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PharmTech.com
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
Principles to Drug Substance
Developmentand Manufacture:
Inside ICH Q11
CQAs
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Control and Validation
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4 Pharmaceutical Technology February 2012 PharmTech .com
EDITORIAL
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James P. Agalloco
President,
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Larry L. Augsburger, PhD
Professor, Department of
Pharmaceutics,
University of Maryland
David H. Bergstrom, PhD
COO, NovaDel Pharma Inc.
Phil Borman
QbD Lead & Data Management &
Analysis Manager
GlaxoSmithKline
Rory Budihandojo
Director, Quality Systems Audit,
Boehringer-Ingelheim Shanghai
Pharmaceuticals Co. (China)
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Vice-President
Compendial Science
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Sciences, Finnbrit Consulting
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Strategy, Global Regulatory Affairs,
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Pharmaceutical Consultant,
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CEO, Emerson Resources, Inc.
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Professor Emeritus,
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University of Bern
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Microbiology Network
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Statistician, PharmStat Consulting
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t Sterile
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➲ On PharmTech.comFebruary 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.
reader comment”The dominance of America in
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for more decades,” in response
to the blog “US Still Strong but
Europe Waning in Life-Sciences
Investment.” Join the conversation
on blog.Pharmtech.com
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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.
agent-in-place
14 Shipping with the enemy?
control, a Senior compliance officer
A nickel’s worth of free advice to
the competition could come at the
expense of your bottom line.
washington report
24 FDa and Justice Department address Drug Quality concerns
Jill Wechsler
More collaboration and expanded
oversight aim to compel manufacturers
to follow GMPs.
bio forum
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carl lawton
Debottlenecking downstream
mAb purification.
statistical solutions
32 reducing common cause Variation
lynn torbeck
Where is the variability coming from
and what have we done to minimize it?
inside ich
52 ich implementation Support
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Sabine Scheitlin
ICH Q8, Q9, and Q10 support and
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outsourcing outlook
54 Biomanufacturing outlook
eric langer
Industry optimism is on the rise for 2012.
Viewpoint
66 Saving the next generation of regulatory Scientists
Frances J. richmond
New educational programs are
key to the industry’s future and to
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10 Pharmaceutical Technology FEBRUARY 2012 PharmTech .com
FROM THE EDITOR
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Every 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
PharmTech.com/forum
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12 Pharmaceutical Technology FEBRUARY 2012 PharmTech .com
PHARMTECH TALK
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FDA’s Social Media InsightStephanie Sutton
Dedicated 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 PharmTech .com
Agent-in-PlAce
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PharmTech.com/aipCautionary 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 month’s column, I noted that we discovered that a filter could perform a secondary task,” our GMP Agent-In-Place grimaced. “Guess what, we’ve got another one. In this case, it is a viral-removal f ilter. 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 staff, especial ly the maintenance 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
won’t use any names, but if we do
use your experience in the column,
you’ll receive a Pharmaceutical
Technology T-shirt.
The easy way to make your tablets
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16 Pharmaceutical Technology February 2012 PharmTech .com
In the Field
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IVE
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ES
Upcoming events:
• INFORMEX, Feb. 13–17, New Orleans
• DCAT Week, Mar. 12–15, New York City
• ExcipientFest/IPEC Regulatory Conf.,
Apr. 24–25, San Juan
• BIO Convention, June 18–21, Boston
IndiadReport from:
A. Nai r
The Asian nation is strategizing t o take the lead over its regional com -
petitors in pharmaceutical exports .
With the $12-billion valued Indian pharmaceutical in -dustry expected to grow at an compound annual growt h
rate (CAGR) of 16%, the Indian government plans to capital -ize on the growth potential in an effort to beat the competi -
tion from its Asian counterparts in the generic-drug and AP I manufacturing market . contin. on page 1 8
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18 Pharmaceutical Technology February 2012 PharmTech .com
IN THE FIELD
contin. from page 16Plans 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.
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20 Pharmaceutical Technology February 2012 PharmTech .com
IN THE FIELDIN 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 gainsGeneric-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 powerAlthough 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 PharmTech .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,
IN THE SPOTLIGHT: TABLETING AND GRANULATION
Particle-size analyzer facilitates dry-powder measurementMalvern 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 characterizationThe 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 accuratelyBosch 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 PharmaceuticalScience & 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.
ApplicationsPharmaceuticals ■ Decolorization in production of active pharmaceutical ingredients ■ 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 PharmTech .com
NIK
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PharmTech.com/washrep
The 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 complianceWest 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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CEIA THS/PH21N Very high performance
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26 Pharmaceutical Technology February 2012 PharmTech .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 partnersThe 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 PharmTech .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 collaborative 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 PharmTech .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 stepProtein 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 captureResearchers 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 chromatographyTwo 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.
ConclusionRecent 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,
Recent results set
the stage for single-
use purification
of monoclonal
antibodies.
Debottlenecking downstream mAb purification.
Carl Lawton
Single-use High Capacity membrane Chromatography
21
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textbooks 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 targetAiming 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 consistencyThe 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-yokeMade 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 controlledAlthough 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
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34 Pharmaceutical Technology February 2012 PharmTech .com
ICH 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 Q11The 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 Q11The 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 PharmTech .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 aheadICH 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 PharmTech .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 blockagePharmTech: 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 PharmTech .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 tensionPharmTech: 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: Faotultari
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 × 107 colony forming units of Brevundimonas diminuta per cm2
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 typePharmTech: 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 maintenancePharmTech: 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 PharmTech .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 expandLast 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-ft2 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-ft2 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-ft2 build-ing, houses production and logistics services, including, packaging, testing, and distribution of clinical supplies. The facility has extensive storage capa- IM
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As biopharmaceutical development and commercialization increases, companies are expanding their cold-chain capabilities.
Expanding Capabilities in the Pharmaceutical Cold ChainPatricia 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,
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-ft2 of warehousing (15 to 25 ° C and 65% relative humid-ity) and refrigerated and frozen storage space. A 271,000-ft3 drive-in cold stor-age unit is maintained at temperatures of 2 to 8 ° C, and a 6131-ft3 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 ft2 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-ft2
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 PharmTech .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 expandIn 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 ft2, 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 ft2. 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 m2 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-m2 good-distribution practice (GDP)-compliant warehouse encompasses 21,000 temperature- control led pal let places, includ-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 m2 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-ft2 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 PharmTech .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,
*To whom all correspondence should be addressed.
Submitted: Sept. 19, 2011; Accepted Nov. 28, 2011.
Ad
AM
GA
uLT
/ O
JO
IM
AG
eS
/Ge
TT
y I
MA
Ge
S
Impurities
To 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 impuritiesAn 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
DMFStarting 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. NABH4 is
sodium borohydride. Pd/C is palladium on carbon.
Salmeterol impurity B (EP)
HO
HO
OH H
NO
HO
HO
OH H
NO
Methyl Salmeterol impurity
(Nonpharma impurity)
OH
HOHO
HO
Salmeterol impurity C (EP)
HO
HO
OH H
NO
Salmeterol impurity E (EP)
HO
HO
OH H
NO
OH
(A)
4-Phenyl butanol
1,6-Dibromohexane, NaH
Toluene, TBAB(A)
(A)
Benzylamine
Benzyl amine
base
No Reaction
OO
Compound 1
Intermediate 1
OBr
DMSO, Benzylamine
Triethylamine
Intermediate 1
Intermediate 2
ONH
as known process
No Reaction
O
O
N
Compound 2
Intermediate 3
HO
HO
O
OH H
N
NaBH4, Methanol
Pd/C, Hydrogen
Salmeterol
O O
H
HO
O
ON
OO
H
HO
BrN-N-diisopropyl ethylamine
Methyl ethyl ketone
O
OH H
Compound 3
Cyclohexyl salmeterol impurity
N
HO
HO
Compound 4
OH H
N
HO
HO
AL
L F
IGu
re
S A
re
CO
ur
Te
Sy
OF
TH
e A
uT
HO
rS
48 Pharmaceutical Technology February 2012 PharmTech .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.
IntermediatesOrganic 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
ONHN N
F
Linezolid
N
HOF
NNOO
O
ONHR
F
N
O
O
N
HO
R
F
N
O
O
NH2
HN
N
O
H2NNH
2
N
N
O
NNN
HN
O OO
OHOH
Cl
ClCl
OH
H2N NH
2
N
N
O
O O O O
OH OH
N N N
HN
F F
Cl
H2N
H
2,4-Diamino-6-hydroxy-pyrimidine
N
N
OHH2N
NH
O
NH
COONa
COONa
N
N
H
HO HO
Cl
O O OO
OH OH
N N N
HN
OH
2N
NH
Structure in
literature / patents
pemetrexed disodium
Cipro�oxacin starting material 6-Hydroxy, starting material Impurity
Dichloro, starting material impurity Chloro impurity (RRT 2.1)
(EP method)
Cipro�oxacin Hydroxy impurity F (EP, RRT 0.5)
O
NH
COOH
COOHN
N OH2N
HNH
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.
ByproductsIn 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 1H 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 [C4DABCO][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
NH2
O
CAS No. NA
CAS No. 38091-73-5 Propionaldehyde MalanonitrileCAS No. 55525-92-3
ea
N
NH
CN
CN
NH2
NC CNO
bc d
CAS No. 90323-61-8 CAS No. 52833-34-8
50 Pharmaceutical Technology February 2012 PharmTech .com
inorganic salts in chemotherapy or in combination with other chemotherapeutic agents after in vivo and in vitro testing.
Transformation productsTransformation 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–AlCl2–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 productsThe 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 productsThe 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 impuritiesTautomers 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
HNC CN
Propionaldehyde Malanonitrile
15 - 20 °C, 1 hSulfur
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
NN
NH
2N
NH2
Impurity 1
Condition 1
formed compound
CAS No. NA
OR
NH2
CN
CN
Impurity 2
Condition 2
formed compound
CAS No. 55525-92-3
CAS No. 138564-58-6
Olanzapine
H2N S
NC
H2N NO
2
N
N
N
NHNO
2
NO2
N
N
N
NHNH
Nonpharmacopeial impurities
NO2
CN
CN
NH
H2N NH
2
NN
Impurity 1N1
C1
C2
C3
C4
C5C6
C7C8
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; AlCl3 is aluminum chloride.
Bromo acetyl derivative
HPLC purity 90.43%
1
OH
OH
O
O
O
O
H
H
Br
BrBr
OH O
O
H
Cl
Chloro acetyl derivative
HPLC purity 9.53%
2 1 2
MDC / AICI 3
Re�ux 24 h
MDC / AICI 3
MDC / water
OH
OH
O
O
O
H
H
Br
O
HO
HO
HOH
ON
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 PharmTech .com
INSIDE ICH
PharmTech.com/ich
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The 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 paradigmIn 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 supportThe 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).
ConclusionSince 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.
AcknowledgmentsThe 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 PharmTech .com
OUTSOURCING OUTLOOK
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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 trendsBudgets 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 trendsThese 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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© 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.
With DPT,development and manufacturing piece together seamlessly.
56 Pharmaceutical Technology February 2012 PharmTech .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. 41this 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
Visit PharmTech.com for additional information about oil-in-water emulsions and liposome adjuvants.
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INDUSTRY PIPELINE
58 Pharmaceutical Technology FEBRUARY 2012 PharmTech .com
MANUFACTURING EQUIPMENT & SUPPLIES
MANUFACTURING EQUIPMENT & SUPPLIES
MANUFACTURING EQUIPMENT & SUPPLIES
INDUSTRY PIPELINEIN U T Y P EY INDUSTRY PIPELINE
Tablet pressFette 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 robotThe Stericlean
robot automates
processes in isola-
tor and cleanroom
environments. De-
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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 resourceThe 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
filtersMeissner’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 toolThe 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
mixersRoss’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 testerBrookfield’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 disconnectorSartorius 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 PIPELINEINDU STR Y PIPELIN EY INDUSTRY PIPELINE
MANUFACTURING
EQUIPMENT & SUPPLIESOUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
Plunger-rod-inserting machineThe 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 servicesMetrics 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
servicesPatheon 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
trainingPDA’s Training
and Research
Institute pro-
vides intensive,
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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-
tionDSM 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-ft2
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 servicesPharma Tech
Industries offers a
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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 servicesCoating 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 enclosureUPM 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 PharmTech .com
OUTSOURCING & CONSULTING SERVICES
OUTSOURCING & CONSULTING SERVICES
IN U T Y P EY INDUSTRY PIPELINE
CLEANROOM EQUIPMENT & SUPPLIES
PACKAGING EQUIPMENT & SUPPLIESLABORATORY EQUIPMENT &
SUPPLIES
Drug-development
servicesVetter’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
servicesSGS 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 servicesHospira’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 servicesWellSpring 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-ft2 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
optionsXcelience
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 wipesVeltek 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 syringesBD 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 systemsCEIA’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
INDU STR Y PIPELIN EY INDUSTRY PIPELINE
LABORATORY EQUIPMENT & SUPPLIES
LABORATORY EQUIPMENT & SUPPLIES
CHEMICALS, RAW MATERIALS, INTERMEDIATES, & EXCIPIENTS INFORMATION TECHNOLOGY
Modular block
heatersCole-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 catalogRestek’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 monitorThe 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
autosamplerShimadzu’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 analysisTo 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
LactoseLubriTose 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
ExcipientsDFE 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
systemNatoli’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
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PRODUCTS AND SERVICES SHOWCASE
62 Pharmaceutical Technology FEBRUARY 2012 PharmTech .com
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Ad Index
Viewpoint
64 Pharmaceutical Technology February 2012 PharmTech .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 66support 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
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C e L e B r a T I N G Y e a r s35
KEEPING YOU CURRENT SINCE 1977 • www.pharmtech.com
66 Pharmaceutical Technology February 2012 PharmTech .com
PharmTech.com/view
VIEWPOINT
DO
RL
ING
KIN
DE
RS
LE
Y/G
ET
TY
IM
AG
ES
Frances J. Richmond
Irecently 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
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