg, FDA
deputy associate commissioner for
regulatory affairs, pointed out that the
agency can do only so much to moni-
tor companies and enforce FDA rules,
and that regulated firms must invest
in quality systems to prevent viola-
tions internally and by suppliers and
contractors. The role of the Office of
Regulatory Affairs (ORA), Sklamberg
explained, is to “help industry be re-
sponsible” through the development of
standards and best practices.
This approach also calls for direct
compliance oversight by corporate
leaders, as illustrated by a November
2011 Warning Letter sent to Novartis
CEO Joe Jimenez. The letter requested
Jimenenez’ personal involvement in ad-
dressing a long list of violations at fa-
cilities in North Carolina and Colorado,
many uncorrected from previous cita-
tions. Jimenez promised company em-
ployees that “neither costs, nor service
level will interfere” in the company’s re-
mediation plan; Novartis subsequently
suspended production at another plant
in Nebraska and recalled several prod-
ucts, a sign that the firm’s manufactur-
ing issues may be more widespread.
An increase in FDA Warning Letters
and inspections, particularly to foreign
facilities and to contract manufacturers,
responds, in part, to continued criticism
of FDA oversight of foreign manufac-
turers. The Government Accountabil-
ity Office (GAO) complained in a Sep-
tember 2010 report that the agency still
lagged in oversight of foreign facilities
and needs better data on overseas facili-
ties producing drugs for the US market.
ORA is addressing these issues by
ramping up inspections and establishing
a searchable public database of inspec-
tion reports, including conditions cited
in FDA 483 reports and summary data
by fiscal year. The field force is trying to
be more efficient, replacing infamous
inspector green notebooks with hand-
held computer devices to record findings
during site visits. Foreign producers of
APIs, such as China’s Sichuan Pharma-
ceuticals, have received Warning Let-
ters, and India’s Synbiotics was blasted
for denying access to an FDA investiga-
tor. Some manufacturers have been hit
with even more stringent enforcement
actions, such as bans on certain imports
from Dr. Reddy’s Mexican facility and
from Yag-Mag Labs of India.
Inspections of API producers and
generic-drug manufacturerss are slated
to increase further under the proposed
generic-drug user-fee program. The
five-year goal is to conduct biennial
GMP inspections of foreign manu-
facturers and, in the process, provide
parity in oversight for domestic and
foreign firms. If Congress approves the
Generic Drug User Fee Act (GDUFA)
this year, as expected, most of the es-
timated $300 million annual GDUFA
revenues will come from manufactur-
ing sites—14% from API manufactur-
ers, and 56% from facilities producing
finished dosage forms—and the rest
from application fees. Preapproval in-
spections will continue as required by
new applications, but may not be nec-
essary for recently inspected sites with
good compliance histories.
Seeking partners
The generic-drug user-fee program also
calls for FDA to use inspection informa-
tion and reports from foreign regulatory
authorities where appropriate, an ap-
proach championed by Sklamberg and
others as a way to extend FDA’s over-
sight capabilities. Several collaborative
programs have been tested, and more
are being implemented.
In December 2011, FDA and EMA
announced a new GMP inspection
initiative that calls for sharing infor-
mation on drug-manufacturing in-
spections in their respective regions
Under this program, which began last
month, FDA will defer or waive routine
GMP inspections of European facilities
previously inspected by central or na-
tionally authorized inspectorates, and
EU member states will conduct fewer
inspections in the US. While preap-
proval inspections will continue as
After several months of fine-tuning its new
organizational structure, the FDA Center for Drug
Evaluation and Research Office of Compliance
(OC) is now demonstrating a clearer sense of what
manufacturers can expect. International and domestic
collaborations such as the EMA–FDA joint GMP
inspection program, along with FDA’s participation in
PIC/S, are managed by the OC Office of Manufacturing
and Product Quality (OMPQ). This group also ensures
manufacturer compliance with GMPs and quality
control standards and monitors implementation
of consent decrees related to manufacturing and
adulteration issues, explained OC Director Ilisa
Bernstein at the latest Food, Drug, and Law Institute
enforcement conference in December 2011.
The new Office of Drug Security, Integrity and
Recalls (ODSIR) has the pressing task of addressing
supply-chain threats, including cargo theft, drug
counterfeiting, and diversion. The office is also heading
up the development of standards for a drug track-and-
trace system.
FDA’s unapproved-drugs initiative falls under the
Office of Unapproved Drugs and Labeling Compliance,
which also monitors health fraud cases and
compounded drugs. OUDLC consults with Medicare
and Medicaid to ensure that federal healthcare
programs do not cover and pay for unapproved drugs.
Drug shortage prevention, mitigation, and
remediation is another responsibility for OMPQ, but
its fellow compliance offices also play a role. OUDLC
checks that unapproved drug initiatives don’t lead to
shortages, and OSDIR similarly tracks the impact of
recalls and other supply chain issues on short supply
situations. OMPQ coordinates with the CDER drug
shortages staff in the new drug review office and
works with manufacturers to resolve manufacturing
quality problems that could lead to or aggravate
shortages.
CDER clarifies compliance operations

28 Pharmaceutical Technology February 2012 Phar mTech. com
Washington Report
needed, repeat GMP inspections may
be avoided for manufacturers of less
risky products, sites with few quality
defects in the past, recently inspected
facilities, and when there is an “urgent
public health need,” such as a drug
shortage, that requires fast regulatory
action. Both parties will keep track of
the number of inspections deferred or
waived and review the program after
three years. Not only does the initiative
aim to save resources for the regulators,
but fewer inspections should reduce the
compliance burden on manufacturers.
This new collaboration follows a suc-
cessful joint inspection program for
APIs, which involves FDA, EMA, and
Australia’s Therapeutic Goods Admin-
istration, along with specific EU mem-
ber states. Launched as a pilot program
in 2008, the initiative prevented many
duplicate inspections of facilities and
established a master list of API supply
facilities, as outlined in a report issued
in May 2011. Inspectors from the three
regions shared information on more
than 100 facility inspections, which
helped identify weaknesses in manu-
facturer quality management systems
and requested corrective actions. In
some cases where inspection reports
indicated satisfactory operations, a
planned inspection involving the same
API could be postponed or canceled.
Participants also entered information
from past inspections of more than 640
sites of mutual interest into a central
database, thereby providing valuable
information on site location, APIs pro-
duced, date and outcome of most recent
inspection, and plans for future inspec-
tions by participating authorities.
The API pilot also involved a small
number of joint inspections, which
helped build confidence in each other’s
operations, but required considerable
effort and time to organize and to eval-
uate. Now, the collaboration is expand-
ing to include additional EU member
states, and possibly more regions in the
future. To further improve the pro-
gram, participants hope to streamline
management of the master list, devise
a common inspection report format
for joint inspections, and develop a
common risk-based policy regarding
re-inspection of sites located in third
countries.
FDA and EMA are looking to extend
the benefits of these joint regulatory ef-
forts to streamline the review of manu-
facturing data in drug applications. In
March 2011, the two agencies launched
a col laborative review process for
quality-by-design (QbD) components
of new drug applications (NDAs),
marketing authorization applications
(MAAs), and supplements (referred
to as variations in Europe). The two
agencies hope to attract sponsors fil-
ing at the same time in both regions by
striving for a consistent and efficient
assessment of the quality/CMC sec-
tions of applications. Drug manufac-
turers also stand to benefit from joint
early consultations that can yield har-
monized advice; each agency, however,
will issue its own review or report on
the submission to meet domestic legal
requirements.
This initiative builds on other FDA–
EMA coordination efforts such as the
joint inspection pilot for preapproval
inspections for new drugs, which failed
to gain strong support from the indus-
try. In 2009, the regulators asked drug
manufacturers planning simultaneous
submissions in both regions to request
joint preapproval inspections as a way
to facilitate the application-review pro-
cess. But only two joint inspections
were performed, according to a report
on EMA–FDA interactions issued by
the agencies in June 2011. Observers
note that the program was limited
to drugs (not biologics), and that few
companies planned simultaneous sub-
missions. The new QbD review collab-
oration, which also excludes biologics,
can provide joint preapproval inspec-
tions as part of the review process and
appears to be attracting more interest
from manufacturers.
Part of PIC/S
Another forum for promoting collabo-
ration and harmonization of drug in-
spection practices and GMP standards
is the Pharmaceutical Inspection Co-
operation Scheme (PIC/S), which FDA
formally joined in January 2011, after
a five-year vetting process. Founded in
1970 by 10 European countries, PIC/S
now has 40 members around the world,
with Slovenia being the latest addition.
Japan and South Korea have applied
for admission; the Philippines, Indo-
nesia, Taiwan, Iran, and New Zealand
are moving forward in the application
process; and China and India are plan-
ning to apply.
Previously a sideline observer, FDA
now can play an active role in PIC/S
programs to train GMP inspectors,
establish risk-based quality standards,
and share “rapid alerts” on drug safety
problems, explained Brenda Holman,
head of ORA strategic initiatives, at
the PDA/FDA conference last Sep-
tember. Holman described how FDA
can help develop PIC/S guides for
meeting GMPs for drugs, APIs, vac-
cines, blood and blood products, and
biotechnology-derived drugs as part of
international collaborations to provide
more effective market surveillance on
a global scale.
As with its members, PIC/S faces
challenges in dealing with increased
outsourcing by manufacturers and
more complex biopharmaceutical sup-
ply chains, Holman noted. Regulators
are dealing with this by teaming up for
joint inspections to conserve resources
as well as to build confidence in the
operations of other regulatory bod-
ies. PIC/S is encouraging inspection
plans based on risk evaluation and is
looking to expand into other relevant
fields, such as oversight of good clinical
practices and good distribution prac-
tices, the latter item reflecting growing
supply-chain concerns.
Although PIC/S policies are not le-
gally binding, information from fellow
regulators on a previous site inspec-
tion may lead FDA to forego its own
site visit, and other PIC/S members can
avoid duplication by relying on FDA
inspection reports. FDA also can gain
information on how other inspector-
ates rank sites for risk and compliance
status, future inspection schedules, and
common practices involving the scope,
format, and duration of site visits. PT
30 Pharmaceutical Technology February 2012 Phar mTech. com
Bio Forum
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W
ith ever increasing titers,
column chromatography has
become a bottleneck in the
downstream processing of monoclonal
antibodies (mAbs) and a major barrier
in the development of a truly disposable
single-use mAb manufacturing facility.
Recent developments in high- capacity
membrane chromatography have shown
the potential to provide disposable chro-
matographic solutions. There are several
reasons to consider single-use purifica-
tion. Emerging trends in the biophar-
maceutical industry are for smaller,
flexible, and multiproduct facilities
that lead to lower manufacturing costs.
These trends have emerged because
of increased bioreactor titers, smaller
market size for new biopharmaceuti-
cals, and the high cost of a dedicated
facility. Single-use purification allows
an organization to capitalize on these
emerging trends.
Protein A as a capture step
Protein A has traditionally been the most
widely used capture step in the purifica-
tion of mAbs. It yields a high purity ma-
terial (> 99.5%) that only needs polish-
ing steps to remove aggregates, residual
host-cell protein (HCP), DNA, virus, and
leached protein A. Its disadvantages are
that it is not single-use ($ 9,000–12,000
per liter), needs an enzyme-linked im-
munosorbent assay (i.e., protein A) re-
lease assay, and requires a fireproof fa-
cility. In an effort to overcome protein A’s
disadvantages, several companies have
introduced cation-exchange chromatog-
raphy (i.e., chromatography beads) as a
substitute capture step with good results.
Cation-exchange capture
Researchers at the biopharmaceutical
company Percivia have demonstrated
efficient capture (> 90 mg mAb/mL of
resin), yield (> 95%) and purity (95% re-
duction in HCP) with the use of a cation-
exchange resin, GigaCap S 650-M (Tosoh
Bioscience) (1). Abbott Laboratories has
used a cation-exchange resin for a capture
step for its drug Humira (adalimumab),
and the biopharmaceutical company
Medarex also has used a cation exchange
resin for capture of a mAb (1–2). In an
optimization study, Genentech (now part
of Roche) used cation-exchange capture
(SP-Sepharose FF, Pharmacia) followed
by hydrophobic interaction chromatog-
raphy (HIC) and strong anion-exchange
chromatography to reduce HCP to tradi-
tional levels achieved with protein A (3).
Single-use high-capacity
membrane chromatography
Two recent studies have used single-use
high-capacity cation (weak C) exchange
membranes as a capture step for mAbs.
The advantages of these membranes are
high dynamic binding capacities, short
processing times, low cost per mem-
brane volume, and single use. Lawton
has optimized the capture step for a
high-capacity cation exchange mem-
brane (Advective Flow Chromatography
“C,” Natrix Separations) and obtained
greater than 75 mg mAb/mL membrane
(10% dynamic capacity) with > 95% pu-
rity and removal of aggregates (4). Kuc-
zewski et al. have described a complete
single-use purification process using the
same high capacity cation exchange
membrane as Lawton (Advective Flow
Chromatography “C,” Natrix Separa-
tions) (4, 5). In its process, Percivia ob-
tained bindings of 55 mg/mL mem-
brane, yields > 95%, HCP reductions of
> 96%, and some removal of aggregates.
Further membrane polishing steps, con-
sisting of anion-exchange flow-through
(Chromasorb, Millipore) and HIC flow-
through (Sartobind Phenyl, Sartorious
Stedim Biotech) reduced HCP to less
than 50 ppm and aggregates to less than
0.5%, which was in an acceptable range.
Conclusion
Recent results using high-capacity
membrane chromatography sets the
stage for single-use purification of
mAbs. Combined with single-use bio-
reactors, f lexible multiproduct facili-
ties can be built for the low-cost manu-
facture of the next generation of mAbs.
references
1. B Lain, M. Cacciuttolo, and G. Zarbis-
Papastoitsis, Bioprocess Int. 7 (5), 26–34
(2009).
2. G. Ferreira et al., BioPharm. Int. 20 (5)
32–43 (2007).
3. D. Follman and R. Fahrner, J. Chro-
matogr. A, 1024 (1–2), 79–85 (2004).
4. C. Lawton, presentation at the BioProcess
International Conference (Long Beach,
CA, Nov. 2011).
5. M. Kuczewski et al., Biotechnol. J. 6 (1),
56–65 (2011). PT
Carl W. Lawton, PhD, is director of the
massachusetts Biomanufacturing Center at the
University of massachusetts, Lowell,
Carl_Lawton@uml.edu.
Recent results set
the stage for single-
use purification
of monoclonal
antibodies.
Debottlenecking downstream mAb purification.
Carl Lawton
Single-use High Capacity
membrane Chromatography
2
1
3
7
6
_
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32 Pharmaceutical Technology February 2012 Phar mTech. com
StatiStical SolutionS
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PharmTech.com/stats PharmTech.com/stats
t
extbooks and journal articles treat
common cause variation as if it
is an inevitable fact of nature and
beyond our control: “In any production
process, regardless of how well-designed
or carefully maintained it is, a certain
amount of inherent or natural variability
will always exist. This natural variability
or ‘background noise’ is the cumula-
tive effect of many small, essentially
unavoidable causes” [Emphasis added]
(1). This attitude cuts off thoughts of
trying to reduce variation. But, with
some reflection, there are several ideas
and techniques that can begin to help
reduce common cause variation.
Work to hit the target
Aiming for and hitting the target,
whether it is x, y or z, seems a simple
idea, but it could be argued that it is ev-
erybody’s responsibility to know what
the target is and to do everything pos-
sible to hit that target every time. One
person achieving the target infrequently
doesn’t help. But 400 people hitting
targets a dozen times a day can have a
dramatic effect on reducing variability.
The target could be something as simple
as setting the temperature on a dryer or
as complex as a management objective.
Keep in mind that a specification range
is not a playground for manufacturing.
This mindset also can influence how
specifications criteria are written. It is com-
mon to write the criteria as “(Low, High).”
I suggest that criteria are better written as,
“Target (Low, High).” The first thing the
operator sees is the target value; people
generally try to achieve the first thing they
see. Second, the low and high criteria lim-
its are given, which eliminates the need to
mentally calculate those limits (e.g., if Tar-
get ±Δ, was used instead). The limits need
not be symmetrical with the target value.
Flexible consistency
The terms sound contradictory but do con-
tain logic. Many activities are at the liberty
of the operator or analyst and, as such, are
subject to considerable leeway in how they
are performed. In these situations, particu-
larly in the analytical laboratory, one strives
to get everybody on the team to do exactly
the same thing, the same way, every time.
If then, at some point in the future someone
proposes a new or better way to perform
the task, the whole team changes to follow
the new process. This group consistency
can have a substantial impact on variation
within a department. Notably, creativity of
the individual is not stifled, but rather chan-
neled to find better ways to perform a task.
operational definitions
“An operational definition describes what
something is and how it is measured” (2).
For example, “sample the batch” could
mean: “Using the 72 in. thief, open the
port on the right side labeled P8, and take
a sample from the top two inches, a sam-
ple from the middle, and a sample two
inches from the bottom. Composite the
three samples into a clean glass jar with
a lid, and label with the date, time, name,
product, lot and vat number.” Operational
definitions reduce variation by promoting
consistency. Standard operating proce-
dures are a form of operational definitions.
Mistake proofing or poka-yoke
Made famous by the Japanese auto mak-
ers, poka-yoke is simple but powerful in
reducing variation, deviations, and dis-
crepancies. The goal is to make activities
as mistake-proof as possible by physical
means or by procedures that are difficult
to do incorrectly. The classical physical
example is to put a mechanical stop on a
drill press to prevent the drillbit from mak-
ing a hole that is too deep. In a paperwork
process, colored pages are used to clearly
identify certain documents.
control what can be controlled
Although controlling what can be
controlled may appear to be an obvious
idea, many factors are commonly ignored
during normal operations. Perceived to be
noncritical process parameters, they are
left to float within some specified range.
However, variables should be controlled to
the fullest extent with the highest accuracy
possible without incurring great expense
or requiring great effort. Again, controlling
only one factor will have a trivial impact,
but a culture of controlling hundreds will
reduce common cause variation. The tools
discussed in this article require support
from management, but it is that support
that makes implementation so powerful.
References
1. D.C. Montgomery and G. C. Runger, Ap-
plied Statistics and Probability for Engineers
(Wiley, New York, NY, 1994), p. 834.
2. P. R. Scholtes, The Team Handbook (Joiner
Associates, Madison WI, 1988), p. 2–28. PT
Where is the variability coming from
and what have we done to minimize it?
Lynn Torbeck
Reducing common
cause Variation
Lynn D. Torbeck
is a statistician at PharmStat
Consulting,
2000 Dempster,
Evanston, IL 60202,
tel. 847.424.1314,
LDTorbeck@PharmStat.com,
www.PharmStat.com.
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34 Pharmaceutical Technology February 2012 Phar mTech. com
I
CH Q11, the pending guideline from
the International Conference on Har-
monization titled Development and
Manufacture of Drug Substances, may be
one of the most anticipated guidelines in
the global pharmaceutical industry in
recent years (1). Since 2004, the indus-
try has been working to reshape its ap-
proach to drug manufacturing based on
FDA’s Pharmaceutical CGMPs for the 21st
Century initiative, which were cemented
between 2005 and 2008 by the so-called
ICH Quality trio guidelines (2). These
globally harmonized guidelines, which
include ICH Q8 Pharmaceutical Develop-
ment, Q9 Quality Risk Management, and
Q10 Pharmaceutical Quality System, de-
tailed quality-by-design (QbD) concepts
for pharmaceutical manufacturing and
redefined the industry lexicon with terms
such as quality target product profile, crit-
ical quality attributes and critical process
parameters (CQAs and CPPs), knowledge
management, product life-cycle manage-
ment, and control strategy (3–5). The Q11
guideline, which was published as a draft
in May 2011 and is expected to be adopted
by the ICH steering committee this year,
both complements and enhances these
concepts by offering industry guidance
and clarity “regarding the description and
justification of development and manu-
facturing processes for drug substances
and the type and extent of information to
be submitted in regulatory dossiers” (6).
Q11 is one of the longest ICH qual-
ity guidelines at 26 pages and spe-
cifically addresses the drug-substance
manufacturing process for chemi-
cal entities and biotechnological/
biological entities.
Although the ICH Quality trio guide-
lines apply to drug substance as well as
drug product, industry and regulators
felt there was a need to clarify QbD or
“enhanced” concepts for drug-substance
manufacture. “There are fundamental sci-
entific differences in the process for drug-
substance manufacture and the process for
drug-product manufacture, including im-
purity control and removal and chemical
transformations,” according to the Phar-
maceutical Research and Manufacturers
Association (PhRMA) representatives on
the ICH Q11 expert working group. These
representatives include: Betsy Fritschel,
Johnson & Johnson and the PhRMA Topic
Lead for ICH Q11; Timothy Watson, PhD,
Pfizer; and Steven R. Mendivil, Amgen.
The ideas behind Q11
The quality of a drug product is linked to
the quality of its drug substance. ICH Q11
therefore seeks to take into consideration
and provide examples as appropriate for
describing the principles and concepts
which are included in ICH Q8, Q9, and
Q10. ICH issued a concept paper for Q11
in April 2008 to identify these elements
and to detail the goals of the proposed
guideline. While defining differences be-
tween a “traditional” and an “enhanced”
approach to drug-substance manufac-
ture, Q11 states clearly that “Traditional
and enhanced approaches are not mutu-
ally exclusive. A company can use either
a traditional approach or an enhanced
approach to drug substance development
or a combination of both” (1). In the tradi-
tional approach, “set points and operating
ranges for process parameters are defined
and the drug substance control strategy is
typically based on demonstration of pro-
cess reproducibility and testing to meet
established acceptance criteria” (1).
Q11 defines an enhanced approach
for drug-substance manufacture as using
risk management and extensive scientific
knowledge to select process parameters
and unit operations that impact CQAs “for
evaluation in further studies to establish
design space and control strategies applica-
ble over the lifecycle of the drug substance”
(1). The guideline provides illustrative ex-
amples and approaches for demonstrating
product and process understanding that is
gained during the process development of
drug substances. It also outlines the infor-
mation recommended for describing the
manufacturing process and control strat-
egy as well as considerations for selecting
starting materials for synthetic and semi-
synthetic entities and source materials for
An Enhanced Approach to
Drug-Substance Development
and Manufacture
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Cover Story: QbD for Drug Substance
Angie Drakulich
The pending ICH Q11 guideline incorporates risk
management and a science-based approach for the
development and manufacture of drug substances.
Pharmaceutical Technology February 2012 35
biotechnological/biological entities and the
related justification. In addition, Q11 ad-
dresses the elements and development of
a control strategy; process validation and
evaluation; and the regulatory evaluation
process of drug-substance manufacturing,
including the harmonization of common
technical document (CTD) submissions
(see sidebar on CTD submissions).
According to FDA members of the ICH
Q11 working group, “identifying what is
common and what is different between
the development and manufacturing of
chemical entities and biotechnological/
biological drug substances was one of
the key goals” in developing Q11 as well.
These ICH Q11 working group mem-
bers include: John Smith, PhD, CDER
(ONDQA) and FDA Topic Lead; Pat-
rick Swann, PhD, CDER (OBP), and
FDA Deputy Topic Lead; Steve Wolf-
gang, PhD, CDER (OC), and Working
Group Expert; Chris Joneckis, PhD,
CBER, and Working Group Expert.
The details of Q11
The Q11 expert working group, which
is made up of individuals from each of
the six ICH parties (that is, the regula-
tory authorities and trade associations
of the US, European Union, and Japan,
plus numerous interested parties and
observers), received more than 1300
comments during Step 3 (which is the
regulatory consultation and discussion
phase) of the ICH process and spent
last fall working through them. Some
of the comments were duplicates or
very similar, according to the PhRMA
Q11 expert working group members,
and the highest percentage of the com-
ments received requested clarification
and revision of the guideline’s process
development section.
Q11 states that manufacturing pro-
cess development should include, at a
minimum, the following elements: iden-
tification of potential CQAs associated
with the drug substance so that those
characteristics having an impact on
product quality can be studied and con-
trolled; defining an appropriate manu-
facturing process; and defining a control
strategy to ensure process performance
and drug substance quality (1).
An enhanced approach to manufactur-
ing process development would addition-
ally include:
• A systematic approach to evaluat-
ing, understanding, and refining
of the manufacturing process. This
process includes identifying through
prior knowledge, experimentation
and risk assessment, the material
attributes and process parameters
that can have an effect on drug-
substance CQAs. It further includes
determining the functional relation-
ships that link material attributes
and process parameters to drug
substance CQAs.
• Using the enhanced approach in
combination with quality risk man-
agement to establish an appropriate
control strategy (e.g., proposed de-
sign space(s) and/or real-time release
testing) (1).
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36 Pharmaceutical Technology February 2012 Phar mTech. com
Cover Story: QbD for Drug Substance
Q11 asserts that the increased knowledge
and understanding obtained from taking
an enhanced approach could facilitate
continual improvement and innovation
throughout the product lifecycle.
Defining CQAs. CQA is a physical, chemi-
cal, biological, or microbiological property
or characteristic that should be within an
appropriate limit, range, or distribution to
ensure the desired product quality. Drug-
substance CQAs typically include those
properties or characteristics that affect
identity, purity, biological activity, and
stability, states Q11 (1).
Impurities are an important class of
potential drug-substance CQAs because
of their potential impact on drug product
safety. For chemical entities, impurities can
include organic impurities (including po-
tential genotoxic impurities), inorganic im-
purities (e.g., metallic residues and residual
solvents). For biotechnological/biological
products, impurities may be process-
related or product-related. Process-related
impurities include: cell substrate-derived
impurities, cell culture-derived impurities,
and downstream-derived impurities (1).
The identification of CQAs for bio-
technological/biological products can
be particularly challenging because they
typically possess a large number of qual-
ity attributes, making it difficult to fully
evaluate the impact on for safety and effi-
cacy of each one, states Q11. The guideline
therefore recommends that in such cases
risk assessments be performed to rank
quality attributes using prior knowledge
and updating that knowledge with de-
velopment data (e.g., knowledge regard-
ing mechanism of action and biological
characterization).
CQAs for biologics products, there-
fore, should also include consideration
of contaminants, “including all adven-
titiously introduced materials not in-
tended to be part of the manufacturing
process (e.g., adventitious viral, bacterial,
or mycoplasma contamination),” recom-
mends Q11 (1).
Selecting and justifying starting and source
materials. The draft Q11 guideline de-
fines starting materials (synthetic, semi-
synthetic) and source materials (biotech-
nological/biological), and provides six
science-based principles to consider when
selecting the starting or source material.
For synthetic drug substances, these prin-
ciples include recognition that changes in
material attributes or operating condi-
tions that occur early in the manufactur-
ing process have lower potential to impact
the drug-substance quality; regulatory
authorities should be provided with an
adequate description to understand how
impurities are formed, how the process
affects formation, fate, and purge of im-
purities, and the suitability of the control
strategy; a starting material should be a
substance of defined chemical properties
and structure and a starting material is
incorporated as a “significant structural
fragment” (1, 7).
When justifying the selection of syn-
thetic or semi-synthetic drug substances,
CTD applicants need to justify how each
proposed starting material is appropriate
in light of the above principles, suggests
Q11. Justifications may include the abil-
ity of analytical procedures to detect im-
purities in the starting material; the fate
and purge of those impurities and their
derivatives in subsequent processing steps;
or how the proposed specification for
A key goal of the International Conference on
Harmonization Q11 guideline, Development and
Manufacture of Drug Substances, is to harmonize
common technical document (CTD) submissions
globally. Section 8 of Q11 focuses on how to
submit results based on an enhanced approach to
manufacturing process development in the CTD format,
specifically with regard to describing and justifying
drug-substance quality and control.
According to FDA, the CTD format was developed
prior to the current emphasis on the importance of
obtaining enhanced product and process knowledge.
Consequently, it lacks any discussion of where to place
information that relates to enhanced approaches to the
development and manufacture of drug substances and
provides no recommendations concerning the type of
information that might be appropriate. “ICH Q11 aims
to provide additional clarity concerning the information
that should be provided on drug development, as well
as recommendations that applicants can consider about
organizing that information. The guidance also makes
recommendations on how to include QbD-related
information within the existing CTD framework,” says
FDA. Below are a few key suggestions about where to
file QbD-based results in the CTD, taken from the draft
Q11 guideline (1):
Quality risk-management information
Applicant filers should document the assessments used
to guide and justify development decisions (e.g., risk
analyses and functional relationships linking material
attributes and process parameters to drug-substance
CQAs) in CTD section 3.2.S.2.6.
Critical quality attributes
CTD applicants should list the drug substance CQAs and
the rationale for designating these properties as CQAs
in CTD section 3.2.S.2.6. However, detailed information
about structural characterization studies that supports
the designation of these properties or characteristics
as CQAs should be provided in other appropriate CTD
format sections (e.g., 3.2.S.3.1–elucidation of structure
and other characteristics, 3.2.S.7–stability). Discussion
of drug substance CQAs as they relate to drug product
CQAs may be appropriate to include in CTD section
3.2.P.2.1, Components of the drug product.
Design space
Filers should describe design space(s) with the
description of the manufacturing process and process
controls in CTD section 3.2.S.2.2. If appropriate,
additional information can be provided in the section
addressing controls of critical steps and intermediates,
that is, CTD section 3.2.S.2.4. Summarize and describe
process development studies that provide the basis for
the design space(s) in CTD section 3.2.S.2.6. Discuss the
relationship of the design space(s) to the overall control
strategy with the justification of the drug substance
specification in CTD section 3.2.S.4.5.
Control strategy
CTD applicants should summarize the overall drug-
substance control strategy in CTD section 3.2.S.4.5.
However, detailed information about input material
controls, process controls, and control of drug
substance should be provided in the appropriate
CTD format sections (e.g., 3.2.S.2.2--description of
manufacturing process and process controls, 3.2.S.2.3-
-control of materials, 3.2.S.2.4--controls of critical
steps and intermediates, 3.2.S.4.1—drug-substance
specification). The evolution of the control strategy
can be described in the manufacturing process
development section, CTD section 3.2.S.2.6.
Of note, the 1987 FDA Guidance for Submitting
Supporting Documentation in Drug Applications for the
Manufacture of Drug Substance is likely to be withdrawn
once ICH Q11 is published as final guidance in the US,
according to the agency.
How to fill out the common technical document when using an enhanced approach
Pharmaceutical Technology February 2012 37
each starting material will contribute to
the control strategy (1). Q11 recommends
using a flow diagram to outline the syn-
thetic route(s) for the manufacture of the
drug substance and to clearly indicate the
proposed starting materials.
ICH Q11 further notes that an appli-
cant generally need not justify the use of a
commercially available chemical as a star-
ing material and goes on to define a com-
mercially available chemical as one that
is sold as a commodity in a pre-existing,
nonpharmaceutical market in addition
to its proposed use as a starting material.
Chemicals produced by custom synthe-
ses are not considered to be commercially
available and therefore should be justified
when used as starting materials (1). Selec-
tion and qualification of biological source
materials (e.g., cell banks) are not described
in the new guideline, but rather, the indus-
try is referred to ICH Q5 for such steps (8).
It’s important to note that the CTD
submission strategy does not change
as a result of the starting material pro-
posal, say the PhRMA Q11 expert work-
ing group members. “Overall impurity
knowledge and control (fate and purge),
including starting materials, intermedi-
ates, raw materials, etc., are still important
whether using a traditional or enhanced
development approach.”
Control strategy and process validation.
Control strategy and process validation
are also large components of the Q11
guideline. A control strategy is a planned
set of controls, derived from current prod-
uct and process understanding, that as-
sures process performance and product
quality (5). Every drug-substance manu-
facturing process, whether developed
through a traditional or an enhanced ap-
proach (or some combination thereof) has
an associated control strategy (1).
The process validation section of
Q11 includes General Principles as well
as highlighting specific principles for
biotechnological/biological products, in-
cluding the consideration of scale up, im-
purity removal, and the use of platform
technology. The guideline’s recommenda-
tions in this area, note the industry Q11
expert working group members, reflect
current practice and expectations for
biologic products.
Life-cycle management. The ICH Q10
guideline on the pharmaceutical qual-
ity system includes quality system ele-
ments and management responsibilities
intended to encourage the use of science-
based and risk-based approaches at each
life-cycle stage (5). Q11 reinforces Q10’s
life-cycle management approach while
also providing more detail for drug-
substance process control. “Manufactur-
ing process performance, including the
effectiveness of the control strategy and
suitability of any design spaces, should be
periodically evaluated,” states the draft
guideline (1).
“ICH Q11 promotes awareness of the
sources of and potential for variation in
the CQAs of the drug substance,” explain
the FDA members of the Q11 working
group. “This knowledge supports well-
informed selection of suppliers capable
of consistently controlling the drug sub-
stance manufacturing process.” Risk
management and quality systems, which
are defined in ICH Q9 and Q10, apply
throughout the lifecycle of the drug sub-
stance when it comes to identifying, quali-
fying, and overseeing suppliers, and in the
management of contractual agreements,
adds FDA.
Furthermore, say the agency’s rep-
resentatives, it is important that senior
management play a critical role in es-
tablishing a qualification program that
assesses the supplier’s ability to provide
the drug substance using a defined sup-
ply chain. “These critical relationships
should be managed through use of
strong communication processes, writ-
ten quality agreements, ongoing review
of the performance of the supplier, and
the identification and implementation of
any needed improvements.”
Applying enhanced approaches. The Q11
document includes several illustrative
examples for application of Q11 princi-
ples to the drug-substance manufactur-
ing process, including how to: link mate-
rial attributes and process parameters to
drug-substance CQAs, select appropriate
starting materials, use quality risk man-
agement to support life-cycle manage-
ment of process parameters, and present
a design space for a biotechnological prod-
uct unit operation.
The PhRMA Q11 expert working
group members point out that the ex-
amples contained in Q11 are not to be
used as templates or best approaches.
“The intent of the examples is important
for the illustration of a high-level concept
not clarified in the text …. (and) are an
oversimplification of science to streamline
the document.”
Looking ahead
ICH Q11 should go a long way in help-
ing industry to implement QbD concepts
across the entire drug-manufacturing
process, including the application of an
enhanced approach beginning with start-
ing materials of synthetic and semisyn-
thetic products and source materials for
biological entities. Still, challenges remain.
Among them, say the Q11 expert working
group PhRMA representatives, will be “the
ability to make continual improvement in a
manufacturing process that is described in
detail in filings in many different countries.
The problems begin when one country ap-
proves the change while other countries are
still considering whether or not to approve
the change. Unfortunately Q11 is not able
to resolve or even address that problem be-
cause regional postapproval changes were
specifically out-of-scope.”
In the meantime, says FDA, “ICH Q11
should help continue the dialogue regard-
ing quality and risk-based approaches
and expand the scope of participants in
that dialogue to include those focused on
drug-substance development and manu-
facture.”
References
1. ICH, Q11 Development and Manufacture of
Drug Substances (chemical entities and bio-
technological/biological entities), Step 2 Draft
Consensus Document (2011).
2. FDA, Pharmaceutical CGMPs for the 21st
Century (2004).
3. ICH, Q8 Pharmaceutical Development
(2005). Note: The revised Q8(R2) version
was finalized in 2009.
4. ICH, Q9 Quality Risk Management (2005).
5. ICH, Q10 Pharmaceutical Quality System
(2008).
6. ICH, Q11 Development and Manufacture of
Drug Substances, Concept Paper (April 2008).
7. ICH, Q7 Good Manufacturing Practice Guide
for Active Pharmaceutical Ingredients (2000).
8. ICH, Q5A–E Quality of Biotechnological
Products. PT
38 Pharmaceutical Technology February 2012 Phar mTech. com
Technical Forum: Filtration
Adjuvants are becoming more
common in vaccine and other drug
formulations to increase therapeutic
response. Some of these substances,
however, are close enough in size
to bacteria that they are unable to
pass through sterilizing-grade filters.
Others have low surface tension
that can reduce a filter’s bacterial
retention. As a result, adjuvants
can cause premature plugging of
filter membranes and reduce filter
capacity. Pharmaceutical Technology
spoke to several industry experts
to gain insight on resolving these
technical challenges.
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Forum participants include Holger
Bromm, director of marketing and prod-
uct management filtration technologies
at Sartorius Stedim Biotech; Jerold Mar-
tin, senior vice-president of Global Sci-
entific Affairs at Pall Life Sciences; Peter
Koklitis, a technical filtration specialist
at 3M Purification in the United King-
dom; and Jim Powell, business develop-
ment manager of Asahi Kasei Bioprocess.
Reducing blockage
PharmTech: Novel adjuvants are often
based on emulsions or liposomes,
which are suspensions of small par-
ticles made up of surfactant or lipid
particles. Because these formulations
have a relatively high viscosity and be-
cause the typical particle size of the mi-
celles or liposomes is close to the size
of the smallest bacteria to retain, they
result in a difficult separation process.
In addition, these fluid streams often
contain high particle loads which can
cause premature plugging of sterilizing-
grade filters. How can pharmaceutical
or filter manufacturers reduce such filter
plugging or pore blockage?
Bromm (Sartorius Stedim): One pos-
sibility for filter manufactures to deal with
these challenges is to develop sterilizing-
grade filters that specifically address these
needs. According to our experience at Sar-
torius Stedim, highly asymmetric mem-
branes, such as polyethersulfone (PES)
membranes provide higher flow rate and
capacity for such type of formulations
compared with symmetric membranes.
According to practical experiences, the
use of a heterogeneous double-layer
membrane construction provides total
throughput advantages compared with
single layer membrane filters. The prefil-
ter (i.e., upstream layer) protects the final
membrane (i.e., downstream layer) from
premature plugging. Of high importance
is to find the optimal graduation between
two membranes. Studies with model solu-
tions and test results with actual formu-
lations in field tests have demonstrated
that the combination of a finer prefilter
membrane with the final 0.2 µm mem-
brane achieves better results compared
with combinations with a coarser prefil-
ter membrane for adjuvants applications.
Pharmaceutical manufacturers should
carry out filtration studies to compare
the performance of different membrane
materials and construction principals of
filters to find out the optimal solution for
their specific formulation. Furthermore,
the use of prefilters should be considered
in such studies to protect final sterilizing-
grade filters effectively and to reduce costs
and filtration time. These studies can be
used to determine the optimal parameters
for the filtration process, such as differ-
ential pressure or temperature. Increasing
the temperature can enhance filterability
depending on the stability of the solution
at higher temperatures. The same filter-
selection process may be applied for other
protein therapeutics or vaccines.
Martin (Pall): Pharmaceutical manu-
facturers can reduce filter plugging by
optimizing formulation and process
conditions for desired filter life, along
with selection of appropriate filters with
suitable capacity. Filter manufacturers can
provide technical support for this process
by conducting feasibility (filterability)
trials, selecting appropriate filter-media
grades, sizing of filter cartridges or cap-
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40 Pharmaceutical Technology February 2012 Phar mTech. com
sules, as well as ultimately applying that
knowledge to the development of new fil-
ters capable of providing greater capacity.
Process parameters such as pressure,
temperature, and flux (i.e., flow per unit
area) can have a large impact on filter
throughput and capacity. For example,
with complex plugging biological fluids,
performing the filtration in a constant
flow mode, increasing pressure differen-
tial to maintain flux rather than operat-
ing under a constant pressure mode can
often have a positive impact on filtration
throughput (capacity). Process tem-
perature can also have an impact but is
product-dependent and needs feasibility
(filterability) tests to determine whether
an improvement can be achieved through
modification. Optimizing these perfor-
mance variables is an acceptable (and
recommended) technique to reduce the
risk of premature blockage for vaccines
or protein therapeutics.
Koklitis (3M): The plugging of mem-
brane filter systems by adjuvants is partic-
ularly undesirable when the process step
has been validated to provide sterility as-
surance. The risk of filter plugging can be
reduced by careful control of the filtration
operating conditions, such as inlet pres-
sure and optimum flux. The lifetime of
the sterilizing-grade filter membrane will
be greatly determined by the particle load
in the process feedstream and the capacity
may be extended with a prefiltration stage.
A prefilter rated at 0.45 μm will remove
larger emulsion micelles or liposomes
which might ordinarily plug a sterilizing
0.2 μm membrane. Another option is to
consider a 0.2 μm-rated bioburden reduc-
tion membrane as a prefilter. This can be
of the same material as the final steril-
izing membrane to simplify validation
and may be effective for removing larger
particle sizes from the process stream as a
result of its pore size distribution. The pre-
filtration system selected should be sized
appropriately to meet the demands of the
process stream to minimize the expense
associated with the final sterilizing mem-
brane stage. When emulsions are used,
the pharmaceutical manufacturer could
investigate an adjuvant formulation with
a sufficiently small particle size to make it
filter-sterilizable.
Some studies with oil-in-water emul-
sions have shown that increasing the
pressure drop across the membrane can
increase filter capacity. The coating of
bacteria on the membrane with emul-
sion has been considered to contribute to
bacterial penetration. In such instances,
higher bacterial retention may be achieved
by increasing the temperature if cold con-
ditions are currently used. However, the
reasons for adopting cold filtration (e.g., to
maintain protein stability) may present an
obstacle to implementing a change.
Powell (Asahi): This is rather hard to an-
swer because the blocking can occur due
to a wide range of issues related to product
use and conditions such as pH, conductiv-
ity, protein concentration, viscosity, tem-
perature, membrane incompatibility with
what is in the adjuvant, and so forth. The
best solution would be to better charac-
terize the adjuvant, the product, and the
combination to find the most stable and
best filter condition possible, where mate-
rial is not precipitating, too viscous, too
high a concentration, and/or at the early
stage or “edge” of aggregation and the fil-
ter type where the adjuvant’s oil, if pres-
ent, does not bind to or change/damage
the membrane itself.
There are really two choices: the brute
force method, where one throws more
membrane at the problem, or the better
method, which would be to choose the
right adjuvant for the job and choose con-
ditions that fit into a high stability win-
dow of operation for the API. Another
more sophisticated solution to these kinds
of clogging problems is to use a cascade
of filters that end in the final desired po-
rosity. The upstream filter(s) can act as
prefilters to increase final filter capacity.
Low surface tension
PharmTech: Low surface tension of some
adjuvant solutions can reduce the effi-
ciency of filters’ bacterial retention. How
can this problem be mitigated?
Bromm (Sartorius Stedim): It is ad-
visable and required by regulators to
carry out a comprehensive filter valida-
tion study, including bacteria-retention
testing, simulating worst-case process
parameters with actual product formu-
lation using process related (i.e., pleated)
scale-down filter devices. The design
of the filtration system should consider
reducing filtration time and differential
pressure because these two parameters,
among others, may increase the risk for
bacterial breakthrough. During a filter
evaluation study, the impact of different
inlet pressure filtration conditions should
be assessed, including constant flow or
constant pressure conditions. Constant
flow conditions may increase the risk of
bacterial breakthrough, because of the in-
creased differential pressure required to
keep the flow constant during the filtra-
tion process and increased filter blocking.
The use of filters specifically designed
for adjuvant filtration as explained above
is highly recommended because those
filters will keep the process parameters
at a moderate level. It is recommended
to carry out a bacterial-retention study
early in the filter-selection process to find
the optimal solution based on retention
efficiency and highest filtration capacity.
Martin (Pall): Statistical and empirical
studies at Pall Corporation have identified
low surface tension of some adjuvant solu-
tions as a risk factor for reduced bacterial
retention efficiency of most sterilizing
grade 0.2 micron rated membrane fil-
ters. The mechanism by which bacterial
retention is reduced under lower surface
tension in these fluids is not yet fully elu-
cidated. Some mitigating factors appear
to be membrane structure and layering of
multilayer media, operating conditions, as
well as reduction of bacterial bioburden
or challenge levels and reducing challenge
duration. Fluid surface tension affects the
interactions between the bacteria and the
membrane flow-path surfaces, but de-
tailed mechanisms are not well known
and specific surface tension thresholds
cannot be determined.
Membrane surface chemistry is also
an element that may mitigate the negative
impact of fluid surface tension. Determin-
ing how and to what extent membrane-
surface chemistry can enhance retention
requires extensive studies. Filters with
positive zeta potential, which provide
enhanced adsorptive removal properties
for bacteria in aqueous ionic solutions,
have been used in the past for such pur-
poses. This was also one of the capability
Tchniahlo Frumt: Faoulari
Pharmaceutical Technology February 2012 41
Technical Forum: Filtration
advantages of asbestos-containing filters,
although these are no longer used because
of asbestos safety concerns.
Koklitis (3M): Such reduced filter
efficiency can be related to the mecha-
nisms involved in bacterial retention,
which can be based not only on sieving
but also on entrapment and electrostatic
attraction. The adsorption of bacteria to
the membrane polymer surface can be
caused by any combination of forces, in-
cluding hydrogen bonding, charge-in-
duced, and Van der Waals interactions.
The presence of liposomes, oils, or sur-
factants in a process stream can disrupt
these adsorptive interactions and con-
sequently reduce retention of bacteria
within the membrane structure.
When there may be a high risk of bac-
terial penetration, it should be identified
and considered in the planning of a filter
validation study. The required minimum
bacteria challenge (1 × 10
7
colony forming
units of Brevundimonas diminuta per cm
2
effective filter area) must apply, although
an upper challenge level can be consid-
ered and restricted to one log higher. In a
full-scale production process, the bacte-
rial challenge to the final filter membrane
may be controlled by introducing a prefil-
tration stage that has been demonstrated
to be effective for bioburden reduction.
The careful management and control of
the operating conditions during process
filtration will also help mitigate the risk
of bacterial penetration, with attention
to flow rate and filter area sizing to avoid
high pressure drop.
Powell (Asahi): This issue is typically not
applicable to Asahi products, but with
some filters, the lower surface tension
can change the effective porosity rating of
the membrane, allowing larger particles
to slip through the membrane’s holes.
These low viscosity adjuvants effect the
thickness of the boundary layer (where
flow velocities at the membrane surface
are at or close to zero) which, in turn,
alters the effective pore size under those
conditions. It can also affect how the API
and contaminants build up around the
membrane’s pores hence altering the ef-
fective pore size. One can screen different
membrane types, porosities, and brands
of filters, and work closely with the mem-
brane filter supplier to choose the best fil-
ter for the application.
Adjuvant type
PharmTech: Can certain types of adju-
vants (e.g., surfactant-containing solu-
tions) cause fewer problems with regard
to filters’ bacterial retention?
Bromm (Sartorius Stedim): A re-
view of validation studies and field tests
for a broader variety of fluid formula-
tions indicates that low surface tension
formulations, such as many adjuvants
or adjuvanted vaccines, present a higher
risk for bacterial penetration of steril-
izing-grade membrane filters. Among
such formulations, according to the
data analyzed, liposome formulations
present a higher risk than surfactant
containing solutions. Therefore, the use
of such formulations may be a suitable
alternative to replace more critical for-
mulations where applicable.
Martin (Pall): It is possible that cer-
tain adjuvants and related low surface
tension fluids may be intrinsically less
likely than others to cause reduced re-
tention efficiency by membrane filters.
However, there is insufficient data at this
time to draw firm conclusions and make
recommendations. In addition, aware-
ness among vaccine producers that selec-
tion of surfactant-containing adjuvants
and processing conditions can influence
bacterial retention efficiency of steriliz-
ing filters is not yet widespread. Until
then, filter manufacturers must continue
to work with vaccine developers to define
appropriate membranes and optimize
reasonable processing conditions to ster-
ilize any vaccine formulation. Certainly,
elaboration of an optimum adjuvant with
such a goal would require an extensive
amount of work and a very close part-
nership between filter manufacturers
and vaccine producers.
Koklitis (3M): The choice of adjuvant
is dependent on meeting the require-
ments of the process under consid-
eration. The pros and cons of using a
particular type of adjuvant must be con-
sidered and compared. When liposomes
are selected as adjuvants their role as an-
tigen carriers is utilized along with their
immunological enhancement effect.
Powell (Asahi): These issues should
be discussed with the membrane sup-
plier’s technical support teams and
if they can’t help, the filters must be
screened to choose the best solution
for the filter application. The answer
depends on the membrane chemistry,
but for large porosity filters, surfac-
tant-containing solutions are typically
not that large of a problem. Smaller
porosity filters can be dramatically
impacted in a negative way.
Flow maintenance
PharmTech: How can manufacturers
maintain product flow or prevent it from
decreasing during adjuvant filtration?
Bromm (Sartorius Stedim): For
the manufacturer of the adjuvants, it
is important to study and understand
the process variables involved in mak-
ing the adjuvant. The process variables
identified to have a significant impact
on the filterability of the formulation
should be controlled carefully and kept
within a narrow operating window.
This will enable constant performance
of the filtration process within estab-
lished process parameters.
Martin (Pall): Filter plugging may or
may not be an inherent part of a filtra-
tion process, depending on the particu-
late nature of the influent solution. An
efficient filter is designed to retain bac-
teria and therefore tends to retain any
particulate of a similar and larger size
(e.g., micelles, liposomes,). The ideal fil-
ter, with an extremely narrow pore-size
distribution, a very high porosity, free of
pinholes or other defects, and with suf-
ficient area, will present the best com-
promise between bacterial retention and
filtration capacity.
If a specific flow rate is desired over
the duration of a filtration operation
where the potential for plugging exists,
the filtration operation should be per-
formed under constant flow mode using
an appropriately sized filtration area.
Product flow can be maintained by in-
creasing the inlet pressure as needed.
Throughput of complex biological flu-
ids often benefits from operation in
contin. on page 56
42 Pharmaceutical Technology February 2012 Phar mTech. com
Pharma Ingredients: APIs & Excipients
The bio/pharmaceutical industry’s in-
tensification in product development
for biologic-based drugs has had an
effect on the demand for supply-chain
services for clinical-trial materials and
commercial drugs. During the past
year, several CDMOs and CMOs have
expanded their cold-chain logistics,
distribution, and storage capabilities.
Other companies, such as third-party
logistics providers, also have enhanced
their capabilities to serve the pharma-
ceutical cold chain. These expansions
are part of an overall growing market
for healthcare cold-chain logistics. The
total size of the healthcare cold-chain
logistic services market is expected
to expand from its current size of
$6.1 billion to nearly $9.5 billion by
2016, according to the IMARC Group,
a research and advisory firm.
Contract-service providers expand
Last May, the CDMO Almac Group
opened a new $120-million North Amer-
ican headquarters in Souderton, Pennsyl-
vania, which provides the company with
parallel service offerings in the United
States and in Europe through the com-
pany’s Craigavon, Northern Ireland, site.
The new 240,000-ft
2
North American
headquarters integrates the company’s
clinical technologies and clinical services
activities into one location after being
housed in separate locations in Audubon
and Yardley, Pennsylvania.
The facility has two interlinked
buildings, the first a 74,250-ft
2
building
providing administrative work space for
Almac Clinical Services, Almac Clinical
Technologies, Almac Sciences, Almac
Pharma Services, and Almac Central
Services. A second 166,135-ft
2
build-
ing, houses production and logistics
services, including, packaging, testing,
and distribution of clinical supplies.
The facility has extensive storage capa- I
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As biopharmaceutical development and
commercialization increases, companies are
expanding their cold-chain capabilities.
Expanding Capabilities in the
Pharmaceutical Cold Chain
Patricia Van Arnum
Patricia Van Arnum
is a senior editor at
Pharmaceutical Technology,
485 Route One South,
Bldg F, First Floor,
Iselin, NJ 08830
tel. 732.346.3072,
pvanarnum@advanstar.com.
bilities for pharmaceutical materials,
including raw materials, in-process ma-
terials, and finished goods. The facility
provides a range of storage solutions,
including temperature- and humidity-
controlled 41,150-ft
2
of warehousing
(15 to 25 ° C and 65% relative humid-
ity) and refrigerated and frozen storage
space. A 271,000-ft
3
drive-in cold stor-
age unit is maintained at temperatures
of 2 to 8 ° C, and a 6131-ft
3
walk-in
storage unit stores products at between
–25 and –15 ° C. Additional critical stor-
age space is offered through the use of
mobile units
In March 2011, in response to increased
client demand for cold and dedicated fro-
zen storage capacity for biopharmaceuti-
cals, Almac’s Pharma Services business
unit expanded its commercial facilities to
include an additional 6124 ft
2
of cold and
frozen storage. The expansion was a joint
investment with a commercial client for
which Almac provides central European
Union importation, warehousing, and
distribution services. This space includes
dedicated -70 °C, –20 °C, and 2–8 °C stor-
age for drug antibody, drug linker, bulk
drug substance, placebo, and filled vials.
The company added 20 additional dedi-
cated freezer units to its existing 10 for the
storage of the monoclonal antibody and
bulk drug substance products.
The opening of its North American
headquarters in 2011 and the addition
of cold-storage capacity in the EU were
in addition to several other expansions
in Almac’s clinical-trial-materials opera-
tions. In January 2012, Almac opened a
new £3-million ($4.7 million) 30,000-ft
2
building at its Craigavon headquarters,
which will house 150 employees from
Almac’s Clinical Services business. In
December 2011, Almac launched a new
forecasting platform, Compass, which is
designed to improve the accuracy and ef-
ficiency of the supply-inventory process
during clinical studies. Compass is part
of Almac’s Supply Chain Management
services to aid in the packaging, label-
ing, and distribution of trial supplies on
a global level. Also, in June 2011, Almac’s
clinical-services business unit increased
its presence in the Asia-Pacific region
with the addition of five new depots in
Japan, Thailand, Hong Kong, and Tai-
wan, thereby providing the company
44 Pharmaceutical Technology February 2012 Phar mTech. com
Pharma Ingredients: APIs & Excipients
with 36 depots in its network with an-
other five planned for 2012.
In August 2011, Catalent Pharma So-
lutions expanded its cold-chain supply
and distribution capabilities in all major
areas of the company’s cold-chain storage
and distribution, including 2–8 °C and
–80 °C capabilities, in some cases more
than tripling existing capacity for stor-
age and distribution. The cold-chain
expansions at Catalent’s European sites
in Bolton, United Kingdom, and Schorn-
dorf, Germany, were scheduled to be
completed by the end of 2011.
Catalent also made other key moves
to improve its clinical-services busi-
ness. In October 2011, the company
opened an European development
and clinical services laboratory in
Swindon, United Kingdom. This ex-
pansion followed recently expanded
clinical-supply service capabilities in
Schorndorf, Germany. Also, in 2011,
Catalent acquired the clinical-trial sup-
plies business of Aptuit, positioning the
company as the number two provider
globally in clinical-supply solutions.
Other companies expand
In December 2011, the logistics company
UPS agreed to purchase Italy-based Pieffe
Group, a pharmaceutical logistics com-
pany. The acquisition adds two major
healthcare distribution facilities, one in
Milan and the other in Rome, to UPS’s
existing global network. The facili-
ties provide a combined space of nearly
753,500 ft
2
, including 12 cold-storage
areas, with options for further expan-
sion. These facilities add to UPS’s global
healthcare distribution footprint of more
than 4 million ft
2
. UPS’s existing health-
care network of 30 facilities worldwide
offers services, such as temperature-
sensitive handling capabilities, regulatory
compliance, monitoring and security, kit-
ting and labeling, as well as order man-
agement and accounts receivables.
In September 2011, the logistics
company DHL launched DHL Smart-
Sensor GMS, a device for temperature
monitoring, as an advanced version of
the company’s SmartSensor RFID. The
DHL SmartSensor GSM is a small, high-
technology device that is packed inside
the DHL shipment and which sends
real-time data to the solution’s web por-
tal. The device uses GSM (Global System
for Mobile Communication) technologies
that permit data to be controlled without
opening the shipment. The device acts as
a data-gathering sensor and sends email
or text-message notifications if problems
arise during transport, such as a change
in temperature or the premature open-
ing up of parcel as the light sensor is ac-
tivated. The device can be used for land
and ocean-freight transports. For air
transport, the device’s GSM antenna is
automatically switched off before take-
off. The sensor continues to retrieve data
but does not send the information in
flight as to not to interfere with the air-
craft’s electronics, according to a Sept. 22,
2011, DHL press release.
In November 2011, DHL Global For-
warding, the air and freight specialist
within the Deutsche Post DHL Group,
expanded its services for temperature-
controlled shipments. The company
entered into a lease with CSafe, a
heat-and-cool container provider for
A new class of nanoparticles, synthesized by a research team at the University
of California, Davis, to prevent premature drug release, holds promise for
greater accuracy and effectiveness in delivering cancer drugs to tumors. Kit
Lam, professor and chair of the Department of Biochemistry and Molecular
Medicine and his team reported on the synthesis of a novel class of micelles
called dual-responsive boronate cross-linked micelles (BCMs) , which produce
physicochemical changes in response to specific triggers.
The researchers reported that micelles reversibly cross-linked by boronate
esters show in vitro and in vivo stability and thus minimize premature drug
release under physiological conditions. After reaching the tumor sites, drug
release is activated by cleavage of the boronate esters by the acidic conditions
around the tumor or in the target cells or by the administration of
mannitol (1). A micelle is an aggregate of surfactant molecules dispersed in
water-based liquid such as saline. They are nanosized, about 25–50 nm , and
can function as nanocarriers for drug delivery.
“This use of reversibly cross-linked targeting micellar nanocarriers to deliver
anticancer drugs helps prevent premature drug release during circulation and
ensures delivery of high concentrations of drugs to the tumor site,” said Yuanpei
Li, a postdoctoral fellow in Lam’s laboratory who created the novel nanoparticle
with Lam, in a Jan. 18, 2012, University of California at Davis press release. “It
holds great promise for a significant improvement in cancer therapy.”
Stimuli-responsive nanoparticles are gaining attention in the field of drug delivery
due to their ability to transform in response to specific triggers, notes the university
release. Among these nanoparticles, stimuli-responsive cross-linked micelles (SCMs)
can serve as a nanocarrier system for tumor-targeting drug delivery.
SCMs and other nanoparticle systems seek to address the problem of premature
drug release, which results in a drug not delivering its payload to a given target.
SCMs can better retain the encapsulated drug and minimize its premature release
while circulating in the blood pool. The introduction of environmentally sensitive
cross-linkers makes these micelles responsive to the local environment of the tumor.
In these instances, the payload drug is released primarily in the cancerous tissue,
according to the release.
The dual-responsive boronate cross-linked micelles that Lam’s team has
developed are a second generation of SCMs able to respond to multiple stimuli
as tools for accomplishing the multistage delivery of drugs to a complex in vivo
tumor micro-environment, according to the university release. These BCMs
deliver drugs based on the self-assembly of boronic acid-containing polymers
and catechol-containing polymers, both of which make these micelles unusually
sensitive to changes in the pH of the environment. The research team has
optimized the stability of the resulting boronate cross-linked micelles as well as
their stimuli-response to acidic pH and mannitol.
This nanocarrier platform shows promise for drug delivery that minimizes
premature drug release and can release the drug on demand within the acidic
tumor micro-environment or in the acidic cellular compartments when taken in
by the target tumor cells. It also can be induced to release the drug through the
intravenous administration of mannitol.
Source
1. K. Lam et al., “Well Defined, Reversible Boronate Crosslinked Nanocarriers for
Targeted Drug Delivery in Response to Acidic pH Values and cis-Diols,” Angew.
Chem., Int. Ed. Engl. online, DOI:10.1002/anie.201107144, Jan. 17, 2012.
Formulation development forum: boronate cross-linked micelles
Pharmaceutical Technology February 2012 45
Pharma Ingredients: APIs & Excipients
the temperature-sensitive air-freight
market. The CSafe heat-and-cool con-
tainers maintain temperature within
a range of 4 °C to 25 °C by means of
rechargeable batteries for temperatures
ranging from ambient to more extreme
temperatures of from –30 °C to 49 °C.
In September 2011, DHL Global For-
warding and Lufthansa Cargo changed
their ownership of their 50–50 joint
venture, LifeConEx, a life-sciences cold-
chain logistics provider, to make it a
100% owned subsidiary of DHL. In April
2011, DHL Global Forwarding opened
a new competence center in Vienna to
expand services to the life-sciences sec-
tor. The facility includes 500 m
2
of re-
frigerated warehouse space for handling
temperature-sensitive products to
allow them to be prepped for air ship-
ment. The center, located at the Vienna
airport, is expected to transship ap-
proximately 20,000 pallets annually in
temperature ranges of 2–8 °C and 15–25
°C. In addition to the warehousing ser-
vice, the company offers loading and
unloading of refrigerated containers,
packing of products, coordination of
freight space, and organization of the
necessary transport equipment. DHL
Freight and LTL ColdChain Europe, a
pan-European road-freight pallet net-
work for the life-sciences and healthcare
industries, are connected to the Vienna
competence center.
In March 2011, Bristol-Myers Squibb
selected Exel, part of DHL, to be its
third-party logistics provider handling
US distribution. As part of the contract,
Exel purchased the existing Bristol-
Myers Squibb distribution centers in
Mount Vernon, Indiana. Exel is pro-
viding logistics operations and finished-
goods distribution services, including
storage and distribution of cold-chain
and non-cold-chain products, clinical-
trial materials, samples, and exports.
Exel also is managing second distribu-
tion in Mechanicsburg, Pennsylvania,
for Bristol-Myers Squibb.
Movianto Nederland, a logistics and
transportation company specializing
in pharmaceuticals and healthcare, is
building a new warehouse in Oss, the
Netherland to offer a large facility for
the storage of deep frozen pharmaceu-
tical products. The new warehouse,
which will be operational by April
2012, will provide a range of new facili-
ties, such as a deep frozen storage area
(< –20 °C) with a capacity for 350 pal-
lets. The 13,000-m
2
good-distribution
practice (GDP)-compliant warehouse
encompasses 21,000 temperature-
cont rol led pal let places, i nclud-
ing 17,700 in the area of ambient
(15–25 °C) 2200 chilled pallet locations
(2–8 °C), and 1100 pallets for narcotics.
The facility includes a mezzanine with
1300 m
2
for repackaging and relabeling
services according to GMP guidelines.
The expanded storage capacity will
serve as a central European warehouse
with a dedicated cross-docking area and
bonded warehouse facility. Movianto’s
transport solution manages freight and
distributes the products to local ware-
houses throughout Europe.
In July 2011, Sherpa Clinical Packag-
ing, a privately held provider of clinical-
trial material-management services,
opened a new cGMP production facility
in San Diego, California, colocated adja-
cent to the CDMO Althea Technologies
campus in Sorrento Valley. Sherpa and
Althea entered into a comarketing agree-
ment in March 2011.
Sherpa’s new facility includes five
controlled access and monitored packag-
ing suites, and walk-in 2–8°C and –20 °C
storage areas. Redundant refrigeration
systems, alarms, and onsite emergency
backup generator power were specified
to minimize potential risks associated
with cold storage. “We purpose-built
the facility to accommodate the needs of
pharmaceutical and biotech clients that
require controlled environments for their
clinical study materials,” said Mark Paiz,
president of Sherpa Clinical Packaging,”
in a July 2011, press release. “The site
offers companies conducting clinical
studies an option to label, package, store,
and distribute on the West Coast, which
is particularly important for many bio-
technology companies whose products
require cold storage.”
Marken, a provider of clinical-trial
management services, reported in De-
cember 2011 that it has expanded its
depot network with a new facility in
Buenos Aires. The Argentina depot joins
Marken’s already operational depots in
Mexico and Singapore and includes a full
range of temperature control, including
controlled ambient, cold storage (2–8 °C)
and frozen (–20 °C) as well as a secured
drug store. Each of Marken’s depots offer
specimen kit distribution, collection,
storage, and management as well as re-
verse logistics for dosage kits, drugs, and
equipment, including reconciliation and
certified destruction. Additional depot
facilities are being developed in Europe,
Asia, and the Americas, according to the
company. This expanded network builds
on Marken’s current Latin America busi-
ness, which serves over 1200 clinical re-
search investigator sites in the region.
In May 2011, BioStorage Technolo-
gies, a provider a sample-management
solutions, opened a new biorepository
facility in Indianapolis, Indiana. The
$4.6-million, 60,000-ft
2
facility is dedi-
cated to the preparation, storage, and
cold-chain transport of human bio-
logical samples for academic centers,
CROs, donor programs, and biotech-
nology companies. The facility expan-
sion provides the company the ability
to offer sample-preparation services,
including automated liquid handling
technology for high-throughput DNA
and RNA extraction and verification.
The new biorepository facility offers a
wide range of storage options, includ-
ing automated carousel controlled-
room temperature storage at 15 °C to
27 °C, bulk sample storage at 15 °C to
27 °C, walk-in cold sample storage at
–20 °C to 5 °C, ultra-low temperature
storage at –70 °C to –80 °C , and –190
°C vapor-phase liquid nitrogen. PT
GMS devices
can be used for
temperature
monitoring and
for providing
real-time data.
46 Pharmaceutical Technology February 2012 Phar mTech. com
To ensure the quality of APIs and finished drug
products, impurities must be monitored carefully
during process development, optimization, and
process changeover. This three-part article series
examines the types of impurities, their sources,
and strategies for the isolation, characterization
and control of impurities. In Part I of this article,
the authors discuss what constitutes an impurity
and the potential sources of such impurities,
such as vendor scheme, solvents, and reagents
for key starting raw material(s).
Kashyap R. Wadekar, PhD,* is a research
scientist (II), Mitali Bhalme, PhD, is an associate
research scientist, S. Srinivasa Rao is a research
associate, K. Vigneshwar Reddy is a research
associate, L. Sampath Kumar is a research chemist,
and E. Balasubrahmanyam is a research chemist, all
with Neuland Laboratories, 204 Meridian Plaza, 6-3-
854/1, Ameerpet, Hyderabad, India, tel. 91 40 30211600,
kashyapwadekar@neulandlabs.com.
*To whom all correspondence should be addressed.
Submitted: Sept. 19, 2011; Accepted Nov. 28, 2011.
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Impurities
T
o ensure the quality of APIs and finished drug prod-
ucts, impurities must be monitored carefully dur-
ing process development, optimization, and process
changeover. The isolation, characterization, and con-
trol of impurities in pharmaceutical substances are being
reviewed with greater attention based on national regulatory
and international guidelines. In Part I of this article, the au-
thors examine the different types and sources of impurities
with specific examples.
Definition and sources of impurities
An impure substance may be defined as a substance of in-
terest mixed or impregnated with an extraneous or usually
inferior substance. The greatest financial impact on the cost
of a drug substance often is found in the final preparation
process. Product yield, physical characteristics, and chemical
purity are important considerations in the manufacture of the
active ingredient, the formulation of the dosage form, and the
manufacture of the finished drug product. Processes to con-
trol the preparation of the drug substance and drug product
must be disclosed to FDA as part of a new drug application. If
production batches do not meet the purity and impurity speci-
fications required, the manufacturer must attempt to upgrade
materials by rework procedures, which are costly because they
consume drug substance and resources and prevent the prepa-
ration of other batches of drug substance. The sources and
types of impurities can be illustrated by considering a general
flow scheme for manufacturing drugs. The formation of im-
purities is interconnected with each stage as shown in Figure 1.
In short, any material that can affect the purity of an API
or finished drug product is considered an impurity. Impuri-
ties arise from various sources, which commonly include
starting material(s), intermediates, penultimate intermedi-
ates, byproducts, transformation products, interaction prod-
ucts, related products, degradation products, and tautomers.
Starting material(s)
Impurity control in starting materials used to manufacture
APIs has long been expected by regulatory agencies (1). An
API starting material is a raw material, intermediate, or API
that is used in the production of an API and that is incorpo-
rated as a significant structural element into the API. API
Evaluating Impurities in Drugs
Part I of Part III
Kashyap R. Wadekar, Mitali Bhalme, S. Srinivasa Rao, K. Vigneshwar Reddy,
L. Sampath Kumar, and E. Balasubrahmanyam
Pharmaceutical Technology February 2012 47
starting materials normally have defined chemical properties
and structure (2). An FDA draft guidance, Drug Substance:
Chemistry and Manufacturing Controls Information, reflects
the concern that starting materials should be selected and
controlled such that any potential future changes to the
quality of the starting material would have an insignificant
impact on the safety, identity, purity, or quality of the drug
substance (3). Based upon the principles outlined in this FDA
draft guidance and ICH guidelines for process understanding
and control over potential adverse effects on the quality of
the produced drug substance,
the following framework has
been offered for the selection
of starting materials:
• Appropriate, discriminat-
ing methodology is used
to determine the quality of
the starting material.
• Specifications are appropriate
to ensure quality of the API.
• The impact of the starting
material quality on API
quality is understood and
controlled.
• The starting material is
available commercially and
is incorporated into the new
drug substance as an im-
portant structural element.
• The starting material is
characterized, and stabil-
ity is well understood.
• The starting material is a
compound whose name,
chemical structure, chemical
and physical characteristics
and properties, and impu-
rity profile are well defined
in the chemical literature (4).
Because of the starting
materials’ potential impact
on the quality of an API,
stricter requirements for a
starting material arise based
on the proximity in the API
synthesis of the starting ma-
terial to the final API. For ex-
ample, fluoronitrobenzene is
a key starting material for the
API olanzapine. If the 2-4-
difluoronitrobenzene impu-
rity is present in the key start-
ing material, the same will
be converted under reported
conditions to 8-fluoro-olan-
zapine, a nonpharmacopeial impurity (US Pharmacopeia [USP]
method, relative retention time [rrt] 1.07). The 2,4-difluoroni-
trobenzene is carried forward along with the fluoronitroben-
zene, resulting in analogous compounds up to the final stage .
In another example, N-[6-(4-phenylbutoxy)hexyl)]
benzenemethanamine (see Figure 2) is a drug master file
(DMF) starting material for the selective long-acting β-2-
adrenoreceptor agonist salmeterol. The drug is used clini-
cally as an inhaled bronchodilator for treating asthma and
chronic bronchitis (5, 6).
Figure 1: Schematic representation of impurity-formation pathways for APIs and finished drug
products. DMF is drug master file.
Metabolite - Impurities
Formulation - Impurities
Genotoxic - Impurities
Polymorphic - Impurity
DMF
Starting Raw Material (s)
Drugs / APIs
(Generic Drugs)
Non-DMF Stages
Kew Starting Raw Material (s)
Starting Material (s) - Impurities
Penultimate Intermediate - Impurities
Byproduct - Impurities
Transformation Products - Impurities
Interaction Products - Impurities
Related Products - Impurities
Degradation - Impurities
Tautomer - Impurities
Figure 2: Reaction scheme of salmeterol and impurities. EP is the European Pharmacopoeia. NaH
is sodium hydride. TBAB is tetra-n-butylammonium bromide DMSO is dimethyl sulfoxide. NABH
4
is
sodium borohydride. Pd/C is palladium on carbon.
Salmeterol impurity B (EP)
HO
HO
OH H
N
O
HO
HO
OH
H
N
O
Methyl Salmeterol impurity
(Nonpharma impurity)
OH
HO
HO
HO
Salmeterol impurity C (EP)
HO
HO
OH H
N
O
Salmeterol impurity E (EP)
HO
HO
OH H
N
O
OH
(A)
4-Phenyl butanol
1,6-Dibromohexane, NaH
Toluene, TBAB
(A)
(A)
Benzylamine
Benzyl amine
base
No Reaction
O
O
Compound 1
Intermediate 1
O
Br
DMSO, Benzylamine
Triethylamine
Intermediate 1
Intermediate 2
O
NH
as known process
No Reaction
O
O
N
Compound 2
Intermediate 3
HO
HO
O
OH H
N
NaBH
4
, Methanol
Pd/C, Hydrogen
Salmeterol
O O
H
HO
O
O
N
O O
H
HO
Br N-N-diisopropyl ethylamine
Methyl ethyl ketone
O
OH H
Compound 3
Cyclohexyl salmeterol impurity
N
HO
HO
Compound 4
OH H
N
HO
HO
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48 Pharmaceutical Technology February 2012 Phar mTech. com
In the case of salmeterol, 4-phenyl butanol reacts with
1,6-dibromohexane to give Intermediate 1, which in turn
reacts with benzylamine in the presence of dimethyl sulf-
oxide and triethylamine to yield N-[6-(4-phenyl butoxy)
hexyl)] benzenemethanamine, a DMF starting material for
salmeterol (see Figure 2). The compound 4-phenyl butanol
is commercially available and prepared from benzene with
succinic anhydride (7–11). If the benzene has a trace amount
of toluene, the toluene is converted to 4-(4-methylphenyl)-
1-butanol. The compound 4-(4-methylphenyl)-1-butanol is
present in 4-phenyl butanol as a starting material impu-
rity, which undergoes further reaction, similar to 4-phenyl
butanol, to afford the methyl salmeterol impurity (see Fig-
ure 2). Similarly, the presence of 2-phenylethanol, 3-phenyl-
1-hydroxypropane, and 4-phenyl-2-hydroxybutane in the
4-phenyl butanol will yield known salmeterol Impurities B,
C, and E, respectively.
Similarly, 6-hydroxy and dichloro impurities, if present
in the DMF starting material of ciprofloxacin, will be con-
verted to European Pharmacopoeia impurity F and nonphar-
macopeial impurity (chloro ciprofloxacin) at 2.1 RRT.
Intermediates
Organic compounds formed during the synthesis of APIs
are termed as intermediates. The compound in the synthetic
chain before the production of the final desired compound
is called the penultimate intermediate.
Impurities due to rearrange-
ment. Developing practical
synthetic routes to render
high-yield products in shorter
stages or in a one- or two-pot
reaction generally involves
formation of rearranged inter-
mediates that ultimately give
the required final product.
As an example, the cycliza-
tion of bromonitrostyrene in
the API ropinirole involves the
rearrangement of the interme-
diate cyclic ion to give the in-
dole ring with the formation
of hydroxamic ester and chlo-
rooxime acetate as impurities.
Impurities due to in situ reac-
tions. Advances in synthetic
chemistry have enabled a
number of stages in a reac-
tion to be carried out in just
one or two pots without the
need to isolate intermedi-
ates. The downside of such
reactions is the unexpected
and numerous impurities
that form because interme-
diates and reagents are not isolated.
As an example, the alkylation of the key starting material
(S)-2-amino butyramide for the API levetiracetam with chlo-
robutyrylchloride using potassium hydroxide in the presence
of tetra-n-butylammonium bromide gives an intermediate
that eventually cyclized into levetiracetam. This intermediate,
however, is present in the final product as an USP impurity A.
Nonreactive intermediates. Nonreactive intermediates are
impurities formed in some intermediate stage by the reac-
tion of reagents used in the next stages due to carryover.
Such impurities remain nonactive in the later stages.
For example, 4-phenyl butanol is a key raw material for the
synthesis of salmeterol Intermediates 1 and 2 (see Figure 2).
Intermediate 1 reacts with 4-phenyl butanol in the presence
of sodium hydride and toluene to yield Compound 1, which
is a nonreactive impurity in further stages. Intermediate 2
reacts with the trace amounts of Intermediate 1 and in the
same conditions react to form Compound 2 (see Figure 2).
Reactive intermediates. Reactive intermediates, as the name
implies, are byproducts or impurities resulting from the in-
termediate stages of the reaction that have the potential to
react with the reagents or catalysts used in later stages. They
are carried forwarded in every stage up to the final API as
a reactive intermediate.
During the process development of salmeterol, an un-
known impurity was detected at 2.08 RRT at a level of 0.11%
and later identified after isolation to be Compound 3 (see Fig-
Impurities
Figure 3: Linezolid (e.g., oxazolidinones class) and pemetrexed disodium tautomer impurity. EP is
the European Pharmacopoeia. RRT is relative retention time.
Part - I
Part - II
Part - III
O
O
O
O
NH
N N
F
Linezolid
N
HO
F
N N O
O
O
O
NH
R
F
N
O
O
N
HO
R
F
N
O
O
NH
2
HN
N
O
H
2
N NH
2
N
N
O
N
N N
HN
O O
O
OH
OH
Cl
Cl
Cl
OH
H
2
N NH
2
N
N
O
O O
O O
OH
OH
N
N N
HN
F
F
Cl
H
2
N
H
2,4-Diamino-6-hydroxy-pyrimidine
N
N
OH
H
2
N
N
H
O
NH
COONa
COONa
N
N
H
HO
HO
Cl
O
O O
O
OH
OH
N
N N
HN
O
H
2
N
N
H
Structure in
literature / patents
pemetrexed disodium
Ciprooxacin starting material 6-Hydroxy, starting material Impurity
Dichloro, starting material impurity
Chloro impurity (RRT 2.1)
(EP method)
Ciprooxacin
Hydroxy impurity F (EP, RRT 0.5)
O
NH
COOH
COOH
N
N
O
H
2
N
H
N
H
O
NH
COOH
COOH
Structure in
draft EP monograph
Pharmaceutical Technology February 2012 49
ure 2). The impurity formed in the final API due to presence
of N-benzyl-6-(4-cyclohexylbutoxy)hexan-1-amine in Inter-
mediate 2 leads to the salmeterol cyclohexyl impurity (12).
The reactive intermediate, N-benzyl-4-phenylbutan-1-
amine is present in Intermediate 2 (see Figure 2). It is formed
by the reaction of 4-phenyl butanol with benzyl amine and
competes in all reaction stages with Intermediate 2 to form
Compound 4 (see Figure 2).
A main challenges faced in developing the olefination
route of the API aprepitant was a subsequent reaction of the
vinyl ether intermediate with dimethyltitanocene to form
an ethyl impurity (13).
Bis-compound impurities. The formation of new or unknown
impurities can occur when scaling up a process, even with
successful runs at a smaller scale. Examining the molecular
weight of such impurities often reveals the compound is ex-
actly double the weight of that being formed in that reaction
step. Such dimeric derivatives are called bis-compound im-
purities. Two bis-compound impurities were formed in the
intermediate and final stages in the synthesis of linezolid,
to be discussed in Part III of this article.
Byproducts
In synthetic organic chemistry, getting a single end prod-
uct, 100% pure, seldom occurs because of the change into
byproducts, which can be formed through a variety of side
reactions, such as incomplete reactions, overreactions, isom-
erization, or unwanted reactions between starting materi-
als, intermediates, chemical reagents, or catalysts. For ex-
ample, in the bulk production of paracetamol, diacetylated
paracetamol may form as a byproduct (14).
In the Claisen rearrangement of the aryl propargyl ether in
diethylaniline at elevated temperatures, formation of the de-
sired chroman product is ac-
companied by the generation
of a furan byproduct in succes
sively increasing amounts (15).
In the ropinirole synthesis,
a somewhat similar case is ob-
served in the final step. The re-
action between the ropinirole
precursor 4-(2-bromoethyl)-
13-dihydro-2H-indol-2-one
and di-n-propyl amine in
water produces ropinirole in
modest yield (57%), together
with styrene as the major by-
product (38%) (16).
In another example, thio-
phenes are important het-
erocyclic compounds that
are widely used as build-
ing blocks in many agro-
chemicals and pharmaceu-
ticals (17). The synthesis of
2-amino-5-methylthiopene-3-carbonitrile is achieved by
reacting a mixture of sulfur, propionaldehyde, malononi-
trile, and dimethylformamide using triethylamine (18–26).
The reaction of propionaldehyde with malononitrile and
sulfur resulted in formation of two unknown impurities
up to 7%, which were isolated and confirmed by
1
H NMR
(nuclear magentic resonance spectroscopy), correlation
spectroscopy, nuclear Overhauser effect spectroscopy, and
single X-ray crystallography to be Impurity 1 (see Figures 4
and 5). These impurities are further found to react with
2-f luoro nitrobenzene to give next-stage impurities and
which are controlled by purification in the respective stages.
Impurity 1 (see Figure 5) is a novel tricarbonitrile bicyclic
compound, and as of the writing of this article, it is not known
in the literature. Prediction of cLogP is 0.65, drug linkness
is 4.04, and the drug score is 0.45 as determined by OSIRIS
Property Explorer, software used to calculate various drug-
relevant properties of chemical structures. Structure–activity
relationship, quantitative structure–activity relationship, and
drug design with other modified organic/inorganic hetrocyclic
moieties could give some biological activity. The molecular de-
signing of Impurity 1 for specific and unspecific purposes (e.g.,
DNA-binding, enzyme inhibition, anticancer efficacy) is based
on the knowledge of molecular properties, such as the activity
of functional groups, molecular geometry, and electronic struc-
ture, and on information cataloged on analogous molecules.
The compound 2,6-diamino-7-ethyl-8-methylbicyclo[2.2.2]
octa-2,5-diene-1,3,5-tricarbonitrile could be coupled with an
active or nonactive peptide to check the biological activity as a
prodrug or drug. The potential therapeutic and prophylactic
activities of antimalarials, antimitotics, and antitumor agents
could also be performed. This bicyclic compound may be used
alone as a single agent or in combination with any organic or
Figure 4. Propionaldehyde with malanonitrile reactions. CAS refers to Chemical Abstracts Service,
No. is number, and NA is not available. Conditions: (a) with piperidine in pyridine, heating (Ref. 27);
(b) with piperidine in pyridine, heating, cyclization (Ref. 28); (c) with piperidine, 1,4-dioxane
(Ref. 29–30); (d) With [C
4
DABCO][BF
4
] in water, Time = 0.0166667 h, T = 20 °C, Knoevenagel
condensation or with aluminum oxide in dichloromethane, T= 20 °C, Knoevenagel condensation
aldol-condensation (Ref. 31–33).; and with morpholine in ethanol, T = 20 °C, Knoevenagel
condensation (Ref. 34–37).
N
N
N N
N N
N
N
NH
NH
2
O
CAS No. NA
CAS No. 38091-73-5 Propionaldehyde Malanonitrile
CAS No. 55525-92-3
e
a
N
N
H
CN
CN
NH
2
NC CN
O
b
c
d
CAS No. 90323-61-8 CAS No. 52833-34-8
50 Pharmaceutical Technology February 2012 Phar mTech. com
inorganic salts in chemotherapy or in combination with other
chemotherapeutic agents after in vivo and in vitro testing.
Transformation products
Transformation products deal with theorized and nontheo-
rized products produced in a reaction. They can be synthetic
derivatives of byproducts and are closely related to byproducts.
A reaction where transformation products occur is the for-
mation of chloro acetyl derivative of salicylaldehyde during
the acylation reaction of salicylaldehyde with bromo acetyl
bromide using methylenedichloride (MDC) and aluminum
chloride (AlCl
3
). Mechanistically, the formation of chloroacetyl
derivative using bromoacetyl bromide could not be expected,
but hypothetically, it could occur as a transformation reaction
due to halogen exchange. During Friedel–Craft acylation with
Lewis acid AlCl
3
in methylene dichloride, the Lewis acid forms
an ionized complex [Cl–AlCl
2
–Br]–, which eventually undergoes
halogen exchange with the bromo acylium ion to yield the chloro
acetyl derivative. Formation of this impurity in reaction is as
high as 7–20%, which is an uncontrolled impurity in the manu-
facturing process. Nevertheless, this impurity would not affect
the purity of the final drug substance because the reaction of
the transformed impurity with 2 (see Figure 6, Part I) forms the
desired product, salmeterol. The presence of the chloro impurity
also has been confirmed by experiment (see Figure 6, Part II).
Interaction products
The term interaction product
deals with the interaction of
two or more intermediates/
compounds with various
chemicals, intentionally or
unintentionally. An interac-
tion product is slightly more
comprehensive than byprod-
ucts and transformation
products. Two types of inter-
action products that are com-
monly encountered are drug
substance–excipient interac-
tions and drug substance–
container/closure interactions.
Related products
The term related products
means that the impurity
has similar structure as that
of the drug substance and
may exhibit similar biologi-
cal activity. This structural
similarity by itself, however,
does not provide any guar-
antee of similar activity. An
example of a related product
is 8-fluoro olanzapine.
Degradation products
Impurities formed by decomposition or degradation of the
end product during manufacturing of the bulk drug are
called degradation products. The term also includes deg-
radation products resulting from storage, formulation, or
aging. Parts II and III of this article will discuss the types
and sources of the degradation products in further detail.
Tautomer impurities
Tautomers are readily interconvertible constitutional isomers
that coexist in equilibrium. For APIs or drug molecules that ex-
hibit tautomerism, there has been a confusion in identifying the
two tautomeric forms. If one tautomer is thermodynamically
stable and is the major form, the other tautomer should be con-
sidered as an impurity or simply termed as a tautomer of the API
or drug molecule. To the best of the authors’ knowledge, there
has been no literature relating to the isolation, synthesis, or char-
acterization of a tautomeric impurity(-ies) from the final API.
Linezolid is an treatment for nosocomial infections involv-
ing gram-positive bacteria. Oxazolidinones possess a unique
mechanism of bacterial protein synthesis inhibition (38–39).
Linezolid has an N-acetyl group (–NH–CO–CH
3
) due to
that lactam–lactim tautomerism, which may occur during
the synthesis but also may be stable. An effective analytical
method needs to be developed to identify both tautomers.
Impurities
Figure 5: Reaction scheme of olanzapine impurities. DMF is dimethylformamide. TEA is
triethylamine. Addn is addition. RT is room temperature. CAS is Chemical Abstracts Service, No. is
number, and NA is not available.
O
H
NC CN
Propionaldehyde Malanonitrile
15 - 20 °C, 1 h
Sulfur
DMF/TEA
(1)
DMF/TEA
addn at 28 to 32 °C
Overnight RT
OR
(2) DMF/TEA
addn at -5 to 10 °C
Overnight RT
N
N
N
H
2
N
NH
2
Impurity 1
Condition 1
formed compound
CAS No. NA
OR
NH
2
CN
CN
Impurity 2
Condition 2
formed compound
CAS No. 55525-92-3
CAS No. 138564-58-6
Olanzapine
H
2
N
S
NC
H
2
N
NO
2
N
N
N
NH
NO
2
NO
2
N
N
N
NH
NH
Nonpharmacopeial impurities
NO
2
CN
CN
NH
H
2
N
NH
2
N
N
Impurity 1
N1
C1
C2
C3
C4
C5
C6
C7
C8
C9
C10
C11
C12
C13
C14
N2
N3
N4
N5
Pharmaceutical Technology February 2012 51
A key starting raw material of pemetrexed disodium
2,4-diamino-6-hydroxy-pyrimidine shows the keto-enol
form occurring in different ratios and which will be converted
to the final drug using a known synthesis (see Figure 3).
Tautomers vary in their kinetic and thermodynamic stabil-
ity, thereby making it difficult to determine whether they could
be separated, isolated, or analyzed. Keeping this in mind, the
use of the term impurity for tautomers in a final API/drug moi-
ety presumably will be an important discussion in near future.
Conclusion
Part I of article highlights the origination and classification of
impurities and provides a perspective on impurities in drug
substances and drug products. The impurity profile of a drug
substance is on increasing importance for ensuring the quality
of drug products. Whatever the class of impurity, its identifica-
tion and adequate control is a tremendous challenge for process-
development chemists. Because no two drugs are alike, neither
are two development pathways. Each drug candidate poses a
different challenge in terms of impurities, and establishing ef-
ficient ways for the isolation and control of impurities is a key
task in process development.
Part II of this article, to be published in the March 2012
issue of Pharmaceutical Technology, will discuss chiral and
polymorphic impurities. Part III, to be published in the
April 2012 issue of Pharmaceutical Technology, will discuss
genotoxic and stability impurities.
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Figure 6: Chloro impurity-formation scheme of salmeterol. HPLC is high-performance liquid
chromatography. MDC is methylenedichloride; AlCl
3
is aluminum chloride.
Bromo acetyl derivative
HPLC purity 90.43%
1
OH
OH
O
O
O
O
H
H
Br
Br
Br
OH O
O
H
Cl
Chloro acetyl derivative
HPLC purity 9.53%
2 1
2
MDC / AICI
3
Reux 24 h
MDC / AICI
3
MDC / water
OH
OH
O
O
O
H
H
Br
O
HO
HO
H OH
O
N
Br
OH O
O
H
Cl
OH O
O
H
Cl
Chloro acetyl derivative
HPLC purity 12.73%
Bromo acetyl derivative
HPLC purity 87.27%
Bromo acetyl derivative
5-(Bromoacetyl)-2-hydroxybenzaldehyde
Chloro acetyl derivative
5-(Bromoacetyl)-2-hydroxybenzaldehyde
2
Pathway as per Figure: 2
Salmeterol
Salmeterol
Part-I
Salicylaldehyde
Part-II
52 Pharmaceutical Technology February 2012 Phar mTech. com
INSIDE ICH
PharmTech.com/ich
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PharmTech.com/ich
T
he mission of the International Con-
ference on Harmonization (ICH)
is to make recommendations to-
wards achieving greater harmonization
in the interpretation and application of
technical guidelines and requirements
for pharmaceutical product registration.
The organization, launched in 1990,
brings together the drug regulatory au-
thorities and the pharmaceutical indus-
try associations of Europe, Japan, and the
United States.
Regulatory harmonization offers
many direct benefits to both regula-
tory authorities and the pharmaceu-
tical industry with beneficial impact
for the protection of public health.
Key benefits include: streamlining the
regulatory assessment process for new
drug applications, and reducing the
development times and resources for
drug development.
Harmonization is achieved through
the development of ICH Tripartite
Guidelines, which are developed through
a process of scientific consensus among
regulators and industry. Key to the suc-
cess of this process, however, is the com-
mitment of the ICH regulators, includ-
ing FDA, EMA, and Japan’s Ministry of
Health, Labor & Welfare, to implement
the final guidelines.
The new ICH paradigm
In 2003, the quality experts in ICH de-
veloped a new vision: “Develop a har-
monized pharmaceutical quality system
applicable across the lifecycle of the
product emphasizing an integrated ap-
proach to quality risk management and
science” (1). This goal led to the creation
of the following Quality guidelines: ICH
Q8 Pharmaceutical Development; ICH
Q9 Quality Risk Management; ICH Q10
Pharmaceutical Quality System, and
the pending ICH Q11 Development and
Manufacturing of Drug Substance (see
cover story in this issue for details).
These guidelines represented meth-
odologies addressing the challenges of
the pharmaceutical industry with re-
gard to emerging techniques based on
the rapid growth of technology and new
opportunities in drug development and
manufacturing. These guidelines intro-
duced in detail a new quality vision for
industry, one focused on science- and
risk-based concepts and approaches,
and one that emphasized an adequate
quality system. In addition, ICH Q9 was
the first harmonized document appli-
cable to processes performed by both
industry and regulators.
Following these developments, the
ICH Quality Implementation Working
group (Q–IWG) worked out a way to fa-
cilitate harmonized implementation of
this new paradigm. The Q8, Q9, and Q10
guidelines, although independent, are in-
terlinked. As a consequence, implemen-
tation support was needed and provided.
Implementation support
The ICH Steering Committee endorsed
the establishment of the Q–IWG to en-
sure the globally consistent implemen-
tation of ICH Q8, Q9, and Q10, and to
make sure that maximum benefit is
achieved from the interaction between
these guidelines (1). In parallel, Q–IWG
supported the development of ICH Q11
to guarantee a harmonized approach.
As its first deliverable, Q–IWG devel-
oped a Question-and-Answer docu-
ment (Q&A) about the guidelines as
well as enhanced training (2).
Q&As. The Q&A document answers
key questions raised at several confer-
ences and workshops. For example,
clarification of process validation and
continuous process verification are in-
cluded, as are answers related to ques-
tions about quality by design (QbD), in-
cluding design space, real-time release
testing (RTRT), and control strategy.
The series of answers about the pharma-
ceutical quality system focus on inspec-
tion practices, knowledge management,
and software solutions (2).
Training program. Defining how the
ICH Quality guidelines work together
throughout the product lifecycle was
a key goal of the Q–IWG training
and workshop series, held from 2009
to 2011, in Tallinn; Washington, DC;
Ottawa; and Seoul, with participation
from the ICH Global Cooperation
Group and the Asia–Pacific Economic
Community. A case study was devel-
oped for the training workshops to ex-
ICH Q8, Q9, and Q10 support
and implications for the future.
Stephan Rönninger and Sabine Scheitlin
ICH Implementation Support
Ensure the quality
of the product
throughout
its lifecycle by
implementing ICH
Q8, Q9, and Q10.
Stephan Rönninger is deputy topic leader
for EFPIA in the ICH Q–IWG and head
of External Collaboration Europe/Japan/
CEMA at F. Hoffmann-La Roche. Sabine
Scheitlin is operational support manager at
F. Hoffmann-La Roche, both based in Basel,
Switzerland, tel. +41 61 688 69 74.
Pharmaceutical Technology February 2012 53
Inside ICH
plain how a product developed using
a science- and risk-based approach
might be challenged during regulatory
assessment. Postapproval manufactur-
ing implementation, quality system
considerations, and potential thoughts
during inspections were included in the
case-study discussion.
In addition, key messages on design
space, control strategy, pharmaceutical
quality systems, and quality risk man-
agement were discussed through inter-
active sessions among participants and
Q–IWG members. Slides of the presen-
tations are available in English and Jap-
anese (3). During these training work-
shops, participants brought up many
additional questions not addressed in
the Q&A document, which triggered
the need for further clarifications.
“Points to Consider” documents. Q–IWG
therefore developed several “Points-to-
Consider” to further clarify concepts and
practices. The single document, covering
additional Q8, Q9, and Q10 implementa-
tion issues, is meant to supplement the
existing Q&A document and the work-
shop materials (2, 3). The industry and
regulators are encouraged, however, to
use all of these documents together.
The Points-to-Consider document
covers the following key areas.
Criticality of quality attributes and process
parameters. The information developed
to determine critical quality attributes
(CQAs) and critical process parameters
(CPPs) will help to develop the con-
trol strategy, ensure the quality of the
product throughout the product life-
cycle, and increase product and process
knowledge as well as the transparency
and understanding for regulators and
industry evaluating any changes.
The following points could be taken
into consideration for establishing
CQAs and CPPs: the relationship be-
tween risk and criticality, various con-
siderations for identifying and docu-
menting CQAs, possible evolution of
the CQAs and CPPs throughout the
product lifecycle, and the relationship of
criticality to control strategy. The criti-
cal aspect is the high risk of significant
impact to product quality, safety, or effi-
cacy, which requires a degree of control.
Control strategy. The main elements
needed to develop and maintain the
control strategy over the product life-
cycle include continual improvement
and change management. Different
control strategies can be applied for
the same product. As stated in ICH
Q10, knowledge management is a key
enabler. Further details are provided
in the Point-to-Consider document
on the suitability of control strategy
at different scales, specifications and
Certificate of Analysis for RTRT, and
on the process for a deciding when to
release a batch (4).
Level of documentation in enhanced regula-
tory submissions. It is helpful for regula-
tors to have a statement describing
the proposed regulatory outcome and
expectations of a QbD or enhanced
approach, as described in the submis-
sion. It is important to note that every
study performed and/or data generated
during product development does not
need to be submitted to the appropri-
ate regulatory authority. The document
provides details on which studies and
data to consider with regard to risk-
management methodologies, design of
experiments, and the manufacturing
process description (4).
Design space. The Q–IWG training
workshops demonstrated that clari-
fication on how to develop a design
space was also desired by the industry
and regulators. The Points-to-Consider
document therefore addresses the veri-
fication and scale-up of a design space,
documentation of the space, and its life-
cycle management (4).
Role of modeling in QbD. The categoriza-
tion of models is a key part. After de-
veloping and implementing models,
considerations on model validation and
model verification during the lifecycle
conclude with the documentation of
model-related information in a regula-
tory submission.
Process validation/process verification. This
section of the Points-to-Consider docu-
ment provides general considerations
on the continuous process verification
(4). Please note that the the term con-
tinued process verification is used in the
FDA process validation guidance to de-
scribe stage 3 of the life-cycle approach
to process validation (5).
Conclusion
Since the approval of its Quality vision
in 2003, ICH has made available appro-
priate guidance and training material
for the industry and regulators to use in
the implementation of science- and risk-
based approaches to drug development
and manufacturing at the global level. It is
important to read, understand, and think
about the concepts presented in the Qual-
ity guidelines before implementing them.
ICH’s goal is therefore to provide the key
information and considerations needed to
achieve a harmonized approach. The ulti-
mate benefit is for patients in that quality is
built into their products, thereby reducing
the number of complaints, deviations, is-
sues, recalls, and inspection observations.
Acknowledgments
The topics described in this article have
been developed and discussed by mem-
bers of the ICH Quality Implementation
Working Group, namely: Jean-Louis
Robert (rapporteur), Diana Amador-
Toro, Robert G. Baum, Nicholas Cappuc-
cino, David Cockburn, Georges France,
Richard L. Friedman, Nigel Hamilton,
Sabine Kopp, Hirotada Nagai, Yukio Hi-
yama, Takao Kyohara, Fusashi Ishikawa,
Sabine Kopp, Urs Kopp, Akira Kusai,
Yoshihiro Matsuda, Motoaki Mitsuki,
Elaine Morefield, Jacques Morénas, Ma-
satoshi Morisue, Markus-Peter Müller,
Tamiji Nakanishi, Moheb Nasr, Kazuhiro
Okochi, Anthony Ridgway, Rachael
Roehrig, Stephan Rönninger, Swroop Sa-
hota, Hideki Sasaki, Tetsuhito Takarada,
Shigheki Tamura, Krishnan Tirunel-
lai, Mats Welin, and Jean M. Wyvratt.
References
1. ICH Steering committee (Brussels, Belgium,
2003).
2. ICH, Q8, Q9, Q10 Implementation, Question
and Answers (Q&A), November 2010 (www.
ich.org)
3. ICH, Q8, Q9, Q10 Implementation, Training
material, November 2010 (www.ich.org).
4. ICH, Q8, Q9, Q10 Implementation, Points to
Consider, December 2011 (www.ich.org)
5. FDA, Guidance for Industry: Process Valida-
tion: General Principles and Practices (Rock-
ville, MD, 2011). PT
54 Pharmaceutical Technology February 2012 Phar mTech. com
OUTSOURCING OUTLOOK
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PharmTech.com/outsource
T
he biopharmaceutical industry is
starting 2012 with good reason for
optimism. Based on preliminary
results from BioPlan Associates’ 9th An-
nual Report and Survey of Biomanufac-
turing, biologics manufacturers and their
vendors are spending more, demand-
ing better technologies, and expressing
greater optimism than at any time in the
nine years we have been assessing this
industry. This year the BioPlan study
finds substantial optimism, with 37.3%
of suppliers indicating that their company
did either “better” or “much better” than
expected in 2011. Even more relevant,
49.4% expect they will do “better” or
“much better” in 2012.
Industry growth rates
Sales growth among vendors is a leading
indicator of the overall performance of
the bio/pharmaceutical industry because
vendor sales are derived from demand for
materials for biologics production. If ven-
dors are doing well and are optimistic for
the future, the bio/pharmaceutical indus-
try is likely to follow. Supplier respondents
indicated that, on average, sales growth is
currently at approximately 14% annually,
up from 13.0% in 2010 and 14.1% in 2007.
Biopharma’s budget trends
Budgets also are a good indicator of in-
dustry strength, and budget estimates
for 2012 are up strongly in areas such as
acquisition of new technologies, capital
equipment, and personnel training and
development. Early results from the
2012 BioPlan survey projects increases
in all 12 areas, except for outsourcing
(see Figure 1).
Macro trends
These overall trends are in large part re-
sulting from global shifts that continue
to drive the bio/pharmaceutical industry.
Below are trends we project in 2012 spe-
cifically relating to biomanufacturing.
Internationalization. The biopharma-
ceutical industry continues to expand
globally. Growth is driven by the need
for prudent expansion of infrastruc-
ture, presence in new markets, and cost
savings through outsourcing and off-
shoring, including R&D, which is tradi-
tionally performed in established high-
technology regional clusters.
Biomanufacturing capacity also is
increasing outside established markets.
Although the US and Western Europe
remain the leaders in biopharmaceuti-
cal manufacturing capacity, more than
37% of bioreactor capacity is operating in
other parts of the world, including nearly
10% in Japan and the Pacific Rim, 9% in
China, and more than 8% in India (2).
Western product developers also are join-
ing with local companies, such as in the
local manufacture of vaccines. As more
biopharmaceutical manufacturing is per-
formed worldwide, product developers are
working to standardize their products and
manufacturing processes, which involves
simplifying their manufacturing pro-
cesses, so they can be reliably performed
with consistent product produced even in
facilities in lesser developed counties.
Single-use manufacturing. The trend to-
ward more global standardized manu-
facturing is contributing to the adoption
of single-use/disposable bioprocessing
equipment, which allows the same manu-
facturing systems to be shipped and in-
stalled at multiple facilities. Some compa-
nies, with major vaccine manufacturers
among the leaders, are starting to think
more in terms of selling full manufactur-
ing and technology packages, including
all needed equipment and technology
transfer, not just finished end-products,
to foreign countries that are seeking
local manufacture of vaccines for do-
mestic distribution. Companies, such as
GE and Biologics Modular, for example,
are developing fully modular, drop-in-
place-type and equipment preinstalled or
simply installed single-use bioprocessing-
based facilities to address the interest for
prepackaged biopharmaceutical manu-
facturing facilities.
Biomanufacturing Outlook
Industry optimism is on the rise for 2012.
Eric Langer
Eric Langer is
president of BioPlan
Associates, tel.
301.921.5979, elanger@
bioplanassociates.com,
and a periodic
contributor to
Outsourcing Outlook.
Figure 1: Average change in biomanufacturers’ budgets (2009–2012).
New technologies to improve efficiencies/costs for
downstream production
New technologies to improve efficiencies/costs for
upstream production
New capital equipment
Training for operations staff
-0.6%
6.8%
6.4%
4.2%
2.5%
6.3%
6.0%
1.6%
6.1%
6.2%
3.3%
6%
5.3%
Average Budget Change 2012
Average Budget Change 2011
Average Budget Change 2010
Average Budget Change 2009
5.2%
3.7%
1.7%
-7% -5% -3% -1% 1% 3% 5% 7%
Source: Preliminary data of the 9th Annual Report and Survey of
Biomanufacturing, BioPlan Associates (Rockville, MD), publication date April 2012.
Average budget change by percentage
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1. 8ôô. 0ALL. 0PT º www. 0PTLA8S. 00N º SAh AhT0h| 0, TX º LAKFw000, hJ
© Copyright 2010 DPT Laboratories, Ltd. All rights reserved.
DPT is the contract development and manufacturing organization (CDMO) that specializes in sterile
and non-sterile semi-solid and liquid dosage forms. With unmatched technical expertise and fully
integrated drug development and manufacturing services, we can help you successfully develop
and commercialize your next product. Partnering with DPT gives you a seamless transition
from pre-formulation to clinical supplies to commercial supply. After all, keeping it all together
is what sets us apart. To get started, visit us at www.dptlabs.com or call 1.866.CALL.DPT.
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56 Pharmaceutical Technology February 2012 Phar mTech. com
Outsourcing Outlook
Single-use bioprocessing technologies.
In 2011, single-use/disposable biopro-
cessing systems further increased their
dominance for the manufacture of bio-
pharmaceuticals for preclinical R&D
and clinical testing. Single-use sys-
tems dominate noncommercial-scale
biopharmaceutical manufacturing in
most regions. Single-use systems are in-
creasingly being adopted for upstream
manufacturing, such as adoption of sin-
gle-use bioreactors and other upstream
equipment. Despite dominance within
precommercialization manufacturing
segments, single-use systems remain
a relatively small market compared to
fixed stainless-steel equipment, cap-
turing only approximately 10% of the
overall bioreactor market. Stainless steel
remains the preference for commercial
GMP manufacturing. In as short as 10
years (approximately about how long it
takes a biopharmaceutical to reach the
market), half or even more of new com-
mercial biopharmaceutical manufactur-
ing systems can be expected to be largely
or fully single-use based.
Microbial manufacturing. Most industry
attention in recent years, including block-
buster products and manufacturing tech-
nology development, has concentrated on
recombinant proteins produced by mam-
malian cell culture. Mammalian cell-
culture capacity and facilities continue to
dominate worldwide biopharmaceutical
manufacturing (2). Microbial manufactur-
ing remains relatively stable with few new
technologies and few major bioprocessing
equipment developers announcing novel
devices. A confluence of trends, however, is
contributing to increased use of microbial
(i.e., bacteria, yeasts, and other fungi) host
cells for recombinant-protein manufacture.
Outsourcing. Companies of all sizes
worldwide continue to increase their out-
sourcing, particularly R&D and manufac-
turing. These activities include increasing
the use of CROs, particularly for high-
throughput screening, lead identification,
toxicological studies as well as greater use
of CMOs for commercial manufactur-
ing. Based on the BioPlan annual survey
that evaluates 24 outsourced activities,
the primary outsourced activities include
product-characterization testing, with
70% of biopharmaceutical companies
outsourcing at least some of this activity.
Other tasks routinely outsourced include
validation services (69% of biomanu-
facturers cited), toxicity testing (65%),
analytical testing/bioassays (61.1%), and
fill–finish operations (60.0%). Relatively
few companies have outsourced all of
their manufacturing, but nearly one-half
of surveyed manufacturers expect to in-
crease their budgets for biopharmaceuti-
cal CMO outsourcing.
References
1. BioPlan Associates, 8th Annual Report and
Survey of Biopharmaceutical Manufactur-
ing Capacity and Production: A Survey of
Biotherapeutic Developers and Contract
Manufacturing Organizations (Rockville,
MD, April 2011).
2. BioPlan Associates, Top 1000 Global
Biopharmaceutical Facilities Index,
www.top1000bio.com/index.asp, accessed
June 20, 2011. PT
For additional analysis on biopharmaceutical product
approvals and other trends, see the expanded version of this
article at www.PharmTech.com/outsourcing .
contin. from p. 41
this constant flow mode, as opposed to
operating at high initial pressure and al-
lowing flux to decay as the filter plugs.
With adjuvanated vaccines, or similar
products at risk for reduced bacterial re-
tention efficiency, preliminary filterabil-
ity trial performed at the initial stages of
process developments can identify filters
providing the highest level of sterility
assurance for further formulation or
process optimization, perhaps including
limited microbial challenges to confirm
initial suitability. Further filterability
studies can then focus on optimizing pro-
cess time and economy under operating
parameters known to further increase
bacterial retention likelihood with these
highest assurance filters. This will maxi-
mize both retention and throughput to
provide for successful sterilizing filtra-
tion, validation, and processing.
Koklitis (3M): As mentioned, the care-
ful management and control of the oper-
ating conditions during process filtration
is usually advantageous for achieving con-
sistency and robustness. In addition, the
choice of filter membrane type can can
contribute to maintaining a consistent
flow. An asymmetric membrane struc-
ture, with a more open upstream zone,
can provide a relatively higher initial flux,
for example, which results in higher filter
capacity for some process streams.
A higher filter surface area can be
obtained per cartridge cylinder by se-
lecting products that use advanced
pleat technologies, thus enabling higher
throughput without increasing filter-
system size. This approach may help
with filtering highly viscous process
streams, such as emulsions.
Powell (Asahi): Large areas of mem-
brane is the brainless solution, but
working with filter vendors and doing
DOE-based filter screening under the
desired, “high stability” API conditions
is the better choice.
Just like in horse racing, where some
horses perform better than others on dif-
ferent courses, choosing the right filter type
or perhaps a cascade of filters can solve the
problem and provide a balanced solution to
your filtration problem. If your feed con-
taminant is primarily a slowly precipitat-
ing molecule of some sort, a relatively small
coarse filter such as a 1 μm or 5 μm might
be able to trap it and allow a medium-sized
sterile grade filter handle the higher flow
rate and process larger volumes.
Depth filters often provide significantly
higher capacity than membrane filters so
placing them upstream of a sterile grade
filter is often a good idea when possible.
As with any filter, but especially depth
filters, a study of undesired reduction (by
binding) in solution components should
be considered. Find a balanced approach
to this cascade of filters, with each filter
sized appropriately to deal with and con-
trol the specific contaminant that causes
the processing roadblock. PT
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INDUSTRY PIPELINE
58 Pharmaceutical Technology FEBRUARY 2012 Phar mTech. com
MANUFACTURING EQUIPMENT & SUPPLIES
MANUFACTURING EQUIPMENT & SUPPLIES
MANUFACTURING EQUIPMENT & SUPPLIES
INDUSTRY PIPELINE IN U T Y P E Y INDUSTRY PIPELINE
Tablet press
Fette Compact-
ing America’s
FE55 tablet press
is equipped to
handle 90%
of common
tablet formats.
The FE55 can
produce single-
and double-layer tablets and perform direct
pressing. The unit features punch stations
that allow for a 50% output increase. Fette
Compacting America, Rockaway, NJ • www.
fetteamerica.com • tel. 973.586.8722
Pharmaceuti-
cal robot
The Stericlean
robot automates
processes in isola-
tor and cleanroom
environments. De-
signed to protect
staff and products,
the robot fully
withstands decon-
tamination with vapor hydrogen peroxide.
Stäubli Robotics offers various solutions for
aseptic automation. Stäubli Robotics, Duncan,
SC • www.staubli.com • tel. 800.257.8235
Mixing technol-
ogy resource
The Ross “Mix-
ing Technology
Insights” resource
provides tips and
techniques on dis-
persion, dry blend-
ing, emulsification,
homogenization,
particle-size re-
duction, high-viscosity mixing, sub-surface
powder induction, sanitary mixing, and other
topics. Each two-page bulletin includes a
sample application or mixer installation from
various industries. Ross, Charles & Son Company,
Hauppauge, NY • www.mixers.com • tel.
800.243.ROSS
Capsule
filters
Meissner’s CS/
CL capsule fil-
ters for process-
ing applications
are available
with membrane media in polyvinylidene fluo-
ride. The filters also are available in microfiber
media of glass fiber and pure polypropylene,
and pure polypropylene depth-filter media.
Connection options include sanitary flange,
hosebarb, and male and female national pipe
thread fittings. The capsules can be used inde-
pendently or integrated into single-use biocon-
tainer and tubing assemblies. Meissner Filtration
Products, Camarillo, CA • www.meissner.com •
tel. 805.388.9911
Visual-observation tool
The APK visual-observation tool is suitable for
random-sampling manual inspection. Users
can program spin speed according to liquid
viscosity or container diameter, thus provid-
ing repeatable rotation speed and duration
for inspected containers. The APK allows the
human eye to detect foreign particles easily.
Eisai Machinery USA, Allendale, NJ •
www.eisaiusa.com • tel. 201.746.2111
Fluid-bed
dryer bags
Kavon provides
custom replace-
ment fluid-bed
dryer bags for
US and Euro-
pean equip-
ment models. The bags are appropriate for
wet granulation, dry filtration, and wet and
dry coating applications. The company offers
flexible 1–4-bag systems in various fabrics
and also repairs bags.
Kavon Filter Products, Wall Township, NJ •
www.kavonfilter.com • tel. 732.938.3135
Double planetary
mixers
Ross’s double planetary
mixers perform heavy-
duty mixing applica-
tions and can accom-
modate viscosities
of approximately
6 million cP. Their vertical mixing design
enables operators to bypass shaft seals, bear-
ings, packing glands, or stuffing boxes in the
product zone. In addition, the agitators are
raised and lowered into and out of the mix
vessel by a hydraulic lift, thus enabling easy
access for cleaning between batches.
Ross, Charles & Son Company, Hauppauge, NY •
www.mixers.com • tel. 800.243.ROSS
Powder-flow tester
Brookfield’s powder-
flow tester provides
efficient analysis of
powder-flow behavior.
The unit is suitable for
manufacturers who
process powders daily
and want to minimize or
eliminate the downtime
and expense that occurs
when hoppers and silos fail to discharge. Cus-
tomers can perform quality-control checks
on materials, characterize new formulations,
and match established products. Brookfield
Engineering Laboratories, Middleboro, MA •
www.brookfieldengineering.com •
tel. 800.628.8139
Aseptic disconnector
Sartorius offers a single-use device that al-
lows the aseptic disconnection of silicone
tubing in biopharmaceutical manufacturing
processes. Qualified by extensive validation
work, the device offers a rapid and secured
disconnection of single-use transfer lines and
bag assemblies in classified and nonclassified
environments, while maintaining product
sterility. Sartorius Stedim Biotech, Bohemia, NY •
tel. 800.368.7178 • www.sartorius-stedim.com
INDUSTRY PIPELINE
Pharmaceutical Technology FEBRUARY 2012 59
INDUSTRY PIPELINE IN D U ST R Y P I PELIN E Y INDUSTRY PIPELINE
MANUFACTURING
EQUIPMENT & SUPPLIES
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
Plunger-rod-inserting machine
The Hasta plunger-rod-inserting
machine is available in speeds of 12,000 or
24,000 pieces/h. The unit has the flexibility
to interface with upstream and downstream
machines, can be customized for additional
capabilities, and is pre-engineered to add a
backstop-inserting unit to the syringe.
MG America, Fairfield, NJ • www.mgamerica.
com • tel. 973.808.8185
Contract services
Metrics is a respected contract pharmaceu-
tical research, formulation, development,
and manufacturing company. Offering
first-in-man (FTIM) development and Phase
I–III clinical-trial materials (CTM), Metrics
has conducted more than 120 FTIM stud-
ies for various chemical entities in the past
five years while producing more than 700
batches of CTM. Metrics, Greenville, NC •
www.metricsinc.com • tel. 252.752.3800
Contract
services
Patheon is a
leading provider
of contract
development
and manufac-
turing services
to the global pharmaceutical industry. The
company supplies products and services to
approximately 300 of the world’s leading
pharmaceutical and biotechnical companies.
Patheon’s fully integrated worldwide net-
work helps ensure that customer products
can be launched anywhere in the world.
Patheon, Research Triangle Park, NC •
www.patheon.com • tel. 905.821.4001
Job-focused
training
PDA’s Training
and Research
Institute pro-
vides intensive,
job-focused
training that clients can apply immediately.
The curriculum is designed to foster profes-
sional development in areas such as aseptic
processing, biotechnology, environmental
monitoring, filtration, microbiology, quality,
regulatory affairs, training, and validation.
Courses can be customized and provided at
the client’s location. Parenteral Drug
Association, Bethesda, MD • www.pda.org •
tel. 301.656.5900
Lyophiliza-
tion
DSM offers a
lyophilization
system with
the precision to
serve demand-
ing cycles. DSM’s
lyophilizers are equipped with LyoAdvantage
software for cycle control, which provides the
accuracy necessary for high-value products.
The system enables scale-up from an 8-ft
2

unit that does not comply with good manu-
facturing practice to any commercial unit.
DSM Pharmaceuticals, Greenville, NC • www.
dsmpharmaceuticals.com • tel. 252.707.4376
Manufactur-
ing and pack-
aging services
Pharma Tech
Industries offers a
brochure that de-
scribes its pharma-
ceutical manufac-
turing and pack-
aging services,
its facilities in
Georgia and Missouri, and its technical capa-
bilities. The brochure also includes customer
testimonials from global pharmaceutical
leaders and photos of its facilities, machinery,
and dedicated employees. Pharma Tech
Industries, Royston, GA • www.pharma-tech.
com • tel. 706.246.3555
Outsourced services
Coating Place is a leader in services from
Wurster fluid-bed formulation development
to commercial manufacturing. The company
performs bead layering, extrusion–
spheronization, roller compaction, and
capsule filling and tableting. Coating Place
processes both solvent and aqueous formula-
tions. Its facilities are registered with the US
Food and Drug Administration.
Coating Place, Verona, WI • www.encap.com •
tel. 608.845.9521
Contract services
Mikart has provided contract development,
manufacturing, and packaging services to
the pharmaceutical industry since 1975. The
company’s capabilities include formulation
development; analytical services; solid- and
liquid-dose manufacturing; packaging in
bottles, blisters, and multilaminate pouches;
project management; and regulatory ser-
vices. Mikart, Atlanta, GA • www.mikart.com •
tel. 888.4 MIKART
Low relative-humidity enclosure
UPM Pharmaceuticals has incorporated a vali-
dated, low relative-humidity enclosure into
its Xcelodose 600 encapsulator. This custom-
designed chamber can be used at relative hu-
midities in the single digits. UPM successfully
completed several research and manufactur-
ing projects with the enclosure and added it
to its manufacturing capabilities. UPM Pharma-
ceuticals, Baltimore, MD • www.upm-inc.com •
tel. 410.843.3738
INDUSTRY PIPELINE
60 Pharmaceutical Technology FEBRUARY 2012 Phar mTech. com
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
IN U T Y P E Y INDUSTRY PIPELINE
CLEANROOM EQUIPMENT & SUPPLIES
PACKAGING EQUIPMENT & SUPPLIES
LABORATORY EQUIPMENT &
SUPPLIES
Drug-development
services
Vetter’s development
service provides support
for drug-development
projects from inception
to market launch. The
services include clinical
manufacturing at facilities in Chicago and
Europe with scale-up and transfer to Vetter’s
large-scale manufacturing facilities. The
services provide primary- and secondary-
packaging development, process develop-
ment, clinical manufacturing, pharmaceutical
analysis, and regulatory affairs services.
Vetter Pharma International USA, Skokie, IL •
www.vetter-pharma.com • tel. 847.581.6888
Contract
services
SGS Life Science
Services provides
clinical research
services and
quality-control
testing. SGS pro-
vides clinical-trial
management (Phase I to IV) and services
encompassing bioequivalence studies, bio-
analytical services, data management, bio-
metrics, and regulatory consultancy. Quality-
control services include analytical chemistry,
microbiology, and toxicology tests that meet
regulatory compliance. SGS Life Science Ser-
vices, Fairfield, NJ • www.sgs.com/lifescience •
tel. 866.SGS.5003
Lyophilization services
Hospira’s One 2 One business is a leading
contract manufacturing organization special-
izing in injectable fill–finish services. The
company meets clients’ global manufactur-
ing and supply demands with lyophilization
capabilities at its three facilities located in
Kansas, Milan, and Melbourne. Hospira One 2
One, Lake Forest, IL • www.one2onecmo.com •
tel. 224.212.2267
Pharmaceutical services
WellSpring Pharmaceutical is a full-service
provider of clinical and commercial manu-
facturing and packaging, blinding, method
development, analytical testing, and distribu-
tion services. Highly qualified managers and
technical professionals work at the compa-
ny’s 100,000-ft
2
facility to ensure that clients’
clinical and commercial products meet high
standards. WellSpring Pharmaceutical Canada,
Oakville, Canada • www.wpcoutsourcing.com •
tel. 866.337.4500
Formulation-
development
options
Xcelience
provides several
formulation-
development
programs that
enable a fast,
cost-effective path to proof of concept. The
company sometimes can reduce the time
to first-in-human trials by 45% compared
with traditional formulation development.
Xcelience’s programs aim to provide advan-
tages through the company’s combination
of expertise, innovation, and quality systems.
Xcelience, Tampa, FL • www.xcelience.com •
tel. 813.286.0404
Sterile wipes
Veltek offers sodium-hypochlorite and
hydrogen-peroxide wipes that are Class 10
laundered, filtered at 0.2 µm, and formulated
with US Pharmacopeia water for injection.
The products have laser-cut edges and are
guaranteed to be sterile with lot-specific
documentation. Veltek, Malvern, PA •
www.sterile.com • tel. 610.644.8335
Transfer
packaging for
prefillable syringes
BD TSCF packaging
ensures the secure
transfer of sterile prefill-
able syringe components into the pharma-
ceutical filling environment. The packaging
is compatible with IDC Biosafe doors for
aseptic filling machines within isolator or bar-
rier systems. This packaging is part of the BD
SCF global offer, which features expertise in
sterile processing of preservative-free drugs;
secure, reliable, easy-to-use systems; and
drug master files and technical dossiers.
BD Medical–Pharmaceutical Systems,
Franklin Lakes, NJ • www.bdpharma.com •
tel. 800.225.3310
Packaging
solution
The NextBottle
package from
Catalent and
One World
Design and
Manufactur-
ing Group is
designed to improve patient compliance.
The product’s dial mechanism dispenses
one pill at a time and automatically reminds
patients of the last day that a pill was taken.
Catalent Pharma Solutions, Somerset, NJ •
www.catalent.com • tel. 866.720.3148
Metal-detection systems
CEIA’s THS/PH21N metal-detection systems
feature high detection sensitivity for con-
taminating ferrous, nonferrous, and stainless-
steel metals, even when the metals are pres-
ent in small quantities. When contamination
is detected, the system rejects the identified
material. The system’s failsafe operation
monitors the opening and closing of the ejec-
tion flap through a redundant conformation
sensor. CEIA USA, Twinsburg, OH • www.
ceia-usa.com • tel. 888.532.CEIA
INDUSTRY PIPELINE
Pharmaceutical Technology FEBRUARY 2012 61
IN D U ST R Y P I PELIN E Y INDUSTRY PIPELINE
LABORATORY EQUIPMENT & SUPPLIES
LABORATORY EQUIPMENT & SUPPLIES
CHEMICALS, RAW MATERIALS, INTERMEDIATES, & EXCIPIENTS INFORMATION TECHNOLOGY
Modular block
heaters
Cole-Parmer Stable-
Temp modular block
heaters offer the flex-
ibility to heat various
sizes of microtubes, centrifuge tubes, vials,
microplates, and polymerase chain reaction
strips or tubes. The heaters are designed
to handle the incubation and activation of
cultures, enzyme reactions, immunoassays,
melting and boiling points, and various other
laboratory procedures. Each digital or analog
heater accepts more than 40 interchange-
able heating blocks that accommodate
sample enclosures. Cole-Parmer, Vernon Hills,
IL • www.coleparmer.com • tel. 800.323.4340
Chromatography
products catalog
Restek’s 2011
“Chromatography
Products” catalog
celebrates the com-
pany’s 25th anniver-
sary with 800 pages
of chromatography
products. The
catalog includes
columns, replacement parts, tools, and ac-
cessories for gas and high-performance liq-
uid chromatography. Restek Chromatography
Products, Bellefonte, PA • www.restek.com • tel.
814.353.1300
Chemical-
reaction monitor
The MB-Rx is an
in-situ chemical-
reaction monitor
designed for labo-
ratories and pilot
plants. Its plug-and-
play functionality
provides chemists
with real-time insight into chemical or bio-
chemical reaction kinetics and key param-
eters. Experiment data are collected with
an insertion probe and can be analyzed on-
the-fly by a software interface. The device
offers analytical performance, and does not
require maintenance. ABB, Quebec, Canada •
www.abb.com/analytical • tel. 418.877.2944
Multiplate
HPLC
autosampler
Shimadzu’s SIL-
30ACMP UHPLC
autosampler
enables users
to configure a complete high-speed LC/
MS/MS system capable of analyzing mul-
tiple samples accurately. It provides low
carryover of 0.0015% or less, minimizing
sample contamination, and a cycle time of
14 seconds. It can hold up to six plates for
increased capacity.
Shimadzu Scientific Instruments, Columbia, MD
• www.ssi.shimadzu.com • tel. 800.477.1227
Laboratory blenders
MaxiBlend and MiniBlend laboratory blend-
ers are available in sizes from 0.5 to 16 qt. The
units are made of 316-L stainless steel and
supplied with V-shells, bins, or double cones.
The units feature a tabletop design and
include programmable logic controls and
safety-interlocked guards. GlobePharma, New
Brunswick, NJ • www.globepharma.com •
tel. 732.819.0381
On-line TOC analysis
To help pharmaceutical companies improve
quality and reduce costs, GE Analytical In-
struments offers a science- and risk-based
program for achieving real-time release of
pharmaceutical water. The program stream-
lines a complex process and helps companies
move total organic carbon testing from the
laboratory to the production floor in approxi-
mately six months. GE Analytical Instruments,
Boulder, CO • www.geinstruments.com •
tel. 800.255.6964
Lactose
LubriTose is a self-lubricating lactose that
offers excellent excipient performance with-
out the need for magnesium stearate, thus
eliminating overblending and production
slowdowns. The product is intended to allow
tablet manufacturers to run large batch sizes
at high speeds for long periods of time and
achieve reliable results. Sheffield Bio-Science,
Norwich, NY • www.SheffieldBioScience.com •
tel. 800.833.8308
Excipients
DFE Pharma is a provider of excipient
services, specializing in the development,
production, and marketing of excipients for
oral solid-dose and dry powder-inhalation
formulations. The company now combines
the former brand names of DOMO-pharma
and DMV-Fonterra Excipients. DFE Pharma,
Goch, Germany • www.dfepharma.com • tel.
+49 2823 9288 770
Punch-
inspection
system
Natoli’s LVS
500 system
uses dual-laser
technology to
provide instant noncontact inspection of
punches, and interfaces with the Tool Man-
agement II (TM-II) database application for
automatic inspection data storage and analy-
sis. The LVS does not have moving parts, thus
requiring minimal maintenance.
Natoli Engineering Company, St. Charles, MO •
www.natoli.com/software • tel. 636.926.8900
Phar mTech. com
PRODUCTS AND SERVICES SHOWCASE
62 Pharmaceutical Technology FEBRUARY 2012 Phar mTech. com
EQUIPMENT & SUPPLIES
OUTSOURCING RESOURCES
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this page
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Analytical Answers
Deformulation (Reverse Engineering)
Particulate Identification
Contaminant Identification
Custom Synthesis
Litigation Support
Have a question? Call 866.470.9602 to
solve your non-routine analytical challenges.
www.chemir.com
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SEALS
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Ask about our RSVP Design Assistance Program.
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custom-built, fabric-reinforced, elastomeric inflat-
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capability, they’re widely used in mixing, drying,
cooling, granulating, coating, conveying and other
processing applications. Freedom of design per-
mits odd and unusual shapes. Compounds in food
grade white, gray and black are certified to be in
compliance with FDA regulations.
Look to
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Pharmaceutical Technology FEBRUARY 2012 63
Mixing/Blending/Drying
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LAB EQUIPMENT
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CHEMICALS/EXCIPIENTS/API’S
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The ideal candidate will possess 5-7 years relevant sales experience in API/PI
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Ad Index
Viewpoint
64 Pharmaceutical Technology February 2012 Phar mTech. com
COMPANY PAGE COMPANY PAGE COMPANY PAGE
3M Purification Inc .....................................23
ABB Analytical ........................................... 19
Brookfield Engineering ............................. 18
Cafosa Gum SAU ......................................... 67
Catalent Pharma Solutions ........................68
CEIA ...........................................................25
Cole Parmer Instrument Co ........................ 12
DFE Pharma ....................................Cover Tip
DPT Laboratories ....................................... 55
ExcipientFest ............................................. 27
Fette Compacting America Inc ................... 21
FOSS NIRSystems ....................................... 35
Hospira One 2 One ...................................... 57
Interphex .................................................. 33
Jubilant  Hollister Stier ................................7
Meggle USA Inc. ......................................... 15
Meissner Filtration Products ......................29
Natoli Engineering Company, Inc ............... 17
Patheon Inc ................................................3
PDA ........................................................... 13
Pharmaceutical Technology .........................65
PTXI .......................................................... 31
Restek Corporation ......................................9
Sartorius Stedim North America Inc ........... 39
Sheffield Bio-Science .................................43
Shimadzu Scientific Instruments .................2
Staubli Corporation .....................................8
Suheung Capsule ....................................... 20
Veltek Associates .........................................5
Vetter Pharma International GmbH ........... 11
contin. from page 66
support graduate students, and with little
of the research funding or other support
needed to ensure that faculty can be re-
cruited and sustained in these key areas
of national importance. Is it any wonder
that our universities are filled with PhD
students whose degrees are not suitable for
transition to industry, yet were seduced
into that path by the promise of graduate
stipends? Is it any surprise that industry
is reluctant to hire these individuals who
may need considerable investment to re-
make them into the kinds of professionals
required in today’s highly competitive and
fast-paced environment? We are led to an
unfortunate dichotomy where indus-
try complains that it cannot get enough
trained individuals to meet its needs, yet
unemployment rates from universities are
distressingly high.
At the University of Southern Cali-
fornia, we have had the opportunity
to grow from about a dozen Masters of
Science (MS) students 10 years ago to
a full-fledged International Center for
Regulatory Science, housing not only a
large MS program in regulatory science
but also a professional doctoral pro-
gram, a new MS in the Management of
Drug Development, and several profes-
sional certificates. We have had almost
no evidence of unemployment for our
graduates. My colleagues who direct
regulatory and clinical programs at
other universities have seen similar re-
sults, and we are now meeting annually
to ensure the orderly development of this
new profession. These useful, but expen-
sive, MS programs in regulatory, quality,
and clinical science provide baby steps
in developing new professions that were
barely acknowledged even a decade ago.
Most of these programs educate those
already in industry positions, their
companies willing to help with tuition
reimbursement. We need to do more
to engage our current students who are
disillusioned about today’s employment
outlook, to show them that good jobs do
exist, and that academic programs are
available to prepare them for industry
jobs. In turn, these young people with
this new-found expertise will invigorate
our companies.
Innovation in pharmaceutical technol-
ogy is crucial to reducing costs, increas-
ing product safety, and minimizing drug
shortages. To accomplish such challeng-
ing objectives, we must have an environ-
ment where techniques and standards are
harmonized by individuals whose train-
ing and experience prepares them for ca-
reers in global pharmaceutical technology.
Only these individuals will be able to
assist the improvement of testing, the de-
velopment of standards, and the construc-
tion of thoughtful management methods.
Our ability to put a better educational
system in place is key to our competitive
advantage. Perhaps the time is right to ex-
amine our educational structure to ensure
that it is prepared to help young people
enter the next global century, not the last
nationally-focused one. PT
Remember your
first chemistry set?
We do. Over the last 35 years we’ve been keeping an eye on you, proudly
watching you grow into the most powerful and influential readership in the industry.
We hope that by providing the insights and information you need to achieve your
goals we might have something to do with that success.
C e L e B r aT I N G Y e a r s
35
KEEPI NG YOU CURRENT SI NCE 1977 • www. pharmtech. com
66 Pharmaceutical Technology February 2012 Phar mTech. com
PharmTech.com/view
VIEWPOINT
D
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K
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Frances J. Richmond
I
recently attended the China Interna-
tional Summit of Over-the-Counter
(OTC) Industry Innovation and Devel-
opment, in Boao, China. At that meeting,
the annual sales of OTC products were
reported to have grown by 17% in 2011,
a disappointment to some of the par-
ticipants benchmarking to a growth in
prescription sales that exceeded 20%. In
comparison, growth in sales of prescrip-
tion products in the United States has
slowed to only a few percent annually. I
use these numbers simply to underline
something that we know already—the
structure of the pharmaceutical industry
is globalizing, and fast. This change adds
new stresses to an already stressed system,
in which the regulatory structure of even
one country can create impediments to
the commercialization of new drugs.
The evolution of the Common Tech-
nical Document and other international
standards and guidances have attempted
to improve the path by harmonizing some
aspects of the developmental require-
ments internationally. However, these
efforts are not sufficient. First, the legal
requirements for drug development in
many countries are tied to monographs
and standards in their respective phar-
macopeias, and to amplify the problem,
regulations may reference older versions
of those pharmacopieas. Thus, each coun-
try can require that a company satisfy a
regionally specific set of tests, greatly com-
plicating a global marketing program.
Second, the industry depends on ex-
pert knowledge of a relatively restricted
talent pool. Quality and regulatory de-
partments are in many cases staffed at
the highest levels by individuals who are
approaching retirement, and even these
folks may have limited international ex-
pertise. When they retire, companies will
have great difficulty replacing them.
Since World War II, the US government
has invested huge amounts of funds in re-
search. The National Institutes of Health
budget alone in fiscal year 2011 was about
$30 billion. Almost every university with
a medical school has a large graduate edu-
cation program, with scholarships and
fellowships for anatomists, molecular
biologists, pharmacologists, and neuro-
scientists, all striving to discover the next
breakthrough. By comparison, as admitted
by the former Principal Deputy Commis-
sioner of FDA at a PDA conference, Joshua
Sharfstein, “Investing billions in the for-
mer (basic science) while starving the
latter (regulatory science) is unbalanced,
like a rower with a massive right arm and
a puny left arm. It’s no surprise that the
result is not the forward movement we are
all hoping for.”
However, FDA is not in charge of US
education. Other government agencies
and groups have never been able to come
to grips with the need to formalize educa-
tion for those individuals who will take
new discoveries to market. Perhaps this
is because it has only recently become
apparent that we desperately need a new
generation of regulatory scientists, for-
mulation engineers, GMP experts, and
industrial manufacturing design engi-
neers. Without these experts, we hobble
the competitiveness of our industry.
When medical schools were formal-
ized in response to the Flexner report of
1910 on the state of medical education
in the US and Canada, planners looked
at the skills and knowledge that would
be needed to provide a suitable educa-
tion in a systematic way. This approach
makes sense to product developers.
The process of education is in itself a
product-development initiative, where
the knowledge and experience of the
student are designed and developed in
a way that ensures their suitability to
the role that they will eventually play in
society. However, that kind of system-
atized approach has not been in evidence
for translational science (as that part of
product development between bench
and bedside has come to be called).
What we do see is a small collection
of graduate science programs that are
run often as offshoots of extension or
professional-development programs, with-
out any continuing sources of revenue to
contin. on page 64
New educational programs are key to the
industry’s future and to safe, available drugs.
Saving the Next Generation
of Regulatory Scientists
Frances J. Richmond,
PhD, is a professor
and director, Regulatory
Science Program, School
of Pharmacy, University of
Southern California (USC),
and director of the USC
International Center for
Regulatory Science.
It has recently
become apparent
that we desperately
need a new
generation of
regulatory scientists.
Your opinion matters.
To contribute to this column,
send your proposal to
adrakulich@advanstar.com
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©

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