I Am Chemical Engineer - Magazine

NOVEMBER 2014 Volume 26 Number 11
Advancing Development & Manufacturing
PharmTech.com
QbD in
Parenterals
Addressing
Particulate
Contamination
MARKET REPORT TECHNICAL Q&A PEER-REVIEWED

Germany Post AMNOG Continuous Manufacturing Sublingual Formulations
magenta
cyan
yellow
black ES522737_PTE1114_CV1.pgs 10.29.2014 21:22 ADV
Controlled Release Alliance
LOOKING TO IMPROVE YOUR

MANUFACTURING EFFICIENCY?
NEW METHOCEL™ DC2 helps you enjoy the
beneÑts o[ dry powder processing
techniques :
• improved powder Òow
• lower manufacturing costs by up to 60%
• shorten development time
• results in more reproducible and robust tablet
properties
• better formulation option for heat and
moisture-sensitive APIs
• no additives, means no regulatory hurdles,
as METHOCELTM DC2 is pure HPMC.
Want to learn more how METHOCEL™ DC2

can help you to [ormulate with cost e[Ñciency
in mind while improving tablet quality.
www.dowpharmasolutions.com
Colorcon works together with Dow Pharma & Food

Solutions through the Controlled Release Alliance
to bring joint resource to accelerate pharmaceutical
product development efforts for controlled release
and reach markets throughout the world.
®�Trademark of The Dow Chemical Company ÅDowÆ or an afÑliated company of Dow.

® The Colorcon logo is a trademark of BPSI Holdings LLC.
magenta
cyan
yellow
black ES522767_PTE1114_CV2_FP.pgs 10.29.2014 22:18 ADV
November 2014
Pharmaceutical Technology europe is the authoritative Advancing Development & Manufacturing
source of peer-reviewed research and expert analyses for

scientists, engineers, and managers engaged in process PharmTech.com
development, manufacturing, formulation and drug

delivery, API synthesis, analytical technology and testing,
packaging, IT, outsourcing, and regulatory compliance Cover: Maria Toutoudaki/Getty Images
in the pharmaceutical and biotechnology industries. Art direction: Dan Ward
18 28 24 30
PharmTech.com
Features Columns and Regulars

COVER STORY 6 Editor’s Comment
24 Parenterals, Particulates and Quality by Design Ebola and the Vaccine Race
The parenteral manufacturing industry is taking
8 Drug Development
action to address particulate contamination issues.
GMP Conformity: A Ukrainian Perspective
TECHNICAL Q&A
12 Outsourcing Review
28 Continuous Solid-Dosage Manufacturing
Outside Looking In
Platform Nears Prototype Installation
A G-Con, GEA and Pfizer collaboration developed a 14 European Regulatory Watch
PCMM (portable, continuous, miniature and modular) Tackling Drug Shortages
system to produce oral solid dosage drugs.
18 European Market Report
FORMULATION AND DRUG DELIVERY Germany Post AMNOG: Insights for BioPharma
30 Injecting Highly Viscous Drugs
41 Troubleshooting
The author reviews the challenges
Using Flow Sensors to Monitor Process System Health
in delivering macromolecule biologics.
44 CPhI RoundUp
CPhI 2014 at a Glance
Peer-Reviewed 46 Corporate Thought Leader Profiles
33 Considerations in Developing
50 Conversation and Community
Sublingual Tablets—An Overview
This review highlights relevant physicochemical 50 Ad Index
drug properties and formulation design
consideration critical to quality and performance
of sublingual tablets. Online Exclusives
API Synthesis & Manufacturing
Advances in Large-Scale Heterocyclic Synthesis
Join PTE’s community www.PharmTech.com/API_Nov14
Join the Pharmaceutical Technology europe group on LinkedIn™* GMPs
and start discussing the issues that matter to you with your peers.
GMPs for Small-Molecule Drugs in Early Development:
Go to PharmTech.com/linkedin
Workshop Summary—Part VI
www.PharmTech.com/GMPs_Nov14
*The linkedIn logo is a registered trademark of LinkedIn Corporation
and its affliates in the United States and/or other countries
Packaging
Anticounterfeiting Packaging 101
www.PharmTech.com/anticounterfeiting_packaging_101
PTE magazine is audited
by the BPA
Pharmaceutical Technology Europe November 2014 3
magenta
cyan
yellow
black ES522816_PTE1114_003.pgs 10.29.2014 22:38 ADV
Published by EDITORIAL ADVISORY BOARD
PharmTech Europe Global Correspondents Kevin Altria Thomas Menzel
Editor Jane Wan Associate Director, Menzel Fluid Solutions AG
Adeline Siew, PhD (Asia, [email protected])
Pharmaceutical Development Jim Miller
[email protected] Sean Milmo
GlaxoSmithKline R&D President,PharmSource
(Europe, [email protected])
PharmTech Group Hellen Berger Reinhard Baumfalk Information Services
Editorial Director (Latin and South America, Vice-President, R&D Colin Minchom
Rita Peters [email protected]) Instrumentation & Control
[email protected]
Vice-President, Particle Design
Sartorius AG Hovione
Art Director
Managing Editor Dan Ward Rafael Beerbohm Clifford S. Mintz
Susan Haigney Head of Quality Systems President and Founder
[email protected] Publisher Boehringer Ingelheim GmbH BioInsights
Michael Tracey
Gabriele Betz Ian Pearson
Manufacturing Editor [email protected]
Jennifer Markarian
Department of Senior Design Team Leader,
[email protected] Sales Manager Pharmaceutical Sciences TSL Projects
Chris Lawson University of Basel, Switzerland
Tim Peterson
Science Editor Tel. +44 1244 629 324 Phil Borman
Randi Hernandez [email protected] Transdermal Product
Manager, GlaxoSmithKline Development Leader, Drug
[email protected]
Senior Sales Executive Rory Budihandojo Delivery Systems Division, 3M
Community Editor Christine Joinson Director, Quality and EHS Audit John Pritchard
Ashley Roberts Tel. +44 1244 629 311 Boehringer-Ingelheim Technical Director
[email protected] [email protected]
Christopher Burgess Philips Respironics
Contributing Editor Managing Director Thomas Rades
Cynthia A. Challener, PhD Burgess Analytical Consultancy Professor, Research Chair in
Ryan F. Donnelly Formulation Desgin and Drug De-
Reader in Pharmaceutics livery, University of Copenhagen
Queens University Belfast Jean Paul Remon
Tim Freeman Ghent University, Belgium
Published by Executive Vice-President,
Advanstar Communications (U.K.) Ltd Human Resources Managing Director Rodolfo Romañach
Honeycomb West, Julie Molleston Freeman Technology Professor of Chemistry
Chester Business Park,
Wrexham Road, Sr Vice-President Filipe Gaspar University of Puerto Rico,
Chester, CH4 9QH, United Kingdom Tracy Harris Director of Drug Product Puerto Rico
Tel. +44 1244 629 300
Fax +44 1244 678 008 Technology, Hovione Beatriz San Martin
Vice-President,
Chief Executive Offcer General Manager Sharon Grimster Senior Associate
Joe Loggia Pharm/Science Group Vice-President, Development Field Fisher Waterhouse LLP
Dave Esola F Star Siegfried Schmitt
Executive Vice-President, Chief
Vice-President, Legal Anne Marie Healy Principal Consultant
Administrative Offcer & Chief
Michael Bernstein University of Dublin, Ireland PAREXEL
Financial Offcer
Tom Ehardt
Vice-President, Media Operations Deirdre Hurley Stane Srcic
Francis Heid Senior Director, Plant Professor
Executive Vice-President
Georgiann DeCenzo Helsinn Birex University of Ljubljana, Slovenia
Vice-President, Treasurer &
Controller Pharmaceuticals Ltd. Griet Van Vaerenbergh
Executive Vice-President
Adele Hartwick Makarand Jawadekar GEA Process Engineering
Chris DeMoulin
Independent Consultant Benoît Verjans
Executive Vice-President,
Business Systems Henrik Johanning CEO
Rebecca Evangelou Senior Vice-President, Arlenda
Compliance, QAtor A/S Andreas Weiler
Editorial: All submissions will be handled with reasonable care, but the publisher assumes no responsibility for safety of
artwork, photographs, or manuscripts. Every precaution is taken to ensure accuracy, but the publisher cannot accept
Marina Levina Global Technical Sales Director
responsibility for the accuracy of information supplied herein or for any opinion expressed. Product Owner-OSD, TTC- SAFC
Subscriptions:
Pharmaceutical Technology Europe is free to qualifed subscribers in Europe.
Tablets Technology Cell, GMS Tony Wright
To apply for a free subscription, or to change your name or address, go to PharmTech.com, click on Subscribe, & follow GlaxoSmithKline
the prompts. CEO
To cancel your subscription or to order back issues, please email your request to [email protected], putting PTE Roberto Margarita Exelsius
in the subject line.
Business Development Director
Please quote your subscription number if you have it.
List Rental: Contact Sarah Darcy; Tel. +44 1244 629 326 Fax +44 1244 659 321
Corden Pharma
Reprints: Reprints of all articles in this issue and past issues are available (500 minimum).
Contact Brian Kolb at Wright’s Media, 2407 Timberloch Place, The Woodlands, TX 77380. Telephone: 877-652-5295 Luigi G. Martini
ext. 121. Email: [email protected].
Chair of Pharmaceutical
Innovation
Copyright 2014. Advanstar Communications (UK) Ltd. All rights reserved. King’s College London
No part of this publication may be reproduced in any material form (including photocopying or storing it in any medium
by electronic means and whether or not transiently or incidentally to some other use of this publication) without
the written permission of the copyright owner except in accordance with the provisions of the Copyright, Designs &
Above is a partial list of the Pharmaceutical Technology brand editorial advisory
Patents Act (UK) 1988 or under the terms of a licence issued by the Copyright Licensing Agency, 90 Tottenham Court
Road, London W1P 0LP, UK. members. The full board, which includes advisory members of Pharmaceutical
Technology North America, can be found online at www.PharmTech.com/EAB.
Applications for the copyright owner’s permission to reproduce any part of
Pharmaceutical Technology publishes contributed technical articles that undergo
this publication should be forwarded in writing to Permissions Dept, Bridge-
gate Pavillions, 4A Chester Business Park, Wrexham Road, Chester, CH4 9QH. a rigorous, double-blind peer-review process involving members of our distin-
Warning: The doing of an unauthorized act in relation to a copyright work guished Editorial Advisory Board. Manuscripts for editorial consideration should
may result in both a civil claim for damages and criminal prosecution. 10% Post
Consumer be sent directly to Susan Haigney, managing editor, [email protected].
Waste
4 Pharmaceutical Technology Europe November 2014 PharmTech.com
cyan
yellow
X-ceptional insights Improved performance thanks
to powerful new components
The Nexera X2 UHPLC system is the perfect • New photodiode array detector
device for routine analysis and applications in designed for ultra-sensitive, low-noise UHPLC
highly regulated environments demanding com- analyses
plex system setups. Its photodiode array detec-
tor provides maximum sensitivity and, therefore, • Compatibility
x-ceptional insights into analyzed compounds. with all major chromatography data systems
and MS software systems
• Increased stability and robustness
due to optimized flow line parts
www.shimadzu.eu
• Expanded flexibility
through support of multiple gradients in a
single system setup
• Complete solution package

of hardware and software for working in
highly regulated environments
magenta
cyan
yellow
black ES522783_PTE1114_005_FP.pgs 10.29.2014 22:19 ADV
EDITOR’S COMMENT
Ebola and the

Vaccine Race
T he Ebola virus was first discovered
in 1976. The New York Times (1)
recently revealed that in 2005, a group
of scientists reported in Nature medicine
that they had developed a vaccine that
protected against the disease when
tested in monkeys (2). However, at that
time, pharmaceutical companies did
not seem interested in pursuing further
development of the vaccine. The lack of market demand back
then did not provide much incentive for R&D investments,
and critics were quick to add that it was also because the
disease only affected poor countries that could not afford to
pay for expensive medicines (1).
The Ebola outbreak in March 2014 marked the turning point.
As the death toll continues to rise, drugmakers are now racing
to develop a vaccine that could control the spread of Ebola.
Clinical trials are underway but while efforts are being made
to speed up the development of Ebola vaccines, there are
challenges ahead and some tough questions to answer.
For example, in an efficacy study, the randomised, controlled
design would mean that one cohort of people does not get
the experimental vaccine. How do you justify not giving the
life-saving vaccine to frontline healthcare workers who are at
risk of catching the disease? In terms of logistics, how do you
ensure proper transportation and cold storage of vaccines in
West African countries with poor infrastructure and no reliable
electricity supply?
And with unproven Ebola vaccines being rushed into
widespread emergency use without full confirmation of their
absolute safety profiles, one can understand why drugmakers
are seeking indemnity against potential losses or claims arising
from the use of these investigational new drugs. Of course,
there will be risks given that pharmaceutical companies are
under pressure to supply experimental vaccines in a matter of
months rather than years. I can’t help but question the fast-track
approach, although it’s probably the right thing to do in this
situation. As the saying goes, “nothing ventured, nothing gained.”
References
1. The New York Times, “Ebola Vaccine, Ready for Test, Sat on the Shelf,”
Press Release, 23 Oct. 2014.
2. S.M. Jones et al., Nature medicine, 11 (7), 786–790 (2005).
Adeline Siew, PhD

Editor of Pharmaceutical Technology europe
[email protected]
magenta
cyan
yellow
VIABLE AIR MONITORING IS
JUST ONETOUCH AWAY
¨
SM A O NETOUCH I CS
A FULLY INTEGRATED PLC CONTROLLED VIABLE MONITORING SYSTEM
FEATURES
PRECISE AND CALIBRATED AIR SAMPLING TO EACH SMA ATRIUM
REAL TIME MONITORING AND CONTROL OF ALL SAMPLE PARAMETERS
IMMEDIATE ALARMING FUNCTION ON ANY SAMPLING LOCATION
FULL INTEGRATION OF FACILITY MAPS AND FLOOR PLANS
LEARN MORE AT WWW.STERILE.COM
V E LT E K ASS O C I AT ES ,I N C
M 1-888-4-STERILE • [email protected]
magenta
cyan
yellow
DRUG DEVELOPMENT: UKRAINE
GMP Conformity:
A Ukrainian Perspective
GMP standards play an increasingly crucial role in ensuring the quality of medicinal products in
Ukraine, but they also have substantial impact on operations of foreign pharmaceutical companies.
Lana Sinichkina is
partner and head of Life T he pharmaceutical market of Ukraine is rapidly
developing in the light of a recently signed
Association Agreement with the European Union
management system and achievement of quality
objectives is borne by the senior management of
the company.
Sciences and Healthcare
Practice, and Leonid and plan of actions regarding European integration • The new edition (3) of UA-GMP clarifies situations
Cherniavskyi is an approved by the government. Harmonisation of when, despite the ban on unexplained overlaps in
associate, both at Arzinger Ukrainian legislation in the field of pharmaceutical personnel responsibilities, certain functions may
Law Office, manufacturing began in 2003 and is led by the State be shared between the head of quality control
http://arzinger.ua. Administration of Ukraine of Medicinal Products and head of production and/or the head of quality
(SAMP). Since then, the SAMP has been constantly assurance or head of the quality unit depending on
implementing the EU requirements of good the size and structure of the company. Such shared
manufacturing practice (GMP), good distribution responsibilities relating to quality may include in
practice (GDP), good storage practice (GSP) and particular the design, effective implementation,
harmonised procedures of inspection of medicinal monitoring and maintenance of the quality
products. GMP and GDP inspectorates successfully management system.
operate within the SAMP. • The qualified person may now be relieved
from performing actions for ensuring that each
Continuing harmonisation production batch imported from outside of Ukraine
with EU GMP standards has undergone, in Ukraine, a full qualitative
The implementation of GMP standards plays an ever analysis, a quantitative analysis of at least all the
growing role in ensuring the quality of medicinal active substances and all the other tests or checks
products in Ukraine but also impacts operations necessary to ensure the quality of medicinal
of foreign pharmaceutical companies. On 16 July products in accordance with the requirements of
2014 the Ministry of Healthcare of Ukraine (MoH) the marketing authorisation (4). Such exception
approved the new edition of the Good Manufacturing may be allowed “in cases stipulated in Ukrainian
Practice Standards (UA-GMP), which is mostly a legislation (inter alia, where importation is made
Ukrainian translation of the EU Guidelines for Good from another state with which Ukraine concluded
Manufacturing Practice for Medicinal Products for an international treaty on measures concerning
Human and Veterinary Use. The changes of the new compliance by medicinal products manufacturers
edition correspond with the respective changes in with GMP standards that are equivalent with the
the EU guidelines, which became effective on 16 Feb. provisions of UA-GMP and provided that necessary
2014, and concern mainly the section “Definition control measures were applied in the exporting
of Terms” and Section 2 “Personnel” of Part I (1). country).” The new edition of UA-GMP requires that
The amendments were made following the needs a qualified person meet the criteria established in
of Ukrainian pharmaceutical industry and took Ukrainian legislation (5).
into account the definitions of terms used in the • Two more responsibilities were added to the list
International Conference on Harmonisation (ICH) Q10 of recommended responsibilities of the heads of
(Spotlight image) Image Source/Getty Images
Pharmaceutical Quality System (2). Some of the production, quality control and, where relevant,
updates and amendments are listed in the following. the head of quality assurance or head of quality
• To the general wording that the “manufacturer unit: participation in management reviews of
should have an adequate number of personnel process performance, product quality, and of
with the necessary qualifications and practical the quality management system; advocating
experience,” the MoH added clarification that continual improvement; and ensuring that
the ultimate responsibility for an effective quality a timely and effective communication and
8 Pharmaceutical Technology Europe NOVEMBER 2014 PharmTech.com
magenta
cyan
yellow
RetaLac®.
Flowable, compactable, wettable.
From Meggle.
RetaLac® the HPMC/lactose co-processed ex- – 50 parts HPMC (K4M) and

cipient enables sustained release formulations 50 parts lactose monohydrate
for direct compression. The benefits speak for – Excellent flowability
themselves. And for RetaLac®: – Significantly easier, faster production
– Active content of up to 60 %
– Outstanding wettability
RetaLac® from MEGGLE:

Makes HPMC directly compressible.
MEGGLE HEAD OFFICE GERMANY

www.meggle-pharma.com
[email protected]
Phone +49 8071 73 476
magenta
cyan
yellow
Drug Development
escalation process exists to raise of confirmation of compliance to confirm the required compliance.
quality issues to the appropriate with UA-GMP standards is applied Furthermore, on 1 Jan. 2013,
levels of management (6). upon manufacturer’s will, in 2011, the requirement to provide the
• The new subsection regarding amendments were introduced to mentioned document confirming
external consultants was the Law of Ukraine “On Medicinal compliance of manufacturing
introduced, requiring that such Products” (Law on Medicines), which conditions with UA-GMP standards
consultants should have adequate required that companies obtain was implemented to the procedure
education, training and experience, the document confirming such of state quality control for imported
or any combination thereof, and compliance. medicinal products. This resulted in a
that records should be maintained In the end of 2011, the Law on ban on import of medicinal products
stating the name, address, Medicines was complemented with in cases when such document could
qualifications and type of service a new requirement to the procedure not be provided.
provided by them (7). of obtaining marketing authorisation Companies that could not obtain
for medicinal products. According the necessary GMP confirmation
Why foreign manufacturers to this amendment, the application from the SAMP for any reason (either
need to prove conformity for marketing authorisation had to did not meet the deadlines or did
with UA-GMP standards be supported, inter alia, with the not pass the SAMP inspection) were
The Procedure on Conducting document issued by the SAMP, unable to import their products to
Certification of Medicinal Products which confirms that the product Ukraine until they managed to obtain
Manufacture (Compliance is produced at manufacturing the necessary confirmation, or in
Confirmation Procedure) concerning facilities that comply with UA-GMP case of failure to obtain one, started
compliance with UA-GMP Standards requirements. It should be noted considering transfer of production to
was approved by the MoH back in that such requirement referred only other manufacturing sites including
2002 and is applied on a voluntary to products produced by foreign local contract manufacturing. There
basis. Although its new edition manufacturers due to the fact that are several examples in 2013–2014
(entered into force in February manufacturing license of local of companies deciding to choose
2013) still stipulates that procedure Ukrainian producers was considered the second option in cases when
Sterility testing made reliable

Celebrate 40 years of excellence
In 2014 we celebrate a landmark in sterility testing – 40 years since we invented
the Steritest™ closed filtration device, which changed sterility testing forever.
Through dedicated research & development we have been instrumental in raising the
industryÕs standards Ð reducing the risk of false positive and negative results, increasing
reliability and improving workflow for microbiologists like you around the world.
We are a one-stop shop that offers an extensive portfolio of quality control products,
as well as preventive maintenance, training, validation support and much more.
www.merckmillipore.com/40years-steritest
Merck Millipore, and the M logo are registered trademarks of Merck KGaA, Darmstadt, Germany.
Steritest is a trademark of Merck KGaA, Darmstadt, Germany.
© 2014 Merck KGaA, Darmstadt, Germany. All rights reserved.
magenta
cyan
yellow
Drug Development
their manufacturers failed to obtain relevant UA-GMP confirmation the reputation and revenues of the
Ukrainian GMP approval. Such document by the SAMP, as well as company in Ukraine.
companies, however, faced and matters of controlling compliance
continue to face substantial gaps in with UA-GMP requirements during References
sales of products in Ukraine (which the term of validity of the named 1. Part I, Guideline “Medicinal Products.
may have been successful before document. The draft also provides Good Manufacturing Practices,”
the ban) because they had not taken for extension of the terms of certain approved by the order of the MoH No.
timely measures to prepare for stages of inspection, leading to 497 dated 16 July 2014, http://ow.ly/
the new requirements to UA-GMP extension of the total time needed CIuV8, accessed 7 Oct. 2014.
compliance confirmation. to obtain the relevant confirmation 2. ICH, Q10 Pharmaceutical Quality
document. Another new requirement System, Step 4 version (June 2008).
Future amendments in is that only a Ukrainian resident may 3. Paragraph 2.1–2.4 “General
UA-GMP and procedure for represent a foreign company during Requirements” of Part I, Guideline
conformity confirmation the procedure of confirmation of “Medicinal Products. Good
As of today, there is a working group UA-GMP compliance before the SAMP. Manufacturing Practices.”
established under the auspices Following the developments 4. Paragraph 2.5 of Part I, Guideline
of the SAMP that is dedicated to in Ukrainian GMP standards and “Medicinal Products. Good
developing GMP-related legislation. compliance, confirmation procedures Manufacturing Practices.”
On 10 Sept. 2014, the SAMP published are important for pharmaceutical 5. Paragraph 2.6 of Part I, Guideline
the draft of the amended procedure companies supplying their products “Medicinal Products. Good
for obtaining the document, which to Ukraine. Failure to adapt Manufacturing Practices.”
confirms compliance with UA-GMP manufacturing facilities or to timely 6. Paragraph 2.9 of Part I, Guideline
requirements. The proposed get the necessary documents from “Medicinal Products. Good
amendments mostly concern regulatory authorities may lead Manufacturing Practices.”
the procedure of inspection of to an inability to obtain marketing 7. Paragraph 2.23 of Part I, Guideline
manufacturing facilities, order of authorisation for a new drug or to “Medicinal Products. Good
adopting the decision to grant the import medicinal products harming Manufacturing Practices.” PTE
Sterility testing made easy

Pioneering excellence with
Steritest™ Symbio Pumps
Merck Millipore is renowned as the pioneer of reliable sterility
testing. Today we are evolving it again, with our new Steritest™
Symbio Pumps – making sterility testing more convenient than
ever before, maximizing safety, and streamlining workflow:
• Compact design to ease operations in laminar flow hoods
and isolators
• Step-by-step operator assistance to ensure test method
reproducibility
• Comprehensive validation and maintenance services to
meet regulatory compliance
www.merckmillipore.com/steritest-symbio
Merck Millipore, and the M logo are registered trademarks of Merck KGaA, Darmstadt, Germany.
Steritest is a trademark of Merck KGaA, Darmstadt, Germany.
© 2014 Merck KGaA, Darmstadt, Germany. All rights reserved.
magenta
cyan
yellow
OUTSOURCING REVIEW
Outside Looking In
European CDMOs want to get into the US market but entry options are limited.
A t the 2014 CPhI trade show, held 7–9 Oct. in Paris,

executives from CDMOs and contract labs whose
operations are solely in Europe expressed their desire
management teams or private equity investors at a
fraction of their replacement value and with contracts
to continue to manufacture legacy products for some
to expand their operations into North America. These period. This has made it relatively easy to enter the
executives, however, were stymied about how to do it. contract services business in Europe, although the
Their interest in North America is not surprising: resulting overcapacity has hurt pricing for contract
opportunities there are much greater than in manufacturing and development.
Europe. There is far more venture capital financing
in North America than in Europe, and the level of Sales and marketing in
Jim Miller is president of
drug development activity is significantly greater. particular can be different in
PharmSource Information
Many European economies are contracting, and North America versus Europe.
government budgets to pay for drugs are under
Services, Inc., and publisher
stress. Further, with its large number of former bio/ Opportunities to acquire facilities on such
of Bio/Pharmaceutical
pharma facilities converted to contract services favourable terms are fewer and further between in
Outsourcing Report,
businesses, Europe experiences price competition North America. Because North America consists
tel. +1.703.383.4903,
in the drug development market that seems more of just two large markets, versus the 20-plus small
Twitter@JimPharmSource,
aggressive than in North America. to mid-size markets in Europe, there weren’t so
[email protected],
many facilities built in the first place, so there have
www.pharmsource.com.
Challenges in entering US market been fewer facilities to divest. As result, European
European companies are challenged on several levels companies looking to enter North America may have
to enter North America. For one thing, European to “pay retail” to acquire a facility or services business.
contractors don’t have a good understanding of the Acquisition valuations of CDMOs in recent years have
North American market. While some may have had an been especially high.
FDA inspection, many haven’t and don’t understand European CDMOs are also hindered by a lack of
FDA requirements and how they differ from European capital necessary to acquire their way into North
requirements. America. They are often poorly capitalised, given that
Further, they have minimal experience in trying their initial buy-in to the industry didn’t require a lot
to sell their services in North America; some may of investment. Further, their low profit margins mean
have one sales representative based in the US, but they haven’t been able to accumulate a significant
many have none. Sales and marketing in particular amount of equity through retained earnings. Also,
can be different in North America versus Europe. For some European CDMOs are employee-owned and
instance, trade show marketing is important in Europe may have particular challenges raising additional
and cold calling is uncommon, but in North America capital without threatening their ownership structure.
it is the other way around. Even if they have sales
representation in North America, European CDMOs Opportunities exist
suffer from low brand recognition and can have a hard The barriers to European entry into the US CDMO
time getting clients to travel overseas for services market are high but not insurmountable. Examples
that are readily available domestically. of European contractors that have successfully
Another challenge for European contractors is established themselves in North America in the
that there is a higher barrier to market entry in North past 10 years include CDMOs Vetter and Almac as
America than they are used to. Most European well as contract labs like SGS and Eurofins. Those
(Spotlight image) Stockbyte/GettyImages
CDMOs were founded as buyouts of facilities that companies, however, had favourable ownership
global bio/pharmaceutical companies wanted to get structures (family trusts or publicly-traded) that
rid of. Facility closures are difficult in Europe because gave them access to adequate capital.
of labour laws and because of fears that mass layoffs Further, it is occasionally possible to acquire
could hurt companies tendering for government drug facilities in North America under favourable terms.
supply contracts. As a result, pharma companies In 2013, European CMO Unither acquired a dose
have been willing to offload unneeded facilities to manufacturing facility with contracts in Rochester, New
12 Pharmaceutical Technology Europe NOvemBeR 2014 PharmTech.com
magenta
cyan
yellow
Outsourcing Review
York, from UCB Pharma; and Fareva languages and cultures, and a wholly view the Irish facilities as far away
was able to acquire a manufacturing different concept of distance. So, for and foreign.
and packaging facility with contracts in instance, North American companies As the bio/pharmaceutical
Richmond, Virginia, from Pfizer in 2011. and contract services industries
It’s also worth noting that North North American consolidate, having a global network
American companies have challenges companies have challenges of facilities, at least in North America
similar to the Europeans’ when similar to the Europeans’ and Europe, has become increasingly
considering entry into Europe. A when considering entry important for competitive success.
common problem has been the failure into Europe. Mid-size European CDMOs and
to realise that Europe is not a single contract labs must figure out how to
market—not even the European have established facilities in Ireland overcome the barriers to their entry
Union—but rather a collection of intended to serve all of Europe, only into North America if they intend to
more than 20 countries with different to learn that continental companies succeed over the long term. PTE
Pfizer Ireland Plant

Receives ISPE Award
The International Society for

Pharmaceutical Engineers (ISPE)
recognised Pfizer Ireland as
the overall winner in the 2014
Facility of the Year Awards
(FOYA) category at the society’s
annual meeting in Las Vegas,
Nevada. FOYA acknowledges the
The Smart Excipient
pharmaceutical manufacturing
industry’s accomplishments
in construction and facility
design and the pursuit of new
technologies.
The focus of Pfizer
Ireland’s Network Strategy
Implementation (NSI) Expansion
Capacity project was the addition
of a new vaccine suite and a
drug substance bioprocess suite.
The new manufacturing suites
included the latest technologies,
such as electronic batch records,
process analytical technology,
and disposable bag processing.
Pfizer Ireland conducted the
project using a lean management
strategy, a 5S program in the
design process, and a Six Sigma
toolkit. The Pfizer Ireland Grange
Castle plant that won the award
is located in Clondalkin, South
County Dublin.
“The society was impressed
with the NSI Capacity Expansion
The new platform excipient for tablets, sachets and more
project and the company’s
• first rate filler-binder properties due to excellent compressibility
ability to effectively manage the
challenges of maintaining supply
• fast and slow disintegrating tablets (chewables, effervescents,
suckables, FDDTs…)
with the demolition of existing
facilities, new construction, • ideal in sachets for direct oral application or dry suspensions
and start-up and integration • outstanding flow and mixing properties
activities,” said Chair of the FOYA • high dilution potential and high content uniformity
Judging Panel James Breen in a • very low hygroscopicity and excellent stability
press release. • GMO-free and non-animal origin
—Randi Hernandez
BENEO-Palatinit GmbH · Phone: +49 621 421-150 · [email protected] · www.galenIQ.com
magenta
cyan
yellow
Sean Milmo
is a freelance writer based in Essex,
UK, [email protected].
Tackling Drug Shortages

Resolving the problem will require more communication between the industry and regulatory bodies.
I ncidents of drug shortages in Europe have been increasing

over the past few years with few signs of an overall reduction
in scarcities across the region. Most of the initiatives to deal
and representatives of the industry and ISPE itself, even
before it was officially published. Its recommendations
focus on the need for manufacturers to improve their
with the issue at the production stage are being taken by the quality systems, use metrics to identify and mitigate
manufacturers themselves. The European Medicines Agency risks, foster a corporate quality culture and for improved
(EMA) and the variety of national competent authorities communication with the authorities on potential shortages.
(NCAs), such as licensing bodies and government ministries “We believe that the industry needs to adopt the proposals in
responsible for drug supplies at the national level, seem the ISPE plan,” John Berridge, ISPE advisor, told Pharmaceutical
content to leave it to manufacturers to put forward proposals Technology Europe. “We would like EMA and NCAs to help us
for dealing with disruption of output at their production plants. make manufacturers aware of the proposals by, for example,
putting details of them on their websites and by joining us in
The industry has been training programmes.”

The Parenteral Drug Association (PDA) is planning to publish
encouraged to develop a technical report on the prevention and management of drug

shortages. Among its suggestions will be the adoption of
its own solutions to concepts on the control of drug shortage risks based on the
criticality of the product and an overall product risk evaluation.
prevent drug shortages The European Federation of Pharmaceutical Industries

Associations (EPIA), the European Generic Medicines
caused by manufacturing Associations (EGA) along with two other pharmaceutical

associations for wholesalers and biopharmaceuticals
and quality issues. producers have been working on an improved process

for communications on shortages. This process would
relate to the way manufacturers inform regulatory
EMA believes that the industry’s risk management tends agencies of “meaningful interruptions of supply” (1).
to be “very reactive rather than proactive.” An agency official EURORDIS, a rare disease patients group, together with
told Pharmaceutical Technology Europe, “Sustained pressure other patients organisations and professional associations,
is needed to bring about a change in a manufacturer’s including those representing community and hospital
approach to quality risk management and supply chain pharmacists, have drawn up a set of proposals, in the form
security.” The agency’s policy has been to encourage “the of a Common Position, on medicines shortages (2). These
pharmaceutical industry to develop its own solutions proposals include a requirement on drug approval applicants
to address the prevention of drug shortages caused by to provide supply shortage risk assessment plans to regulatory
manufacturing and quality issues,” the official added. agencies before gaining marketing authorisation. Manufacturer
Nevertheless, medicine manufacturers want more action and/or marketing authorisation holders (MAH) would have to
on the issue from the European Union and the governments inform the regulatory agencies as soon as a shortage becomes
of the 28 member states. They reckon the problem has to be possible. If a shortage occurs, a calendar of production until
resolved through a broader approach embracing the expected end of the shortage would have to be provided.
manufacturers, distributors, healthcare professionals and
even the patients themselves. An unclear definition of drug shortages
Although there is broad agreement in the pharmaceutical
Recommendations from industry groups sector that the problem of shortages has been worsening in
A number of industry groups have been drawing up or recent years, groups differ in their judgement of the
GLOBE: ZOONAR RF/GETTY IMAGES
are close to finalising proposals for dealing with shortages prevalence and severity of the problem, depending on their
stemming from manufacturing disruptions. Patient position in the supply chain. The European Association of
associations and management consultancies have also been Hospital Pharmacists (EAHP) told Pharmaceutical Technology
making recommendations. Europe that 87% of 600 hospital pharmacists it surveyed
The Drug Shortages Prevention Plan of the International considered it to be a problem, particularly with oncology drugs
Society for Pharmaceutical Engineering (ISPE) was and antibiotics. There is, however, a lack of consistent and
discussed at a meeting in early October 2014, attended in-depth data on shortages mainly because it is collected by
by EMA representatives, national regulatory authorities, national agencies, if at all, and there is no Europe agreement
magenta
cyan
yellow
Unrivaled quality...
by design
Patient safety should be driving your

selection of drug packaging components.
West’s NovaPure® components were
designed to help ensure the efficacy
and safety of your drug. With West,
you have a partner by your side
from discovery to the patient.
Contact West today.

North America +1 800-345-9800
Europe +49 2403 7960
Asia Pacific +65 6860 5879
www.westpharma.com
West and the diamond logo, By your side for a healthier world™
and NovaPure® are registered trademarks or trademarks of West
Pharmaceutical Services, Inc., in the United States and other jurisdictions.
Copyright © 2014 West Pharmaceutical Services, Inc. #8680 •1014
magenta
cyan
yellow
on the definition of a “shortage.” Some NCAs have turned with Pharmaceutical Technology Europe. For quality and
down a request from EMA for the drawing-up of catalogues of manufacturing-related issues to be tackled properly in
drug shortages in their countries because what was meant by relation to shortages, a combination of measures had to be
the term was unclear, especially since the term can have taken, Marechal-Jamil added. In addition to the initiation of
different connotations in different languages. shortage-prevention plans at the corporate level, she said
“We cannot agree on a definition of shortages,” says there had to be a harmonised definition of drug shortage,
Marten Forrest, spokesperson for the Swedish Medical a harmonised shortages reporting process with identical
Products Agency (MPA), explaining why his agency had trigger points, triaging procedures and timelines, as well as
not created a shortages list. “For example, there is the an improved flow of information along the supply chains.
question of what sort of supply difficulties can be referred One key issue yet to be resolved and upon which
to as a ‘shortage’ and whether these difficulties are global, there are divergent views even among the regulators is
European or national,” he continues. “It is difficult to draw the relation between GMP rules and supply disruptions
up a list of medicines shortages without a definition.” caused by weaknesses in quality control systems, which
could lead ultimately to medicine shortages. “Quality
defects are usually caused by some kind of GMP
There is the question failure but not always,” says the EMA official.
However, a different view is taken by some national
of what sort of supply agencies that believe they can deal with production
deficiencies causing supply disruptions without reference to
difficulties can be referred GMP rules. “The obligation to ensure the continuous supply
of medicines so that the needs of patients in the UK are met
to as a shortage. is a condition of a manufacturer’s licence [so] this is not a
GMP matter,” says a spokesperson for the Medicines and
This lack of clarity about what are shortages can lead to Healthcare products Regulatory Agency (MHRA). “MHRA
gaps in the reporting of them or of manufacturing disruptions routinely inspect manufacturers for compliance with the
that could cause shortages. “Not all manufacturers are conditions of their licence and with EU guidance on GMP,”
notifying us about problems they are having which are or he continues. “To date there has been no occasions where
could cause shortages,” said Forrest. “One of the important MHRA has needed to take action against a manufacturer in
signals of existing shortages is phone calls or email messages relation to this obligation (in respect of its licence conditions).”
from pharmacists asking for more information about a Nonetheless, ISPE reckons there is a close enough
shortage of a particular medicine we don’t know about.” connection between GMP standards and those underpinning
systems preventing supply disruption and procedures for
Underlying reasons and root causes reporting potential shortages to the authorities. “Since the
The industry now wants much more research into the causes EU’s revised GMP guidance will say that manufacturers must
of shortages, particularly into incidents linking them with notify competent authorities about impending interruptions
manufacturing difficulties. “We don’t know what are the in supplies due to quality issues, GMP inspectors would seem
amount of shortages arising from manufacturing problems,” to be in a position to ask for details about what steps are
says Berridge. Some governments see the influence of being taken in manufacturing plants to avoid disruptions,”
globalisation on patterns of pharmaceutical manufacturing as says Berridge “[They will also be able to ask] for details of the
being a major cause of shortages. “The globalisation of the company’s procedure for making notifications of disruptions
pharmaceutical industry means that medicines are often to the authorities.” The issue of medicines shortages in
manufactured in just a few sites worldwide,” explains a Europe will clearly require a lot of dialogue between the
spokesman for the UK Department of Health, which is industry and regulators before significant progress is
responsible for drug supplies in the country. “Production made in resolving it. More communication between the
schedules have to be planned months in advance and this industry regulators is required to resolve the problem.
along with the move to ‘just-in-time’ manufacture to reduce
the cost of stockholdings means that there is little flexibility in References
the system when problems do arise,” she adds. 1. Birgitte Holst, Novo Nordisk A/S, “Communications Principles
In a recent report on medicines shortages in Europe, in cases of Q and Manufacturing driven supply disruptions,”
birgli AG, a Swiss-based management consultancy linked presentation at the PDA Drug Shortage Workshop (Washington
government-initiated price-curbs on medicines and legislative DC, September 2014).
support for parallel trading to reductions in manufacturing 2. EURORDIS and six other organisations, “Common position
sites and the use of ‘just-in-time’ supply chains. between patients’, consumers’ and healthcare professionals’
“Before shortages can be reduced, the underlying organisations involved in the activities of the European
reasons and root causes of shortages should be well Medicines Agency on supply shortage of medicines,”
understood,” explained Julie Marechal-Jamil, EGA’s senior www.geneticalliance.org.uk/docs/final_common_position_
manager quality and regulatory affairs, in an interview supply_shortages_signatures.pdf, accessed 15 Oct. 2014. PTE
magenta
cyan
yellow
The Largest Global
Footprint of Harmonized
Testing Labs...
Right In Your Backyard.
With the largest network of harmonized bio/pharmaceutical

GMP product testing labs worldwide, Eurofins BioPharma
Product Testing is everywhere you are.
While delivering a true local lab experience, our

international presence ensures personal quality service
BioPharma backed by a unique global breadth of harmonized
Product Testing capabilities to solve all your testing challenges.
www.eurofins.com/biopharma
For the most complete range of global testing services,
harmonized quality systems and LIMS, you’ll never
need to look further than your own backyard.
Services Facilities
Chemistry/Biochemistry Microbiology Residuals & Impurities Testing Belgium Germany Spain
Cell Banking Services Molecular & Cell Biology Stability Testing & Storage
Denmark Ireland Sweden
Facility & Process Validation Raw Materials Testing Viral Clearance & Viral Safety
Method Development & Validation Release Testing Professional Scientific StaffingSM France Italy U.S.
magenta
cyan
yellow
expert Health Technology Assessment
(HTA) body, the G-BA determines
the level of added benefit of the
new drug relative to the appropriate
comparative therapy (ACT) chosen
by the G-BA as well as the certainty
of evidence presented by the
manufacturer. A brief description
of these two inputs that go into the
G-BA’s final decision is included in
Table I. Patient-relevant criteria for
additional medical benefit include
improving health, extending survival,
shortening the burden of illness and
reducing side effects, or improving
Germany Post AMNOG: quality of life, and are outlined in

the IQWiG methodology paper (2).
Originally, the law was written to
Insights for BioPharma include the possibility that patented

products already on the market
would have to undergo retrospective
The authors take a look at some of the recent developments
benefit assessments; however,
in the German pharmaceutical market.
manufacturers were recently spared
from this potential headache (3).
Once the G-BA reaches a final
conclusion, pricing negotiations begin
Jill E. Sackman,
DVM, PhD, is a senior
consultant, and Michael
M anufacturers exploring opportunities in global markets face
dynamic demographic and disease trends, changing market
demands and evolving regulatory requirements—all of which differ
with the statutory health insurance
(SHI) umbrella organisation, GKV–SV
(Gesetzliche Krankenversicherung–
Kuchenreuther, PhD, from one country to another. While emerging markets continue to Spitzenverband), which negotiates
is a research analyst, both represent a new channel of demand for pharmaceutical products, on behalf of all SHIs and also private
at Numerof & Associates, manufacturers have quickly realised that significant attention must still sickness funds in Germany. It is
Inc., St. Louis, MO, be given to more established markets, such as Germany. It’s no longer important to highlight that the ACT
www.nai-consulting.com. sufficient to expect that regulatory data from prospective randomised is not only used by the G-BA in its
clinical studies alone will be enough to convince payers to provide a assessment, it is also the price
price premium for new products. In this article, the authors take a look anchor for these negotiations. For
at some of the recent developments in the German pharmaceutical drugs found to have no added benefit,
market, identify pricing and reimbursement challenges and discuss their price is capped in reference
strategies manufacturers should consider for sustainable success. to the price of the comparator.
Reference pricing to the comparator
Overview of German market and AMNOG can be either advantageous if the
Germany is the third largest pharmaceutical market worldwide and ACT is already a high-priced therapy
accounts for approximately 23% of the European pharmaceutical or devastating if the ACT is a generic
market (1). Of equal importance to manufacturers, drug prices in drug. Thus, manufacturers looking
Germany are often used as reference prices in 19 other countries. to enter breakthrough therapeutic
Taken together, gaining access to this market at an acceptable areas where the current standard
price has major implications for long-term success. In a cost- treatment is a generic will be
constrained economy, the German government has taken steps to particularly challenged. Therapeutic
reduce healthcare spending, and unfortunately for manufacturers, products that demonstrate added
one way they have sought to do this is through The Act on the benefit are priced above the ACT
Reform of the Market for Medical Products (Arzneimittelmarkt- but may still face a minimum price
Neuordnungsgesetz—AMNOG). This piece of legislation was enacted reduction of 7% (formerly 16%) by law,
in 2011 and mandates a more rigorous benefit evaluation procedure unless it has been replaced as part of
for new pharmaceuticals (and their subsequent label expansions), the price negotiations. Unfortunately
thereby adding significant challenges to the market access process. for manufacturers, while the number
WESTEND61PREMIUM/GETTY IMAGES
In AMNOG’s new system, manufacturers continue to set the initial of products that have gone through
price for new prescription drugs after regulatory approval. This price is the entire assessment and pricing
valid for one year. During this time, the manufacturer’s value dossier is process remains small since the
reviewed by the Federal Joint Committee (G-BA), which represents the law was enacted three years ago,
self-governance structure of the German healthcare system. With the early evidence suggests only limited
help of the Institute for Quality and Efficiency in Health Care (IQWiG), an correlation exists between benefit
magenta
cyan
yellow
Protecting product quality
AT EVERY STEP
One trusted partner for end-to-end temperature

control and supply chain integrity
Medicinal products demand special protection at SENSITECH CAN HELP YOU:
every step in the supply chain—from the production • Document specific Controlled Room Temperature
line to the patient. (CRT) throughout your supply chain.
Sensitech can help. We combine industry-leading • Validate that your products have not been
environmental monitoring and control with end-to- adulterated during transit.
end logistics security. The result is a comprehensive • Satisfy regulatory expectations for chain of
solution for ensuring product quality and integrity custody documentation.
across your entire supply chain.
Learn how Sensitech can help protect your products—

and the patients who rely on them.
www.sensitech.com
Amsterdam Bangalore Boston Hong Kong Melbourne Santiago Shanghai

© 2014. Sensitech Inc. All rights reserved.
magenta
cyan
yellow
European Market Report
harms and omission of data for

Table I. Decision criteria for G-BA’s/IQWiG’s benefit assessment. relevant patient subpopulations.
Factors shown to impact A more detailed breakdown of the
Input Categorisation
categorisation decision G-BA’s negative rulings as of October
Number of appropriate clinical 2013 is presented in Figure 1 (7).
Qualitative studies available; use of valid As Figure 1 illustrates, even
Proof, indication, hint
certainty of measurement instruments; risk of though the outcome of benefit
or no proof
results bias (e.g., non-blinding); endpoint
assessment is a key driver of price
type (e.g., hard, surrogate)
negotiations, manufacturers have not
Major, considerable, always prepared dossiers adequately.
Quantitative Effect size at outcome level,
minor, non-quantifiable,
extent of confidence interval associated This, in turn, compromises the
no added benefit, or
added benefit with effect outcome of the assessment and
reduced benefit
subsequent price that is agreed upon.
Such problems with incomplete
Table II. G-BA decision breakdown on “Degree of Added or inadequate evidence may be
Benefit” for new pharmaceuticals within a specific patient overcome as drugmakers gain better
subpopulation (N=169). understanding of the requirements.
Degree of added benefit Percent of cases To this end, the Federal Joint
Committee offers consultation
Major 0% opportunities for manufacturers
Considerable 10% to give advice on trial design (e.g.,
patient segmentation, comparator
Minor 25%
selections and endpoints). Not all
Not quantifiable 7% manufacturers, however, have
Lower 1% communicated with the G-BA to
discuss the technical issues and
Not proven 57%
challenges around preparation of the
benefit dossier, or earlier to discuss
Figure 1: Reason for no proof of added benefit ruling for new pharmaceuticals the clinical trial (6).
within a specific patient subpopulation (N=113). Despite the market access
challenges that manufacturers
have experienced so far, only a
few products have been pulled
Evidence inappropriate despite negative G-BA rulings and
demands for substantial rebates.
32%
38% Novartis became the most recent
Appropriate comparator manufacturer to do this, withdrawing
not considered its oral antidiabetic Galvus from
the German market after failing to
No beneft shown
secure a mutually beneficial price
with payers (8). Given the size and
10% Evidence incomplete revenue potential associated with
this marketplace, the fact that
20% few products have been pulled is
not surprising. However, Hagen
Pfundner, the chairman of Germany’s
pharma lobby VFA and head of Swiss
ratings and price reductions. Rather, Not surprisingly, there has been drugmaker Roche’s German unit,
G-BA’s benefit rating has primarily considerable variance observed in the believes that a recent update to the
served as a door opener for price levels of additional benefit reported AMNOG legislation could lead to
negotiations (4). by pharmaceutical manufacturers “an increasing number of opt-out
and the G-BA. In contrast, the decisions” (9). In the past, a product’s
Benefit assessments G-BA’s decisions have more closely original launch price in Germany
ALL FIGURES ARE COURTESY OF THE AUTHORS
and pricing negotiations resembled IQWiG’s recommendations served as the published list price for
As of May 2014, 79 products have with a few notable exceptions (e.g., other markets. This approach is no
been assessed by the G-BA within belimumab, cabazitaxel, eribulin) (6). longer the case. Since April 2014, the
169 patient subpopulations. More Reasons the G-BA has offered for newly negotiated reimbursement
than 50% of these early benefit ‘no proven added benefit’ include amounts are published as visible
assessments have led to ‘no added inadequate comparator, lack of a ex-factory prices, effectively replacing
benefit’ rulings by the G-BA (see relevant study to back claims of the original list prices as source for
Table II) (5). benefit, lack of data on potential referencing. Drugmakers fear the
magenta
cyan
yellow
Introducing tool-less
valve maintenance.
Meet the revolutionary new valve,

Pure-Flo® EnviZion™
.
The days of weeklong shutdowns and lost productivity due to valve diaphragm change-outs are over.
With a breakthrough mount-and-turn design and no tools or torquing required, the Pure-Flo®
EnviZion™ valve has reduced valve maintenance time from an average of 23 minutes to just 3. That
means significantly less downtime and over 90 percent annual maintenance cost savings.
Combined with an active thermal compensation system that ensures a high integrity seal to prevent
leakage, the time between maintenance is also dramatically improved. The result? Better productivity and substantially
lower total cost of ownership. Now that’s ITT Engineered Valves thinking. Contact your local ITT representative or visit us at
www.engvalves.com/Env/TCO to see how much the EnviZion valve can save you.
engvalves.com
@ITTEngValves
ITT Engineered Valves
ITTEngineeredValves
Cam-Line® Cam-Tite® Dia-Flo® Fabri-Valve® Pure-Flo® Skotch®
magenta
cyan
yellow
Figure 2: Case summary of IQWiG’s benefit assessment of Kadcyla.
Drug Kadcyla (trastuzumab emtansine, Roche)
Indication Patients with unresectable, locally advanced or metastatic breast cancer that is HER2+
A. Patients with HER2+, B. Patients with HER2+, metastatic C. Patients with HER2+, metastatic breast D. Patients with HER2+, metastatic breast
Subgroups
locally advanced, breast cancer, with prior treatment cancer, with prior treatment with taxanes cancer, with prior treatment with taxanes
assessed by unresectable breast with anthracyclines, taxanes and and trastuzumab, but without and trastuzumab, for whom treatment with
G-BA cancer trastuzumab anthracyclines anthracyclines is not an option
Comparator
defned by Radiotherapy Lapatinib + capecitabine Anthracycline (doxorubicin, epirubicin) Individual treatment under consideration of
G-BA the respective approval of the drugs used
No additional beneft Indication of a major added beneft No additional beneft proven No additional beneft proven
G-BA resolution proven (no relevant (no relevant data were available) (no relevant data were available)
data were available)
The company deviated from the G-BA’s specifcation by considering the total target population, for which it used lapatinib + capecitabine as comparator therapy.
Notes Thus, no added beneft was found for subpopulations A, C and D. For subpopulation B, there were positive effects in the outcome categories “mortality”, “health-
related quality of life” and “serious/severe AEs”, and negative effect in the outcome category “non-serious/non-severe AEs.
information could challenge the entire study design and were based on granted to their products (e.g., Pixuvri
pricing framework within Europe (and evidence generated on a pre-AMNOG and Inlyta) (12). Moving forward,
globally) either causing a downward world. Moving forward, proactively manufacturers will need to ensure
spiral in reimbursement across the consulting with the G-BA to define that all relevant subpopulations have
region or heavy parallel exports the comparator(s), clinical endpoints robust and statistically significant
from Germany to other countries. and patient cohorts will be essential. clinical endpoints to support
If this new law is not overturned, it Manufacturers need to do this early reimbursement, with increasing
poses a significant risk to profits in in product development, especially demand for quality of life data. If
the industry, especially considering prior to starting Phase III trials. the resources required to study
that price discounts have been Internally, manufacturers should also multiple populations using multiple
as high as 70% following G-BA’s enhance communication between comparators are too great, pursuing
benefit assessment and range on regulatory and market access teams a narrower indication for a clearly
average between 16–30% (10). More to strategically plan for both market defined patient population and
broadly, the new rule reinforces authorisation requirements and against a single comparator serves as
the importance of manufacturers G-BA’s requirements. a viable alternative.
understanding the nuances of this Even before G-BA consultations, Manufacturers will also have
market and having strategies in-place manufacturers need to give greater to keep in mind that every new
to achieve successful market access. consideration to the product’s indication for a product will trigger
indication. While the indication another round of benefit assessment
Recommendations does not determine how the and a new price negotiation. Here,
for manufacturers benefit assessment is conducted, attempts to negotiate a higher
While Germany is certainly not the completed assessments indicate price with subsequent indications
only market that is enforcing more that it can influence the G-BA’s may be met with resistance by the
stringent pricing and reimbursement comparator choice and a pivotal GKV-SV and prove to be a significant
policies for new therapeutic products, trial’s relevance. For products with challenge for manufacturers. Thus,
it is perhaps scrutinising the quality broad indications, IQWiG and the drugmakers should give greater
and appropriateness of clinical data G-BA are demanding clinical data consideration to the trade-off
more so than any other country. for multiple patient subpopulations between a fast product launch and
Taken together with the fact that and against multiple ACTs. For the highest value launch.
other markets look to Germany to example, these commissioning bodies Aside from data collection and
determine pricing, manufacturers recently distinguished between defining a product’s indication,
should place a greater emphasis four subpopulations and ACTs for manufacturers must also develop
on G-BA’s recommendations when Roche’s Kadcyla (see Figure 2) (11). a solid pricing strategy earlier on in
structuring clinical studies. To date, Manufacturers that have failed to the product development process
the majority of AMNOG submissions anticipate and include such data and have capabilities to better
did not have much guiding input are seeing a significant reduction predict a products negotiated
from the G-BA prior to clinical in the overall level of added benefit price. There is currently no formula
magenta
cyan
yellow
regarding the rebate amount the pharmaceutical References

company has to grant on its retail price. Furthermore, 1. German Pharmaceutical Industry Association/BPI, IMS World
while evidence demonstrating added benefit is required Review 2012.
to avoid reference pricing, it is by no means the sole 2. IQWiG, General Methods Version 4.1. (28 Nov. 2013).
determinant of pricing decisions. Rather, the extent to 3. G. Collier, A tweak or an outrage? Germany passes new
which a product’s price will be marked down following pricing law. 24 March 2014, www.scripintelligence.com/
a positive benefit assessment is largely dependent home/A-tweak-or-an-outrage-Germany-passes-new-pricing-
on its original launch price as well as the market size law-350844, accessed 8 Aug. 2014.
and price of the appropriate clinical comparator. As 4. IMS Consulting, Pricing and market Access outlook–2013 edition.
5. LEO Pharma Germany, It’s difficult to meet HTA criteria
more products go through the product review and
according AMNOG—reason why? (10 June 2014).
pricing process and as more data become available,
6. J. Ruof, et al., eur J Health econ. 15, 577–589 (2014).
manufacturers should consider developing algorithms
7. PRMA Insights, PrmA Insights Focus: Pricing and
to forecast the benefit assessment outcomes and the
reimbursement Success in Germany under AmNoG (2013).
product’s final net price.
8. F. Kermani, “Novartis Pulls Galvus From Germany After Failed
The first three years of the AMNOG reform have proven
Price Negotiations,” The Pink Sheet Daily (19 June 2014).
that demonstrating added benefit is no small feat for
9. L. Burger and T. Severin, “Germany’s stance on pricing
manufacturers, and while complaints continue to be
threatens drug firm profits,” http://uk.reuters.com/
heard from pharmaceutical stakeholders, the law shows article/2014/02/18/us-germany-drugs-analysis-idUK-
no signs of slowing down. AMNOG has not only set new BREA1H09E20140218, accessed 14 Aug. 2014.
rules for reimbursement and pricing of pharmaceuticals 10. D. Bahr and T. Huelskoetter, “Comparing the Effectiveness
in Germany, it also forces the industry to adapt at a of Prescription Drugs: The German Experience,” www.ameri-
global level, rethinking how it brings new products to canprogress.org/issues/healthcare/report/2014/05/21/90120/
market. Manufacturers that prepare thoroughly for benefit comparing-the-effectiveness-of-prescription-drugs-the-
assessment and the negotiation processes within it will german-experience/, accessed 14 Aug. 2014.
be best positioned for success. 11. Institute for Quality and Efficiency in Health Care,
Trastuzumab emtansine–Benefit assessment according to
Aknowledgement §35a Social Code Book V.
The authors would like to thank Stefan Seliger, PhD, for his 12. C. Henry, “Oncology drugs under AMNOG,” PmLive (7 May
review and insights. 2014). PTE
N AL LA
Q
EW IT B
U
SUPPORTING PHARMACEUTICAL
PH CO R
Y O
A N ATO
R TR R
M O I
MANUFACTURERS
A L E
C
EU TE
TI ST
C IN
A G
L
S
Materials Development • Testing • Assurance
www.lucideon.com/pte
magenta
cyan
yellow
P articulate matter in parenteral drugs has
been recognised as a risk to patients for
nearly two centuries. Contaminants can come
from the environment, packaging materials,
formulation ingredients, interactions between
the formulation and the product packaging,
or be generated during processing (1).
Therefore, with an in-depth understanding
of the raw material, product, packaging
properties and manufacturing processes, it
should be possible to establish systems to
reduce particulate matter contamination of
parenteral formulations. An apparent increase
in the number of recalls due to particulate
contamination has drawn the attention of
the industry and led to a greater focus on
improving quality systems across the supply
chain. One aspect of those efforts is the
implementation of quality by design (QbD)
to ensure consistent and robust quality.
Consequences of particulate matter

In a 2013 article, Stephen E. Langille, a senior
microbiology reviewer in the Office of
Pharmaceutical Science at FDA’s Centre
for Drug Evaluation and Research (CDER),
estimated that approximately 190 million
Parenterals, litres of intravenous fluids are administered

to patients each year in the United States (1).
Several different clinical effects ranging from
minor problems to serious complications
Particulates and death have occurred as a result of the

injection of particulate matter (1). Therefore,
particulate matter contamination is a real
and Quality concern for the pharmaceutical industry.

The consequences depend significantly on
the size, shape, quantity and composition of
by Design
the particulate matter, as well as the method
of administration and level of risk presented
by the patient (1). Large, hard non-spherical
particles can block blood flow and cause
emboli, while large, softer, spherical particles
The parenteral manufacturing industry is taking action may collect in organs and cause damage
to address particulate contamination issues. over time. Premature infants and patients
suffering from severe tissue damage may be
at greater risk from harm due to particulate
matter contamination. Similarly, vascular
injection appears to present higher risk. In
addition, critically ill patients tend to receive
Cynthia A. Challener, PhD, is a contributing editor large quantities of parenteral therapies and
to Pharmaceutical Technology europe. often larger doses of particulate matter (1).
Recent recalls
Particulate contaminants are generally classified
as extrinsic, intrinsic or inherent, according
Maria Toutoudaki/Getty Images
to Tony Perry, director of regional quality for

pharmaceutical packaging with SCHOTT North
America. Extrinsic particulates originate from
outside the process and include, for example,
garment fibers and plastic particles. Intrinsic
magenta
cyan
yellow
magenta
cyan
yellow
QbD in Parenterals
particulates are generated from within industry expert. The expert adds between the drug and the interior
the glass vial such as glass flakes that the continuing predominance surface of the glass container. “The
that delaminate from the vial wall. of protein therapeutic agents has occurrence of these reactions is
Inherent particulates are derived from also resulted in more numerous the result of a complex interplay
the formulation itself, such as when a mechanisms by which particulates of different variables, such as the
portion of it aggregates or crystallises. can develop, because proteins are type of glass container, glass type
There have been recent recalls known to interact with components (composition), pH range, drug type
attributed to all three types of of the primary packaging system and/or drug formulation (chemistry
particulates. In August 2014, under certain conditions. of the formulation). Importantly, a
change in a single variable can make
the difference between success
Particulate contamination in parenteral drugs packaged in
and failure,” observes Dan Haines,
glass vials has created significant drug shortages recently.
scientific advisor, Pharma Services
with SCHOTT North America.
Baxter voluntarily recalled in the As demand from customers and Additional risk factors have the
US two lots of Dianeal Low Calcium regulatory authorities for ever- potential to influence the possibility
Peritoneal Dialysis Solution due to higher quality continues to grow, of delamination, including the storage
the presence of oxidised stainless there is also a greater awareness time and temperature, the container
steel, garment fiber and polyvinyl of the possibility of particulate manufacturing conditions and the
chloride particulate matter identified contamination, according to sterilisation process.
during the manufacturing process (2). Weikmann. “There is definitely a
Cephalon’s January 2012 voluntary heightened sensitivity in the industry Taking action
recall of Treanda (bendamustine to particulates given the greater The industry as a whole has tried to
HCL) for Injection was based on the understanding of their potential bring more visability to the particulates
identification of glass fragments in safety implications, and that led to issue, according to DeGrazio.
a single vial (3). In December 2012, a greater number of reports,” says “Parenteral manufacturers have
Hospira issued a voluntary recall in the Fran L. DeGrazio, vice-president of taken a number of actions to address
US of three lots of carboplatin injection global R&D, strategic programme the issue, including optimisation of
due to presence of visible particulates management and technical customer comprehensive quality management
identified as carboplatin crystals (4). support for West Pharmaceutical systems starting with supplier audits
In fact, particulate contamination Services. In particular, according to through to final visual inspections,
in parenteral drugs packaged in glass an industry expert, there is a growing as well as implementing permanent
vials has created significant drug awareness of the importance of process monitoring approaches that
shortages recently, according to Perry. subvisible particles with diameters in are designed to detect potential
He notes that according to the FDA the range from 2–10 microns, which hazards,” Weikmann says.
Office of Manufacturing and Product are currently below the “radar” of One biopharmaceutical company,
Quality, from 2008–2012, the presence compendial testing. “The number of for example, is focusing on
of visible particles accounted for 22% particles in that range is enormous understanding shear effects on
of all drug recalls (5). compared to the number of particles particulate formation, particularly
with diameters above 10 microns, from filling pumps, through
Many contributing factors and these colloidal particles can measurement of changes in
Various industry players point to aggregate over time, producing visible conformation that could eventually
many different reasons for the particles,” the expert explains. lead to aggregation, and thus
increase in recalls due to particulates. Industry understanding of the particulate formation, according to
“Today, quality has never been higher, physical and chemical mechanisms an industry expert. His company
but the manufacturing process is of particulate formation is also is also using instruments such
more versatile and complex than improving. For instance, shear as the FlowCAM (Fluid Imaging
ever before,” states Wolfgang denaturation can produce visible Technologies) and Micro-Flow
Weikmann, senior vice-president of particles, according to an industry Imaging (ProteinSimple) to investigate
quality for Vetter Pharma-Fertigung. expert. “There are instances where subvisible particles.
“As a result, there are numerous the type of filling pump (piston vs. Other activities at
individual process steps and a peristaltic) makes an observable biopharmaceutical companies include
multitude of single components (e.g., difference in the development of making adjustments to fill and finish
the glass barrel, stoppers, caps) particulate matter in a drug product,” processes and the development of
that serve as potential sources for the expert says. new material and system innovations,
particulate contamination during Investigations of glass delamination such as polymers and special biotech
production,” says Weikmann. The mechanisms are also providing delivery systems, to reduce possible
growing use of prefilled syringes is insights that are leading to new particulate contamination. Glass
another contributor to the increased glass manufacturing methods. manufacturers are also responding by
incidence of problems with visible Glass delamination is normally adjusting manufacturing processes
particulate matter, according to an the result of chemical reactions and developing alternate methods
cyan
yellow
QbD in Parenterals
that minimise the types of issues that product may help to identify potential specific implementation actions. “It
have been seen in the marketplace, risks in the process including is definitely necessary to have the
according to DeGrazio. possible sources for particulate right level of technical ability within
Importantly, there is greater contamination,” says Weikmann. the organisation to understand and
sharing of knowledge between For a CDMO like Vetter, he adds that implement QbD effectively,” Perry
all of the involved parties. “Closer the QbD approach is an important states. In addition, the organisational
cooperation with suppliers, logistic concept, primarily because of the mindset must be aligned and willing
partners and technical engineering many advantages it offers to industry to take on such programmes and to
supports the implementation of stakeholders. “This approach enables live by the relevant principles and
corrective and preventive actions consistent and robust production of disciplines. “QbD cannot be seen as
along the supply chain,” notes high quality products and, therefore, the next fad and is most successful
Weikmann. Collaborations with the reduction of batch failures and when driven from the top of the
critical external partners, such as stock-outs. It also offers the potential organisation,” adds Perry.
container producers that have shifted for greater confidence in drug Time and cost are also issues.
the focus to quality instead of treating quality and may reduce the need “Incorporating QbD into a process
glass vials as a commodity, are for intensive oversight by regulatory takes more time, and due to the need
helping drug companies understand authorities,” Weikmann asserts. for improved understanding and
products and processes and improve For glass manufacturers, a greater testing, costs more money,”
overall quality, according to Perry. QbD approach ensures a good DeGrazio says. She goes on to say,
“By incorporating supplier expertise understanding of which material and however, that in the long run, use of
up front and engaging in information process inputs have an impact on a QbD approach should reduce many
exchange from the beginning to the glass particulates, as well as the ways of the downstream issues that can
end of the drug development process, in which the process and material occur, and for those that do occur,
manufacturers can ensure that the interactions could lead to certain allow for better knowledge as to why.
material is used in the correct way,” glass characteristics that predispose As a result, QbD should ultimately
he says. Perry also notes that new the glass to particulate formation, help the industry reduce costs.
guidance covering inspections is also according to DeGrazio. Additional challenges can also
providing manufacturers with further The implementation and success of include finding the right business
support to ensure quality. QbD is also a way to help build long- partners that share the same
quality understanding and meeting
increasing regulatory requirements,
Glass manufacturers are responding by adjusting
such as the FDA’s process validation
manufacturing processes and developing alternate methods.
guidance, according to Weikmann.
Benefits of a QbD approach lasting relationships with customers References

Another approach that many and key partners, according to 1. S.E. Langille, PDA J. Pharm. Sci. and Tech.
companies are taking to improve Perry. “By taking a global view of our 67 (3) 186-200 (2013).
quality, reduce the risk of particulate processes and products, we have 2. Baxter, “Baxter Voluntarily Initiates U.S.
contamination and avoid recalls been able to shift our focus from Recall of Two Lots of Peritoneal Dialysis
involves the implementation of price-based discussions to total cost Solution Due to Presence of Particulate
programmes such as Six Sigma, risk of ownership and quality. With QbD, Matter,” Press Release, 13 Aug. 2014.
management, right first time and we have adopted more of a risk- 3. Cephalon, “Cephalon, Inc. issues a volun-
QbD, according to Perry. “The focus based approach to production and tary nationwide recall of Treanda (benda-
is now on minimising the risk and in the end have been able to look mustine HCL) for Injection 25mg/Vial Due
doing it right the first time. These further down the value chain to make to Particulate Matter,” Press Release,
tools ensure that processes are sure we are doing what is right for 27 Jan. 2012.
well managed by understanding the patients,” he comments. 4. Hospira, “Hospira Issues Voluntary
key process parameters and risks Nationwide Recall of Three Lots of
associated with those parameters,” A variety of challenges Carboplatin Injection Due to Visible
he explains. These numerous benefits of QbD Particulate Matter,” Press Release,
“The very heart of the QbD concept aren’t realised without significant Dec.14, 2012, www.fda.gov/Safety/
is that quality is built into a product effort, however. QbD is essentially Recalls/ucm332353.htm, accessed
based on an in-depth understanding a holistic, proactive, science- 7 Oct. 2014.
of the compound and the process and-risk-based approach to the 5. John G. Shabushnig, Insight Pharma
by which it is developed and development and manufacturing of Consulting, LLC, “Detection and
manufactured. Critical steps in the drugs, and proper implementation Control of Visible Particles in Injectable
fill and finish process of parenteral presents a variety of challenges for Products,” www.pda.org/docs/default-
manufacturing that affect quality the manufacturer. According to an source/attendee-presentations/north-
are identified and their influence industry expert, the biggest issue america/2014/2014-pda-annual-meeting/
evaluated. Matching the appropriate is the lack of a clear translation john-shabushnig-phd.pdf?sfvrsn=5,
processes to the actual needs of the from the broad principles of QbD to accessed 30 Sept. 2014. PTE
cyan
yellow
PCMM model
PTE: What are the
advantages of the four
aspects (portable,
Continuous Solid-Dosage continuous, miniature and

modular) of the PCMM model and how
do they relate?
Manufacturing Platform Steiner (GEA): The key point is that

continuous processing is the element
that enables process intensification.
Nears Prototype Installation Continuous processing and the

manufacture of smaller product
quantities in a continuous manner
A G-CON, GEA and Pfizer collaboration developed a PCMM (portable, continuous, mean that machinery product-
miniature and modular) system to produce oral solid-dosage drugs. contact surfaces are becoming much
smaller. Hence, the equipment is
becoming smaller, more portable,
and by definition, modular. So,
Jennifer Markarian
E xperts predict an eventual shift from batch to continuous
manufacturing processes. Regulators have expressed support
for continuous manufacturing, which is a crucial piece for any
there are four elements: continuous
processing is enabling miniaturisation;
miniaturisation is allowing processing
pharmaceutical effort. Analytical and manufacturing equipment and systems to become portable and
control systems have been developed to fit the needs of continuous modular. And when you put all that
production, and companies are moving forward. In September 2013, GEA together, you get the PCMM paradigm.
Pharma Systems and G-CON Manufacturing announced a manufacturing O’Brien (Pfizer): Continuous
collaboration with Pfizer to develop a PCMM (portable, continuous, processing technologies have been
miniature and modular) system to create a compact and mobile around for more than 50 years. In the
manufacturing platform for oral solid-dosage (OSD) drugs. The PCMM pharmaceutical industry, we have
prototype integrates GEA’s ConsiGma continuous manufacturing platform been at the point where processing
and MODUL P rotary tablet press, in a 36-ft. wide G-CON autonomous equipment can routinely be configured
GMP cleanroom structure called a megaPOD. The prefabricated in a continuous or semi-continuous
process skid and POD form an environmentally isolated facility that can manner for quite some time. Of greater
be installed in standard warehouse space. Maik Jornitz, president of importance is that our new paradigm
G-CON Manufacturing; Richard Steiner, business development manager shift has enabled dramatic reductions
for ConsiGma at GEA Pharma Systems; and Michael O’Brien, head of in size (miniaturisation), which in turn
Pharmaceutical Sciences Technology & Innovation at Pfizer, spoke with begets true modularity. Reduced
Pharmaceutical Technology Europe about the project. footprint, in combination with true
modularity, allows processing trains
Project status to be enclosed in dramatically smaller,
PTE: What is the status of the PCMM project? autonomous, GMP-compliant spaces
Steiner (GEA): At the moment, we are working on at a relatively low cost. As a natural
finishing the industrial skid. The collaboration is more than consequence, the self-contained
just a project on paper, we’re creating a tangible process processing entity no longer needs a
solution that will soon be manufacturing real product. Right now, traditional ‘brick and mortar’ factory
we’re in the factory acceptance testing phase for the equipment, infrastructure. Portability enables
which is almost finished. Soon the equipment will be combined with strategically driven redeployment
the G-CON megaPOD, finally bringing the project from concept to options and allows the facility to be
reality. classified such that accelerated capital
O’Brien (Pfizer): We are hoping to begin assembly early in the first depreciation is possible.
quarter of 2015 in a Pfizer Groton (Connecticut, US) warehouse. The Jornitz (G-CON): The PCMM model
following are some of the principles that will be demonstrated by the is the manifestation of the industry’s
prototype: vision and need for flexible and rapidly
• Continuous processing enables steady-state conversion of powder deployable manufacturing systems.
to uncoated tablets within minutes. Future facilities won’t necessarily
• Rapid deployment (i.e., design, construction and implementation be large-scale, dedicated, single-
of a facility in less than one year with practical options for product sites, but smaller, more agile
Photo ephemera/Getty Images
redeployment) is possible. manufacturing facilities that comply

• Identical equipment can now be used for clinical and commercial with the central tenets of FDA’s
manufacturing, effectively eliminating the uncertainty and “Quality for the 21st Century” initiative.
significantly reducing the costs of traditional development to These agile production sites will be
manufacturing and site-to-site technical transfers. modular—or podular—and designed to
28 Pharmaceutical Technology Europe NovEmbEr 2014 PharmTech.com
magenta
cyan
yellow
Technical Q&A: Continuous Manufacturing
be mobile. Continuous manufacturing, traditional models and actually offers tableting or direct compression,
used in both OSD applications and a lot of advantages, especially in including online PAT quality control, all
bioprocessing, will support the benefits terms of its portability, flexibility and in one system.
that can be gained from miniaturised productivity. The whole system was O’Brien (Pfizer): At Pfizer, we
or small-volume production processes. put together with existing equipment, have a number of ongoing projects in
The PCMM consortium is exploiting including the commercialised CMT various stages of development that
all these options to fully optimise continuous inline blending technology are investigating continuous and semi-
the efficiency and flexibility of future from Pfizer. We didn’t have to invent continuous processing technologies
production processes. anything new; we’ve just put it together for both API and other drug product
PTE: What scale is meant in a smart new way. development and manufacturing
by “miniature”? O’Brien (Pfizer): There is a body processes. It should be noted that we
O’Brien (Pfizer): We of work around achieving regulatory are also working with global regulatory
expect to operate within understanding and ultimately their bodies to ease the adoption of PCMM
a range of 5 to 30 kg per hour, which acceptance of both the technology and related advanced manufacturing
roughly translates to an annual and general paradigm. FDA and EMA technologies.
capacity of 0.5 to 1 billion uncoated have expressed support for and seem PTE: What role do you
tablets per year. to expect broader implementation think continuous
Steiner (GEA): Comparing batch on continuous manufacturing in the manufacturing (PCMM or
processing with continuous systems is pharmaceutical industry, but many other) will play in oral solid
difficult in terms of absolute numbers, aspects will need to be worked dosage in the next five to 10 years?
but the footprint or volume of such a through in terms of what is required O’Brien (Pfizer): From our vantage
system could be up to 60–70% smaller for regulatory filings and routine point, it wouldn’t be a surprise
than a conventional installation. Being operation. Challenges also remain to see PCMM and other related
continuous actually eliminates the in moving from the batch test OSD continuous development and
question of scale: the only factor is and release to a real-time release manufacturing paradigms ultimately
time. The equipment is physically paradigm. It is unclear whether become the new norm in the
smaller, but as it’s run continuously, regulatory agencies in developing pharmaceutical industry.
it’s easy to manufacture production- markets will readily embrace the new Jornitz (G-CON): Continuous
scale volumes of product. There’s no technology. We also anticipate that manufacturing will dominate facility
need for scale-up any more or long workforce planning and retraining and process designs, as well as the
product transfer times from R&D to will be crucial to the successful manufacturing modus.
full-scale manufacturing. implementation of this new paradigm. Steiner (GEA): Continuous
manufacturing will continue to grow.
Challenges Future of The pharmaceutical industry is facing
PTE: What do you see as continuous processing increasing demands for faster supply
the biggest challenges in PTE: Do you have chains, and continuous technology is
employing the PCMM continuous manufacturing an enabler of more flexible and faster
model? projects outside of PCMM? routes to market. I reiterate the key
Steiner (GEA): From my perspective, Steiner (GEA): GEA’s aspect that continuous manufacturing
I would say that we’ve not really ConsiGma is a multipurpose platform is an enabler of miniaturisation; the
encountered any insurmountable for continuous manufacturing that has subsequent portability and modularity
hurdles. Regarding technical been designed to transfer powder into lead to ‘process excellence,’ which in
challenges, the miniaturisation coated tablets in development, pilot, turn, delivers ‘business excellence,’
aspect was challenging, but we clinical and production volumes in a saving both cost and time, improving
found solutions. Economically, we’ve modular, compact unit. The system manufacturing efficiency and
discovered that the system price for can perform dosing and mixing of raw enhancing the output quality of the
the PCMM compares very well with materials, wet granulation, drying, whole organisation. PTE
Process validation for continuous manufacturing processes
Although some aspects of process validation for continuous generally applies to validating traditional batch processes—
processes are the same as those for traditional batch processes, for example, the establishment of critical quality attributes
there are some unique considerations. Gretchen Allison, senior (CQAs), critical process parameters (CPPs) and corresponding
director and team leader for Global Quality Validation, Pfizer acceptance criteria for a given product and process,” explains
Global Supply, spoke with Pharmaceutical Technology Europe Allison. “Other process validation considerations that apply
about these issues. to both traditional batch manufacturing and continuous
“Key considerations for validating a continuous manufacturing are the use of quantitative statistical methods
manufacturing process rely on many of the established (as appropriate) to evaluate the validation data and the
principles of basic pharmaceutical process development, evaluation of intra-batch and inter-batch variation.”
guides and standards that the pharmaceutical industry To read the full interview, visit www.PharmTech.com/Allison.
Pharmaceutical Technology Europe NovEmbEr 2014 29
magenta
cyan
yellow
Injecting Highly
Viscous Drugs
The author reviews the challenges in delivering macromolecule biologics.
I t’s been 61 years since Watson and Crick published

“A Structure for Deoxyribose Nucleic Acid” in the
April 1953 issue of Nature. Nineteen years later, Paul
and Crohn’s disease. It has a molecular weight of
approximately 148 kDa. Humira (C 6428H9912N1694O1987S46)
is 25 times the size of the insulin molecule and
Berg’s team at Stanford University created the world’s is anything but simple. The high mg per mL
first recombinant DNA molecule. In 1976, Swanson concentrations of these macromolecule drugs result
and Boyer founded Genentech. In 1982, Eli Lilly in high enough viscosities of the injectable product to
launched Humulin, the first human insulin produced cause problems for device designers, manufacturers,
using recombinant DNA technology, developed by primary container suppliers and patients.
Genentech. Since the 1990s, biologic drugs have
been the centre of attention for the pharmaceutical What are the practical options?
industry, both in terms of therapeutic opportunity and The cost and convenience drivers for self-administered
Andy Fry is the founder of business activity. therapies, especially for chronic conditions, result in
of Team Consulting, andy. EvaluatePharma World Preview 2014 predicts that regular but infrequent injections of relatively large
[email protected]. global sales of prescription drugs are expected to payloads of molecules, injected weekly, possibly
exceed $1 trillion by 2020 (1) of which more than 50% fortnightly, or even quarterly. Injection of 1 mL in a
are expected to be biological products, dominated single, self-administered dose has historically been
by monoclonal antibodies. But just like insulin, regarded as the upper threshold of acceptability,
these protein-based drugs are rendered useless if but single injected doses of up to 2.5 mL are now
taken orally. A means of delivery other than a tablet being actively explored. Discomfort or pain are major
or capsule is, therefore, called for, and there are considerations, but time also forms a part of the
challenges associated with it. equation. In general, patients don’t want to hold an
autoinjector (an increasingly common delivery device
Size is important format for biological drugs) in place for more than 15
People with diabetes have been successfully injecting seconds, a time window that includes needle insertion
themselves with insulin, often several times each as well as the actual injection.
day, for more than 90 years. It might be expected
that self-injection of any other drug should be as Syringeability
straightforward. However, it is not quite that simple. Syringeability refers to the force required to inject
Insulin, with a molecular weight of 5.8 kDa, is a rather a given solution at a given rate via a chosen needle
ADAM GAULT/SPL/Getty Images
large molecule when compared with drugs such as length and gauge. Flow through a hollow needle is
aspirin (at 180 Da) or even penicillin (at around 335 Da). characterised by the Hagen-Poiseuille equation:
Now consider Humira, a hugely successful product
128QµLA
used to treat a range of autoimmune conditions, F= (Eq. 1)
including rheumatoid arthritis, ankylosing spondylitis πD4
30 Pharmaceutical Technology Europe NovEmbEr 2014 PharmTech.com
magenta
cyan
yellow
F = syringe stopper (plunger) force Figure 1: Viscous formulation delivery by DosePro needle-free injector
Q = volumetric flow rate (Courtesy of Zogenix)
μ = dynamic viscosity
L = needle length 60
D = needle bore diameter
58
A = syringe plunger area
Typical viscous
Injection time (milliseconds)

56
Although syringe plunger friction
protein formulations
and tissue resistance at the needle
54
tip will add to syringe plunger force, 52
viscous resistance within the needle
is particularly relevant as larger 50
molecules and higher mg/mL 48
concentrations result in higher
viscosity formulations. Needle gauge 46
is key; although a finer needle means
44
easier and less painful insertion, it
also has a smaller bore. Equation 1 42
shows that plunger force varies with
40
D4. If an injector device is fitted with a
27 G needle (bore size 0.191 mm) and
0 1000 2000 3000 4000 5000 6000
the needle is changed to a 30 G (bore Viscosity (cP)
size 0.140 mm) of the same length,
the plunger force needed to give the
same flow rate (Q) (and therefore Newtonian fluids that exhibit non- and dampers to minimise peak forces;
the same injection duration) has to linear behaviours: precisely moulded cyclic polyolefin
increase by 350%. • ‘Dilatant’ fluids exhibit shear- syringes, which are more robust than
For a spring-powered autoinjector, thickening behaviour, for example, glass; and reduced friction stoppers
the spring must provide adequate cornflour mixed with water goes and syringes. But why not just change
force at the end of stroke (as the last from liquid to solid when trying to the approach to injected delivery and
drop of drug is delivered). However, stir the mix. side-step some of these challenges?
the stiffness or rate of a traditional • ‘Pseudoplastic’ or shear-thinning
coil spring dictates that at the start fluids, such as tomato ketchup, Large-volume injectors
of delivery, the spring force will become mobile and free-flowing If we treat injection time as an
be significantly higher. Add on the when shaken. This group includes opportunity, not a challenge, it presents
syringe plunger friction and tissue blood and high concentration an interesting device scenario. When
resistance, plus a safety margin to formulations of high molecular applying the Hagen-Poiseuille equation
allow for tolerances, and it becomes weight drugs. for an autoinjector, the flow rate (Q) in
apparent that some surprisingly high Andrea Allmendinger of Hoffman-La Equation 1 of 1 mL or 2 mL in perhaps
forces have to be handled by the Roche presented a paper (2) looking 10 seconds is driven largely by the
injector mechanism and, specifically, into this topic with regard to high- acceptable operating time for the
reacted through the prefilled syringe concentration, large-payload patient. But if the injection device could
(usually of type 1 borosilicate glass) macromolecule drugs at the Parenteral be worn for 15 minutes during delivery,
at the heart of the autoinjector. Not Drug Association Universe of Prefilled then the flow rate for the same
surprisingly, breakages, failures and syringes in Basel, November 2013. This injection size reduces by 9000%—and
malfunctions are among the problems paper illustrated how complex the Equation 1 tells us that the plunger
faced by autoinjectors delivering subject can be, but made interesting force would reduce in the same ratio.
higher viscosity biologic drugs. reading. The statistician George Box In fact, the drug formulation could be
At this point, it should be once stated “Essentially, all models less concentrated (and less viscous),
emphasised that the rules of fluid are wrong, but some are useful,” and though of larger volume (e.g., 5 mL),
dynamics cited, though applicable this view has strong resonance when while the flow rate and force to deliver
for a great many situations, are only exploring viscous product delivery would remain manageable. This is the
Figure 1 is courtesy of Zogenix.
strictly valid for Newtonian fluids (i.e., with a syringe and needle. operating territory for the large-volume
those for which shear rate is directly Although there may be some injector (LVI) or bolus delivery device.
proportional to flow rate). So-called rheological assistance due to shear A number of devices of this type
“ideal fluids” exhibit zero stress thinning during injection for some are in development, which use a
under any flow conditions. At the products, a variety of approaches to variety of primary containers (glass,
opposite extreme, ideal solids do not reduce delivery challenges are actively plastic, flexible, rigid, traditional
flow under any conditions. Between being pursued. These approaches and novel variants) and a range
gavni/Getty Images
these two extremes, Newtonian include thin-walled or tapered needles of mechanisms, power sources
fluids, exhibiting a neat, straight-line to reduce viscous resistance and and control systems (mechanical,
relationship are joined by other, non- minimise pain; constant force springs electrical, electronic, hybrid). The LVI
Pharmaceutical Technology Europe NovEmbEr 2014 31
magenta
cyan
yellow
addresses some of the key challenges Cf = orifice flow coefficient the practical range of interest, as
confronting the autoinjector and (0.95 for a practical, round- Figure 1 illustrates.
much effort is being devoted to the edged orifice)
technical, pharmaceutical and user- D = orifice diameter Which to choose?
related aspects of LVI devices. A = syringe plunger area All three injection technologies
discussed have their place, but
Needle-free delivery uses a fine, high velocity jet generated selection is often left until late in the
by driving liquid through an orifice at high pressure to pierce development of the drug product,
the skin and underlying tissue. which can mean that opportunities
can be missed. Early exploration of
Needle-free delivery Comparing this with Equation 1, formulation options together with
Needle-free delivery has been a the only fluid property in the Bernoulli the increasingly wide range of real,
reality since the late 1940s, and equation is ρ (density) and there practical options for parenteral
several technologies are now is no viscosity term. Because drug delivery can provide significant
available. Needle-free delivery uses formulations generally have densities benefits to everyone from the
a fine, high velocity jet generated close to that of water, the implication pharmaceutical company to the
by driving liquid through an orifice is that a needle-free device will patient.
at high pressure to pierce the deliver the same volume, at the same
skin and underlying tissue. The rate, using the same energy, largely References
governing equation (by Bernoulli) irrespective of viscosity. 1. EvaluatePharma World Preview 2014,
can be rearranged as shown in Strictly speaking, this holds true Outlook to 2020, www.evaluategroup.
Equation 2. for orifice plates of zero length and com/public/Reports/EvaluatePharma-
hence is not the only governing World-Preview-2014.aspx, accessed
4Q 2
F = 2ρA ( C π D2 ) (Eq. 2) relationship for a practical, real- 2 October 2014.
f life device. Nevertheless, although 2. Andrea Allmendinger, “Injection forces
practical orifii do have a finite length during subcutaneous drug administra-
F = plunger force and do exhibit some viscous loss, tion,” presentation at the PDA Universe
Q = volumetric flow rate needle-free devices are largely of Prefilled Syringes (Basel, November
ρ = fluid density unaffected by product viscosity in 2013). PTE
We’re more than

just a magazine...
* 52 8 3
#
The ePT weekly e-newsletter delivers critical information on
ePT recent contract awards, company mergers & acquisitions,

and fresh news of interest to a highly desired community of
pharmaceutical manufacturing professionals.
PT Sourcing & The PT Sourcing and Management monthly e-newsletter + access to

is the authoritative source on sourcing and management podcasts web seminars
Management within the pharmaceutical’s global supply chain.
Advanc
ing Developm surveys
ent & M JULY 20
anufac 12 Volu
m e2
turing
Equipment & Equipment & Processing Report focuses on
Processing pharmaceutical manufacturing process and

technology, providing manufacturing news, related
Report regulatory issues, and current trends.
Pharmaceutical Technology Europe’s weekly
PTE e-Alert electronic e-newsletter PTE e-Alert provides

news, market developments, industry surveys and Get all this and more.
information on up and coming trade events.
Subscribe now at
PharmTech Digital provides readers around the world with
www.pharmtech.com
Digital authoritative peer-reviewed research and expert analyses in
the areas of process development, manufacturing, formulation
Magazine and drug delivery, API synthesis, analytical technology,
packaging, IT, outsourcing, and regulatory compliance.
Extend
32 Pharmaceutical Technology Europe NovEmbEr 2014 PharmTech.com R ed
magenta
cyan
yellow
PEER-REVIEWED
Considerations in Developing
Sublingual Tablets—An Overview
Muhammad Ashraf and Vilayat A. Sayeed
T he oral mucosal lining offers a preferable route for the

local and systemic administration of certain drugs and
for the treatment of some diseases (see Table I) (1). This
route has several distinct advantages over the enteral and
parenteral routes of drug delivery due to its rich blood supply,
rapid onset of action, enhanced bioavailability, avoidance of
the first pass and food effects, increased patient compliance,
and ease of self-medication. Over the years, a number of
products taking advantage of oral mucosal drug delivery have
been introduced in the market.
Oral mucosal drug absorption is governed by (a) the
permeability of the oral mucous membrane and the anatomy
of the underlying tissues, (b) the physicochemical properties
of the drugs, and (c) the formulation design. The focus of
The rich blood supply and the relative thinness this review is on the latter two points, as an understanding
of the sublingual mucous membrane provide a of these elements enables the selection of drug candidates
unique opportunity for systemic delivery of certain suitable for oral mucosal delivery and optimises drug delivery.
drugs. This route of administration offers distinct
advantages, such as rapid onset of action and Anatomical structure of the oral mucosa
improved patient compliance, particularly in geriatric, The oral cavity has four distinct regions that can absorb drugs—
psychiatric, and paediatric patients. This review the sublingual, buccal, gingival, and palatal regions. These
highlights relevant physicochemical drug properties regions differ from one another in histological structure and
and formulation design considerations critical to biochemical composition of the mucosal membrane, and their
quality and performance of sublingual tablets. It also ability to retain the dosage form long enough to allow com-
highlights commonly used technology platforms and plete drug absorption. The sublingual membrane on the floor of
critical-to-quality drug development elements that the mouth under the tongue and the buccal membrane lining
need to be addressed in regulatory submissions. the cheeks are commonly used for systemic drug delivery.
The mucosal lining consists of three distinct layers. The
Disclaimer: The views and opinions presented in this article outermost layer is the epithelial membrane, which
are those of the authors and do not necessarily reflect views or consists of stratified squamous epithelial cells and has a
policies of the Food and Drug Administration.
protective barrier function. The innermost layer of the
epithelial membrane is called the basement membrane
that replenishes the epithelium. Below the epithelium lies
Muhammad Ashraf, PhD, is a senior quality reviewer and
the lamina propria followed by the submucosa. The lamina
*Vilayat A. Sayeed, PhD, is director, Division of Chemistry III,
Office of Pharmaceutical Science, CDER, FDA, Vilayat.Sayeed@ propria is a hydrated and less dense layer of connective
FDA.HHS.GOV. tissue containing collagen and elastic fibers. The oral
ANTHONY BRADSHAW/GETTY IMAGES
submucosa is also richly supplied with blood vessels.

*To whom all correspondence should be addressed.
Following absorption through the mucous membrane
Submitted: 23 Jan. 2014. Accepted: 23 Feb. 2014. in the sublingual region, the drug instantly diffuses into
venous blood. The venous blood from the sublingual region
of the oral cavity drains into a common trunk, which then
CITATION: When referring to this article, please cite it as M. Ashraf drains via the internal jugular vein, the subclavian vein, and
and V. Sayeed, “Considerations in Developing Sublingual Tablets—
An Overview,” Pharmaceutical Technology 38 (11) 2014.
the brachiocephalic vein directly into the superior vena
cava (2, 3). Thus, venous return from these regions enters
magenta
cyan
yellow
Sublingual Formulations
delivery system. On the other hand, the buccal mucosa is not

Table I: Drugs available as sublingual tablets.
continuously affected by saliva or by tongue movements and
Drug Manufacturer is suitable for prolonged retention of dosage forms such as
Nitroglycerin (Nitrostat) Pfizer mucoadhesive sustained drug delivery systems.
Isosorbide dinitrate Multiple manufacturers
Fentanyl citrate (Abstral) Galena Biopharma Commercially available sublingual tablets
Presently, a small number of commercially available drugs use
Buprenorphine hydrochloride Multiple manufacturers
the sublingual mucosa for drug administration. These drugs
Ergotamine tartrate (Ergomar) Rosedale Therapeutic are used for the emergency treatment of angina pectoris,
Ergoloid mesylates Watson hypertensive crises, breakthrough cancer pain, and migraine.
Asenapine (Saphris) Merck Sharp & Dohme The buccal route has been exploited for hormone replace-
Buprenorphine hydrochloride ment therapy. Table I lists some of the approved drugs that
Multiple manufacturers
and naloxone hydrochloride are available as sublingual tablets (9).
Zolpidem tartrate
Purdue Pharma
(Intermezzo) Potential drug candidates for oromucosal delivery
The literature is full of studies that have demonstrated the
the systemic circulation, bypassing the pre-systemic drug enhanced potential of several drugs when administered via
elimination, unlike in oral administration. Direct drainage oromucosal route. However, this potential has not been fully
into systemic circulation results in immediate systemic utilised commercially in developing drugs for oromucosal
availability of the drug and rapid onset of action. It should delivery. The following examples illustrate superior therapeutic
be noted that smoking, which causes vasoconstriction, may management when drugs were administered via the oromu-
affect drug absorption. cosal route as compared to oral administration.
In a comparative effectiveness study of sublingual
Permeability of the oral mucosa and drug absorption captopril, nifedipine, and prazosin, it was reported that
The salivary glands present in the oral cavity secrete saliva that sublingual captopril may be a better alternative to sublingual
has a pH of 5.5–7.0. Saliva consists of proteins and carbohydrate nifedipine in treating hypertensive emergencies based
complexes called mucus and enzymes such as amylase and on less side effects (10). Another study has shown that
carboxylesterase. Mucus is negatively charged at the physi- sublingually administered captopril and nifedipine are
ological pH, forming a cohesive gelatinous film on all oral cavity effective in the treatment of hypertensive emergencies;
surfaces. This cohesiveness permits mucoadhesion of the drug however, for severe forms of hypertension, this study
to the epithelial tissue leading to drug absorption (4, 5). recommends sublingual nifedipine (11).
The epithelial membrane is 100 –200 µm thick in the Sublingual administration of verapamil has exhibited
sublingual region and 500–600 µm thick in the buccal region (6). significantly higher maximum plasma concentration of the
The epithelial membrane in both regions is non-keratinised. The drug (Cmax), a faster absorption rate, and greater bioavailability
permeability of the mucosa varies from region to region in the as compared to its oral administration (12). It has also been
oral cavity depending on thickness and degree of keratinisation shown to produce a rapid and significant reduction in
of the epithelial membrane (7). ventricular rate (13). Sublingual administration of furosemide
Membrane-coating granules deposited at the apical surfaces was shown to offer a therapeutic advantage over the oral route
of the epithelial cells and neutral lipids, such as ceramides of administration (14).
and acylceramides, impart a barrier function to keratinised Oromucosal administration of midazolam was compared
epithelium resulting in decreased permeability. Conversely, with the rectal administration of diazepam for the emergency
cholesterol, cholesterol esters, and glucosyl ceramides in the treatment of acute febrile and afebrile (epileptic) seizures in
non-keratinised epithelial cells of the sublingual and buccal children (15). Oromucosal midazolam was found to be more
regions render it permeable to drug absorption (8). effective than the rectal diazepam.
The profuse blood supply, combined with the relative The sublingual tablets of buprenorphine and naloxone have
thinness and higher permeability of the sublingual mucosa, shown useful results for the treatment of opiate addiction (16).
permits rapid absorption and desirable bioavailability of certain The study has proposed office-based treatment of addiction
drugs following sublingual administration. Thus, the sublingual using sublingual administration of these drugs.
mucosa is a suitable site for achieving a clinically effective drug Zolmitriptan is used for the treatment of migraine and cluster
concentration in a shorter period of time when rapid onset of headaches. A sublingual formulation of zolmitriptan exhibited
action is desired. For this reason, rapidly dissolving sublingual faster absorption and higher drug exposure as compared to
tablets are highly effective for the emergency treatment of subcutaneous injection and is expected to be highly efficient
angina, breakthrough cancer pain, or migraine. for the emergency treatment of these conditions (17).
It should be noted that the sublingual region is constantly In a randomised, double-blind clinical trial, comparing
washed by saliva and by movements of the tongue, and 40 mg of sublingual piroxicam with a 75 mg intramuscular
thus is not suitable for the prolonged retention of a drug injection of diclofenac for the emergency treatment of acute
magenta
cyan
yellow
Table II: Physicochemical properties of sublingually administered drugs.

Drug Molecular weight Largest dose** Water solubility pKa Log P
Nitroglycerin 227 0.6 mg 1.8 mg/mL -5.6 0.94
Fentanyl citrate 336* 0.8 mg 0.025 mg/mL (citrate) 8.4 2.9
Buprenorphine 467.6 2–8 mg Insoluble in water 8.24, 10.0 4.9
Asenapine maleate 285.8* 10 mg 3.7 mg/mL 8.6 4.9
Nicotine 162.234 4 mg Slightly soluble 8.21 0.99
Ergotamine tartrate 583.68* 2 mg Insoluble in water 6.3 2.4
* Molecular weight of the base.
**Largest dose for sublingual tablet.
renal colic, sublingual piroxicam was found as effective as the glutamic acid, L-ascorbic acid, nicotinic acid, and thiamine, are
intramuscular diclofenac (18). transported via a carrier-mediated process (31–34).
Self-injected epinephrine is used for the treatment of Lipids present in the oral mucous membrane offer the main
anaphylaxis. In a study, sublingual epinephrine resulted in barrier to the permeability of hydrophilic drugs. On the other
rapid absorption and higher peak plasma concentration in hand, well-hydrated connective tissues provide resistance
animal models when compared to self-injected epinephrine. to lipophilic drugs. Thus, the potential transport path across
The study proposed sublingual epinephrine as an alternative the oral mucous membrane may be either polar or non-
to self-injected epinephrine (19, 20). polar. Non-polar molecules cross through the lipid regions
Estrogens in menopausal women with cardiovascular of the epithelium, while polar molecules travel through ionic
disease have been shown to produce coronar y and channels present in the intercellular spaces of the epithelium,
peripheral vasodilation, reduction of vascular resistance, or aqueous pores present in the epithelial cells. For this reason,
and improvement of endothelial function. Sublingual an understanding of a drug’s lipophilic or hydrophilic nature
estrogens have exhibited faster drug absorption (i.e., shorter during the developmental stage of the drug product appears
Tmax higher Cmax) than orally administered forms (21, 22). to be the most useful index for evaluating its suitability for
The sublingual administration of vaccines may be used absorption across the oral mucosa.
against various infectious diseases. Preclinical studies have Physicochemical properties of drugs. Table II lists the
found that sublingual vaccines can be highly immunogenic physicochemical properties of some commercially available
and may protect against influenza virus and Helicobacter drugs administered sublingually. These properties of the drugs
pylori (23–25). facilitate their absorption by passive diffusion through the
oral mucosa. Partition coefficients and ionisation constants of
Development of sublingual tablet formulations several drugs are described in the literature (35–38).
For optimal sublingual formulation development, it is neces- For efficient absorption through the oral mucosa, the drug
sary to understand the mechanism of drug absorption, physi- must be hydrophobic enough to partition into the lipid bilayer,
cochemical and mechanical properties of the drug, function but not so hydrophobic such that once it is in the bilayer, it
of the excipients in the formulation, and taste-masking tech- will not partition out again. Satisfactory oral absorption of
niques for better patient compliance. drugs has been observed over a wide range of log P (octanol/
Mechanism of mucosal drug absorption. Following water partition coefficient) values of 1 to 5. As the log P
sublingual administration, the drugs are absorbed across the value increases beyond 5, the solubility in saliva is usually
mucous membrane by one of the following mechanisms: not enough to provide adequate concentration for diffusion
• Passive diffusion through the lipid bilayer (39). According to the diffusive model
• Active or carrier-mediated transport of absorption, the flux across the lipid bilayer is directly
• Endocytosis. proportional to the concentration gradient. Therefore, lower
Although the process of passive diffusion is spontaneous, solubility in saliva results in lower absorption rates and vice
the rate of diffusion is dependent on the molecular weight and versa. In general, a drug formulated for sublingual or buccal
solubility of the drug, concentration gradient, temperature, administration should have a molecular weight of less than
the surface area of the membrane, and the proximity of 500 (as free base) to facilitate its diffusion (39).
the molecule to the membrane. When a drug exists in its Because drugs diffuse through the lipid bilayer in the
unionised form in saliva, it is absorbed by passive diffusion. unionised form, based on the pH-partition theory, the pKa of
Physical models have been proposed to describe drug drugs also plays a crucial role in drug transport across the
absorption from saliva through the lipid bilayer of the mucous oral mucous membrane. It is important to note that the oral
membrane into systemic circulation (26–29). The rate of drug cavity, unlike the gastrointestinal tract, has a narrow range
absorption across the mucous membrane is directly related of pH, usually from 5.6 to 7.6. Thus, a basic drug administered
to its partition coefficient (30). Some compounds, such as as a salt, predominantly exists as a free unionised base if
magenta
cyan
yellow
the pH is raised above its pKa value and this increase in flavours, and other taste-masking agents are essential
the unionised fraction of a drug increases its bioavailability components for formulations containing drugs with an
(40). For this reason, the inclusion of a suitable buffer in the unpleasant taste. Sugar-based excipients quickly dissolve
formulation of an ionisable drug makes it possible to control in saliva and produce endothermic heat of dissolution. They
the pH of aqueous saliva in a range most appropriate for the create a pleasant feeling in the mouth and are most suitable
optimal absorption of such drugs. Drugs that do not contain for sublingual tablets along with other flavours. The coating of
ionisable groups are not affected by changes in pH. bitter drugs is not an option for drugs to be dissolved in saliva.
Unlike the gastrointestinal tract, the absorptive surface of Sublingual tablets promote rapid absorption and higher
the oral cavity is much smaller; therefore, large doses cannot bioavailability with an almost instant onset of action. If
be administered via this route. Thus, only potent drugs, which the dissolution of the drug is incomplete, contact time is
require small doses to obtain the desired therapeutic effect, short, and/or permeation is too low, part of the dose may be
can be administered from this route. In addition to these swallowed and consequently not absorbed through the oral
critical drug attributes, it is highly desired that drugs for mucosa, with subsequent effects on bioavailability. Many
oromucosal delivery be adequately taste masked. Otherwise, sublingual tablets may be compromised by the possibility
it is difficult to achieve patient compliance. of the patient swallowing the active drug substance before
Characteristics of sublingual tablets. In view of the it has been released and absorbed via the oral mucosa into
short residence time in the mouth, rapid disintegration the systemic circulation.
and dissolution is crucial for drug absorption following A sublingual tablet designed to promote the retention
administration of sublingual tablets. For this reason, of the active drug substance under the tongue, to prevent
sublingual tablet formulations should be designed to its swallowing, and to minimise inter and intra individual
disintegrate and dissolve rapidly in saliva, without the aid of variability, has been reported. This approach made use of
water to achieve this objective. ordered mixtures of fine drug particles and bio-adhesive
The physical and mechanical characteristics of a tablet, material attached to coarser excipient carrier particles.
such as size, hardness, porosity, and wettability, affect its Tablets composed of these units have the potential to
disintegration time. A smaller tablet size, with low hardness rapidly disintegrate and release the units, which adhere to
and high porosity, disintegrates more rapidly than a larger or the sublingual mucosa, and thus prolong the contact time at
harder tablet. However, a tablet with a high porosity and low the absorption site (47Ð48). Directly compressible sublingual
hardness is more friable, and this presents problems in tablet tablets developed using this approach led to the bio-adhesive
packaging and handling. During development, all approaches retention of the drug in the oral cavity and optimal exposure
to increase the mechanical strength of tablets should be of drug substance to the dissolving fluids in the mouth, which
studied, without compromising disintegration and dissolution. resulted in complete and rapid sublingual absorption.
The amount and type of disintegrants also play a significant
role in achieving rapid disintegration. Effervescent agents Manufacturing sublingual tablets—
have been used to facilitate disintegration (41). The inclusion Technology platforms
of water-soluble excipients, such as saccharides, helps in Although several technologies are available to manufacture
achieving rapid dissolution by enhancing the wettability of sublingual tablets, usually compression molding, direct com-
the tablet matrix. Moreover, the manufacturing process and pression, and freeze drying have been commonly used for com-
critical process parameters also affect disintegration and mercial manufacture of sublingual tablets. The compression
dissolution of sublingual tablets. molding process has been used since the early nineteenth cen-
Following sublingual administration, the patient is advised tury for the preparation of nitroglycerin tablets. Presently, the
to abstain from swallowing the tablet and avoid eating, direct compression and freeze-drying methods are commonly
drinking, or chewing to facilitate drug absorption through exploited for commercial manufacture of sublingual tablets.
the oral mucosa. Even swallowing saliva is to be avoided, to Compression molding. Tablets manufactured by the
prevent ingestion through the gastrointestinal tract where compression molding process exhibit rapid disintegration
drug absorption may be inefficient. Because these aspects and dissolution, which is usually within 5Ð10 seconds. These
pose some inconvenience to the patient, they should be tablets pose special challenges during handling and shipping,
taken into account at the product development stage to because of the poor mechanical strength, and may require
improve patient compliance. special packaging (49, 50). Alternatively, the mechanical
Some drugs may have a bitter or unpleasant taste. When strength of the tablets may be enhanced by employing a
such drugs are dissolved in the saliva for mucosal absorption, suitable binder. However, the binder level should be
they may also interact with the taste buds in the mouth optimised to avoid any deleterious effects on disintegration
and produce the bitter, unpleasant taste, and may not be and dissolution of the tablets.
acceptable to patients. Patient acceptability of formulations The formulations for the compression molding process
is improved by various physicochemical approaches that typically contain soluble excipients to impart quick and
prevent the interaction of drugs with taste buds and thus complete dissolution, and taste modifiers for patient
eliminate the negative sensory response (42Ð46). Sweeteners, compliance (51). Molded tablets have also been prepared
magenta
cyan
yellow
Choosing the Proper Dissolution
Method When Testing
Solubilization Performance
| O N -D EMAND WEBCAST Originally aired October 22, 2014
Register for free at www.pharmtech.com/dissolution
EVENT OVERVIEW:
With the increase in use of advanced formulation methods to

improve solubility of drugs, standard dissolution methods are BONUS
not always capable to refect the full in-vivo potential. CONTENT:
By attending this
This webinar will take a close look at dissolution testing of webcast you will
solid dispersions made with polyvinyl caprolactam–polyvinyl receive a FREE
whitepaper/
acetate–polyethylene glycol graft copolymer (Soluplus®) Executive
and how to design an appropriate dissolution test that is Summary of
this program
discriminatory for APIs with diferent prerequisites.
Standard compendial dissolution tests do not necessarily refect

Presenters
the actual performance potential of solid dispersions in terms of
ANDREAS GRYCZKE
later bioavailability due to their simplistic setup. This webinar will Global Development and Technical
Marketing Solubilization
focus on a workfow to fnd the proper dissolution test for solid Pharma Ingredients and Services
dispersions, using a Soluplus-based formulation as an example. BASF
The target is to show a methodology to have discriminating Moderator

dissolution methods, which represent the expected performance RITA PETERS
Editorial Director
ranking in-vivo among diferent formulations. Pharmaceutical Technology
Key Learning Objectives:

Who Should Attend:
n Importance of the right choice of dissolution method when
This webcast targets all
testing solid dispersions.
pharmaceutical scientists and
n Workfow to choose the right dissolution method depending formulators from R&D and
on the Soluplus-based formulation requirements. analytical departments that have
an interest in the solubilization
of poorly soluble drugs, and in
Presented by Sponsored by
understanding the importance
of choosing a proper dissolution
method in the solubilization tests
to reveal the full potential of the
tested solubilization method.
For questions, contact Sara Barschdorf at [email protected]
magenta
cyan
yellow
directly from a molten matrix, in which the drug is dissolved multiparticulate actives (coated crystals and uncoated
or dispersed (heat molding), or by evaporating the solvent or coated microgranules) (61). In these tablet s, the
from a drug solution or suspension at room pressure (no simultaneous presence of a disintegrant with a high swelling
vacuum lyophilisation) (52). or disintegrating force, defined as “disintegrating agent,”
The compression molding process involves moistening of and a substance with a low swelling force (starch, cellulose,
the formulation blend with a solvent (usually hydro-alcoholic), and direct-compression sugar), defined as “swelling agent,”
followed by molding into tablets under low pressure. The moist was claimed as the key factor for the rapid disintegration
tablets are finally dried (53). The lower compression pressure of a tablet. The tablet manufactured by this technology is
employed for molding and drying of the moist tablet produces reported to have adequate mechanical strength (62).
a highly porous tablet structure with enhanced dissolution. Daiichi (Tokyo, Japan) developed a fast disintegrating
The choice, ratio, and amount of granulating solvents are composition of moderate strength, using a combination of
critical to the physicochemical characteristics, performance, starch or cellulose, and one or more water-soluble saccharides
and stability of the tablets, and should be optimised (54, 55). (63). Erythritol was found to be the best sugar for this type of
Several patented technologies are also available for commercial formulation, showing rapid disintegration that was negligibly
manufacture of compression molded tablets. affected by tablet hardness, good tolerability and sweetening,
Takeda (Osaka, Japan) has developed a mixture containing and a refreshing mouth sensation because of its endothermic
a combination of starches and sugars. This mixture, after heat of dissolution.
blending with the drug and wetting with a suitable amount of Freeze dr ying. The process of freeze dr ying
water, can be compression molded. The tablets manufactured (lyophilisation) is expensive, time-consuming, and produces
from this proprietary mixture are reported to have sufficient tablets of poor mechanical strength. For these reasons, it
mechanical strength and exhibit rapid disintegration (56). is not commonly used to manufacture sublingual tablets.
Novartis Consumer Health (Basel, Switzerland) has filed However, it does have advantages over the other processes,
a patent application for tablets prepared by dispensing the as the tablets made by this process have high porosity, and
drug solution or suspension into molds, evaporating the when placed under the tongue disintegrate and dissolve
solvent from the molds by heating under reduced pressure, instantly. It is a process of choice for products that are
or microwave radiation, and then sealing the dried units unstable or are heat sensitive.
directly in the mold (57). The process involves lowering the temperature of
Nippon Shinyaku (Kyoto, Japan) compression-molds and dries the product in an aqueous medium to below freezing,
a kneaded mixture containing drug and a water-soluble sugar. followed by applying a high-pressure vacuum. To extract
This process is claimed to impart sufficient physicochemical the water in the form of a vapour, which is collected as
stability to the tablet, good appearance, and dissolution time of ice on a condenser, a gradual temperature rise is applied
less than 30 seconds in the oral cavity (58). during the drying process. The product temperature at
Direct compression. The direct compression method is the ice sublimation interface and the formulation collapse
commonly used for commercial manufacture of sublingual temperature are critical to obtain a freeze-dried cake of
tablets. It is a simple and cost-effective process, as it quality structure. This process retains the physical structure
employs ingredients that can be mixed well and do not and preserves the material for storage or transport.
require further granulation steps prior to lubrication and The resulting tablets are usually light and have highly porous
compression. Sublingual tablets manufactured by the direct structures that allow rapid dissolution or disintegration.
compression method exhibit good mechanical strength and The freeze-drying process may result in a product with an
acceptably fast disintegration (59). amorphous structure, leading to an enhanced dissolution rate.
The directly compressible sublingual tablet formulation However, tablets manufactured by freeze drying process have
contains directly compressible soluble excipients, a super poor stability at a higher temperature and humidity (64).
disintegrant, and lubricant. It may also contain microcrystalline
cellulose, dry binder, buffers, surface-active agents, sweeteners, Considerations critical to product quality
and flavours. Sugar-based excipients are widely used as bulking To develop a sublingual tablet that can elicit the desired
agents because of their high aqueous solubility, sweetness, physicochemical and mechanical properties of the drug
pleasant feeling in the mouth, and good taste-masking. Nearly product at the site of absorption, it is important to under-
all sublingual formulations incorporate some saccharide- stand, control, and monitor the following critical to quality
based material (60). The choice of a suitable disintegrant and attributes: particle size of the API, wetting time, disinte-
its amount are critical for achieving a fast disintegration and gration and dissolution, content uniformity, hardness, fri-
dissolution rate. Sometimes effervescent agents are used to ability, size and weight variation, stability, texture and taste
increase disintegration and dissolution of sublingual tablets. masking, etc.
Several novel approaches of incorporating disintegrants Most of these tests are universal quality determinants of
and other soluble and/or insoluble excipients to obtain conventional tablet dosage forms and are equally relevant
rapid dissolution and adequate mechanical strength are for sublingual tablets. However, the disease management
reported. One example is the Flashtab technolog y of and conditions of use for sublingual tablets require a
magenta
cyan
yellow
very short residence time in the oral cavity. This critical physiological conditions of the oral cavity by using different
determinant particularly calls for very rapid disintegration, pieces of equipment (70–72).
dissolution, and absorption of the product resulting in quick The palatability of a sublingual formulation, especially those
onset of action. containing APIs that have an unpleasant taste, is another
The drugs that are administered sublingually generally critical factor for patient compliance as the drug product
have low solubility. Therefore, to enhance dissolution, it is disintegrates, dissolves, and is absorbed in the oral cavity.
crucial to reduce and control the particle size of the API. Various taste-modifying techniques are reported in the
This attribute is important in the case of all drugs with low literature including sweeteners, flavouring agents, inclusion
solubility. However, a tighter control on particle size of API and molecular complexes, granulation, salt formation, pro-
is desirable in sublingual drug products to maintain the drug, viscosity modifiers, solid dispersions, and the use of
reproducible quality and performance of the drug product in lipoproteins among others (73).
view of the limited window of dissolution and absorption time. To address this critical patient compliance concern,
The conditions prevailing in the oral cavit y for suitable taste-masking strategies should be studied in
disintegration and dis solution of sublingual t ablet s the product development stage and incorporated in the
are markedly different from the tablets that are orally product design. The technologies that are reported in the
ingested. For this reason, the compendial disintegration literature for the evaluation of taste include the electronic
and dissolution test methods are not suitable for testing tongue, measurement of frog taste nerve response, the
sublingual tablets. It is important to note that compendial spectrophotometric method, and a human taste panel (74–76).
methods for disintegration and dissolution tests were
developed to test the in-vitro performance of tablets Conclusion
developed for disintegration and dissolution in the stomach The scientific principles employed and the knowledge gained
following oral ingestion. Other specialised tablets, such as during the product and process development for the manu-
modified-release or enteric-coated tablets, may also partly facture of a sublingual drug product that is fit for its intended
release the drug in the stomach. In contrast, sublingual use should be provided in the appropriate quality section of
tablets are designed to completely disintegrate and dissolve ICH M4Q (R1) of the application submitted to FDA (77). As the
in the oral cavity under the tongue. quality of the drug product cannot be adequately ensured
To address this critical difference, researchers have merely by in-process and finished-product testing, critical
proposed various approaches to test disintegration and to quality controls for raw material, process and equipment,
dissolution of sublingual tablets. These approaches employ packaging, fitness of test method, and risk analysis should
physiological conditions of the oral cavity as a guide in be discussed following the principle highlighted in ICH Q8 (R2),
testing disintegration and dissolution of sublingual tablets. Q9, and Q10 and presented in the submission to FDA. The
One such disintegration method employs a 10 -cm proposed specification to ensure the quality of the sublingual
diameter Petri dish filled with 10 mL of water that contains tablet should be based on the ICH quality guidances, with
eosin, a water-soluble dye. A 10-cm diameter circular tissue adequate justification and supportive data (78).
paper is placed in the Petri dish. The tablet is carefully Where applicable, qualification data should be provided
placed in the centre of the dish and the time for the tablet in the application to support the use of excipients not used
to completely disintegrate into fine particles is noted as the previously in the FDA-approved product. The objective of
disintegration time (65). This method has been used widely the drug product is to ensure that the drug available to the
to test the ability of the sublingual tablets to disintegrate consumer is not only safe and effective, but has also been
and dissolve in a minimal amount of water, which is properly manufactured and packaged to meet the established
more representative of the moisture available under the quality target product profile over its intended shelf life. A
conditions of use. well-developed product will effectively address these issues
Another popular in-vitro method involves a texture by including appropriate control strategies and establishing
analyser (TA) instrument to accurately determine the the functional relationships of the material attributes, critical
disintegration time. In this method, a tablet under constant process parameters and patient needs to meet the tablet
force is immersed in a defined volume of water. The time quality attributes as discussed in the article.
for the tablet to disintegrate is determined by measuring In conclusion, this review demonstrates that there are a
the distance the probe travels into the tablet. The time– number of commercially available sublingual formulations
distance profiles generated by the TA software enable the manufactured using various technologies. The publically
calculation of the beginning and end of disintegration time. available information on sublingual tablets implies that this
The influences of the applied force, the volume of water, and dosage form has good potential to enhance drug delivery in
water temperature were found to be critical experimental treating a number of indications. In most reported cases, it has
conditions (66–68). been shown that the sublingual dosage form not only improves
The wet ting test, designed by Bi et al., compares the patient’s compliance, but also reduces the time for the
favourably with the conditions prevailing in the sublingual onset of the drug action, and increases the bioavailability of
region of humans and animals (69). Other authors employed drugs as compared to conventional tablets.
magenta
cyan
yellow
References 41. F. Wehling, S. Schuehle and N. Madamala/Cima Labs Inc., “Effervescent
1. H. Zhang, J. Zhang, and J.B. Streisand, Clin. Pharmacokinet. 41 (9) 661-680 Dosage Form with Microparticles,” US Patent 5178878 (1993).
(2002). 42. C. Kumaresan, Pharmainfo.net. (9 Sept. 2008).
2. K.L. Moore, A.F. Dalley, and Anne M.R. Agur, Eds. Clinically oriented 43. J.P. Reo and J.K. Fredrickson, Am. Pharm. rev. 5 (4) 8-14 (2002).
Anatomy (Lippincott Williams & Wilkins, Philadelphia, PA, 6th ed., 2009), 44. R. Kannuri, T. Challa, and H. Chamarthi, Int. J. Pharm & Ind. res. 1 (3) 200-
p. 944. 210 (2011).
3. C.A. Squier and P.W. Wertz, “Structure and function of the oral mucosa 45. A.M. Morella, I.H. Pitman, G.W. Heinicke, “Taste masked liquid suspen-
and implications for drug delivery,” in oral mucosal Drug Delivery, M.J. sions,” US patent 6197348 (2001).
Tathbone Ed. (Marcel Dekker, New York, NY, 1996) pp.1-26. 46. D. Sharma et al., Int. res. J. Pharmacy. 3 (4) 108-116 (2012).
4. W.M. Edgar, br. Dent. J. 172 (8) 305-312 (1992). 47. S. Bredenberg et al., eur. J. Pharm. Sci. 20 (3) 327–334 (2003).
5. M.J. Rathbone, B.K. Drummond, and I.G. Tucker, Adv. Drug Deliv. rev. 13 48. S. Bredenberg and C. Nyström, J. Pharm. Pharmacol. 55 (2) 169 -177 (2003).
(1-2) 1-22 (1994). 49. K.G. Van Scoik, “Solid pharmaceutical dosage in tablet triturate form and
6. S.Y. Chen, C.A. Squier, in The Structure and Function of oral mucosa, J. method of producing same,” US patent 5,082,667 (1992).
Meyer, C.A. Squier, and S.J. Gerson, Eds. (Pergamon, Oxford, 1984) pp.7-30. 50. L. Dobetti, ”Fast disintegrating tablets,” US Patent 6,596,311 (2003).
7. W.R. Galey, H.K. Lonsdale, and S. Nacht, J. Invest. Dermatol. 67, 713-717 (1976). 51.M. Okada, Y. Ikeda, K. Ono, T. Kurazumi, S. Kasai and K. Imamori, ”Quickly
8. D. Harris and J.R. Robinson, J. Pharm. Sci. 81, 1-10 (1992). soluble solid oral preparations,” US Patent 6,455,053 (2002).
9. FDA, orange book: Approved Drug Products with Therapeutic equivalence 52. L. Dobetti, Pharm Technol. Drug Deliv. Suppl. 44-50 (2001).
evaluations, www.accessdata.fda.gov/scripts/cder/ob/default.cfm, 53. J.W. Conine and M.J. Pikal, “Special Tablets,” in Pharmaceutical Dosage
accessed 2 Oct. 2014. Forms: Tablets, H. A. Lieberman, L. Lachman and J.B. Schwartz, Eds. (Marcel
10. S.G. Wu et al., Nephron. 65 (2) 284-7 (1993). Dekker, New York, NY, 1989), pp. 338-339.
11. G. Guerrera et al., minerva Cardioangiologica. 38 (1-2) 37-44 (1990). 54. I.A. Chaudry and R.E. King, J. Pharm. Sci. 61 (7) 1121-1125 (1972).
12. D.N. John et al., br. J. Clin. Pharmacol. 33 (6) 623-627 (1992). 55. F.W. Goodhart et al., J. Pharm. Sci. 65 (10), 1466- 1471 (1976).
13. S. Fort et al., br. J. Clin. Pharmacol. 37 (5) 460-463 (1994). 56. T. Makino, M. Yamada, and J. Kikuta/Takeda Chemical Industries, “Fast
14. L. Haegeli et al., br. J. Clin. Pharmacol. 64 (6) 804–809 (2007). Dissolving Tablet and Its Production,” EU Patent 0,553,777 A2 (1993).
15. J. McIntyre et al., The Lancet 366 (9481) 205-210 (2005). 57. P. Humber-Droz, M. Seidel, and R. Martani/Novartis Consumer Health, “Fast
16. P.J. Fudala et al., N. engl. J. med. 349 (10) 949-958 (2003). Disintegrating Oral Dosage Form,” PCT Patent WO 97/38679-A1 (1997).
17. Z. Bayrak et al., eur. J. Pharm. biopharm. 78 (3) 499-505 (2011). 58. K. Nakamichi, S. Izumi, and H. Yasuura / Nippon Shinyaku Company Ltd.,
18. A. Supervia et al., br. J. Urol. 81 (1) 27–30 (1998). “Fast Soluble Tablets,” EU Patent 0,627,218 A1 (1994).
19. M.M. Rawas-Qalaji, F.E. Simons, and K.J. Simons, J. Allergy Clin. Immunol. 59.Z. Bayrak, C. Tas, U. Tasdemir, H. Erol, C.K. Ozkan, A. Savaser and Y. Ozkan,
117 (2) 398-403 (2006). eur. J. Pharm. biopharm. 78 (3) 499-505 (2011).
20. X. Gu, K.J. Simons, and F.E.R. Simons, biopharm. Drug Dispos. 23 (5) 60. R-K Chang et al., Pharm. Technol. 24 (6) 52–58 (2000).
213–216 (2002). 61. M.D. Costanzo, “Flashtab and T-Mask Technologies,” in Proceedings of the
21. M. Volterrani et al., Am. J. med. 99, 119-122 (1995). 7th International Glatt Symposium (1997), pp. 1–9.
22. T.M. Price et al., obstet. Gynecol. 89 (3) 340-345 (1997). 62. G. Cousin, E. Bruna, and E. Gendrot/Laboratories Prographarm, “Rapidly
23. G. K. Pedersen et al., PLoS oNe 6 (11) e26973 (2011) doi:10.1371/journal. Disintegratable Multiparticular Tablet,” US Patent 5,464,632 (1995).
pone.0026973. 63. T. Murakami et al., Proc. Intl Symp. Control. rel. bioact. mater. 26, 855–856
24. J.H. Song et al., Proc. Natl. Acad. Sci. USA. 105 (5) 1644-1649 (2008). (1999).
25. S. Raghavan et al., Infect. Immun. 78 (10) 4251–4260 (2010). 64. W. Habib, R.K. Khankari and J. Hontz, Crit. rev. Ther. Drug Carrier Sys. 17,
26. A.H. Beckett and R.D. Hossie, “Buccal absorption of drugs,” in Handbook 61-72 (2000).
of experimental pharmacology, B.B. Brodie and JR Gillette Eds. (Springer- 65. J.S. Ferran et al., “Orally Disintegrating Tablets and Process for Obtaining
Verlag, Berlin, 1971), pp. 25-46. Them,” WO 103629 (2003).
27. A.H. Beckett, R.N. Boyes, and E.J. Triggs, J. Pharm. Pharmacol. 20 (2) 92-97 66. G. Abdelbary et al., Int. J. Pharm. 292 (1-2), 29-41 (2005).
(1968). 67. S.K. el-Arini and S.D. Clas, Pharm. Dev. Technol. 7 (3), 361-371 (2002).
28. N.F.H. Ho and W.I. Higuch, J. Pharm. Sci. 60 (4) 537-541 (1971). 68. P.J. Dor and J.A. Fix, Pharm. Dev. Technol. 5 (4), 575-577 (2000).
29. K.R.M. Vora, W.I. Higuch, and N.F.H. Ho, J. Pharm. Sci. 61 (11) 1785-1791 69.Y. Bi et al., Chem. Pharm. bull. 44 (11) 2121-2127 (1996).
(1972). 70. N. Narang and S. Jyoti, Int. J. Pharm. Pharm. Sci. 3 (2), 18-22 (2011).
30. L.S. Schanker, Adv. Drug. res. 1, 71-106 (1964). 71. J.H. Park et al., Pharm. Tech. 32 (8), 54-58 (2008).
31. F. Sadoogh-Abasian and D.F. Evered, br. J. Nutr. 42 (1) 15-20 (1979). 72. M.M. Rawas-Qalaji et al., AAPS PharmSciTech. 7 (2), E72-E78 (2006).
32. D.F. Evered and J.V. Vadgama, biochem. Soc. Trans. 9 (1) 132-133 (1981). 73. S. Deepak et al., Int. res. J. Pharmacy 3 (4), 108-116 (2012).
33. D.F. Evered, F. Sadoogh-Abasian and P.O. Patel, Life Sci. 27, 1649-1661 74. K. Woertz et al., Int. J. Pharm. 417 (1-2), 256-271 (2011).
(1980). 75. Y. Katsuragi, M. Kashiwayanagi and K. Kurihara, brain res. Protoc. 1 (3), 292-
34. D.F. Evered and C. Mallett, Life Sci. 32, 1355-1358 (1983). 298 (Aug 1997).
35. S.D. Roy and G. Flynn, Pharm. research, 6 (2) 147-151 (1989). 76. S. Kamalpreet and V.R. Kapoor, Ind. J. Pharm. Sci. 72 (2), 211–215 (2010).
36. S. Bredenberg et al., eur. J. Pharm. Sci. 20 (3) 327-334 (2003). 77. FDA, Guidance for Industry, Q4b evaluation and recommendation of
37. S. Riahi et al., J. Chinese Chemical Soc. 55 (2) 345-355 (2008). Pharmacopoeial Texts for Use in the ICH regions (Rockville, MD, February
38. N.Y. Li, Y. Li and J.W. Gorrod, med. Sci. res. 20, 901-902 (1992). 2008).
39. C.A. Lipinski et al., Adv. Drug Deliv. rev. 46, 3-26 (2001). 78. FDA, International Conference on Harmonization—Quality, www.fda.
40. A.M. Al-Ghananeem, A.H. Malkawi, and P.A. Crooks, AAPS PharmSciTech. gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
7 (1) Article 23 (2006). ucm065005.htm, accessed 2 Oct. 2014. PTE
magenta
cyan
yellow
TROUBLESHOOTING
Using Flow Sensors

to Monitor Process
System Health
Monitoring compressed air use helps identify problems
early and provides data for improving energy efficiency.
C ompressed air is used throughout the

pharmaceutical manufacturing facility to actuate
valves, manipulate products or pressurise vessels
Flow is related to but independent of the principles
of air pressure. Although air pressure determines
the amount of force or torque at the field device, the
Craig Correia
is head of Process
Automation at Festo USA,
in processes from API production to secondary proper volume of air must be supplied to reach and [email protected].
packaging equipment and at every process in maintain the pressure. Volumetric flow, however, is
between. Proper monitoring of compressed airflow seldom measured in pharmaceutical plants today.
and consumption can tell operations personnel much A leaking seal inside an actuator or a broken tube
about the health of the system and provide specific might not be enough to cause a pressure drop and
and crucial diagnostic information before larger can easily go undetected. Without a flow sensor,
problems occur. Monitoring also provides necessary the problem may not be realised until there is a
data to ensure that long-term energy costs in the further or complete failure of the component and a
plant do not mysteriously increase. downstream process fails. A pharmaceutical plant
can have as many as 5000 pneumatic solenoid valve
controlling processes and more than five miles of
Flow sensors provide tubing, so there is a lot of opportunity to improve
crucial diagnostic information. this analysis.
Most applications or skids used in pharmaceutical Flow sensor function

production and packaging have an air preparation Flow sensors are available as stand-alone products
assembly on the front end (see Figure 1) to regulate that can be mounted inline in an existing tube or pipe
pressure, filter the air to cleanliness levels required (see Figure 2a) or integrated into an air-preparation
by the US Food and Drug Administration, provide a assembly with the filter and regulator (see Figure 2b).
manual on/off valve and monitor the system pressure. The flow sensor will send digital and analog signals
The pressure sensor in this assembly will alert the back to the controller for analysis, data collection
control system if there is a pressure drop that will or display on a touch screen. Most are freely
cause actuation components to not perform properly programmable to set threshold values, window
or a pressure spike that can result in component or comparators and hysteresis directly on the sensor.
instrument damage. Flow sensors measure flow rates and/or volumetric
air consumption. Flow sensors for compressed air are
Figure 1: A control cabinet in an API manufacturing also suitable for use with nitrogen, thus allowing them
process contains an air-preparation assembly. to be used to monitor vessel sealing and blankets.
Air loss as failure indicator

In its simplest use, a flow sensor, similarly to a
pressure sensor, will provide a digital signal to the
controller when its limits are exceeded. The flow
sensor complements the pressure sensor well in this
basic capacity because it ensures the equipment has
the required airflow to function as designed.
DANLEAP/GETTY IMAGES
Analog data provides an important tool for improving

the heath of a system. It is possible to monitor the
flow rate of a given process or timeframe and do
comparative analysis. This information is available to
magenta
cyan
yellow
Troubleshooting
Figure 2: Flow sensors can be mounted (a) in-line (Festo, SFE3) or (b) embedded • Define why and how the flow
in an air preparation unit (Festo, SFAM). data will be used and select a
sensor capable of providing flow
(a) (b) rate, volumetric consumption,
comparative flow analysis or some
combination.
• Define pipe or tube size when the
sensor will be mounted in-line.
• Determine if electrical signals
should use PNP or NPN-type
configurations.
• Calculate the number of analog and
digital inputs required based on the
number of flow meters and ensure
these inputs are available.
In addition, users should create
Figure 3: Flow meters with high Benchmarking efficiency a functional description of how the
capacity are typically installed at the Industry is increasingly considering sensor will be used and what type
front end of equipment (Festo, SFAM). energy efficiency, and compressed of analysis is expected so changes
air is recognised as a critical energy can be made at the control and
resource. Large companies are programming level. Looking ahead,
putting reduction targets into project once this analysis is available, set up a
objectives, which impacts equipment plan on how it will be used. Data can
selection. Equipment manufacturers be reviewed as part of preventative
desire to quantify how new models maintenance programmes. Certain
have gained efficiency. alerts can force operations personnel
Flow sensors make air to investigate further.
consumption transparent. Using the Particularly with the energy
cumulative air consumption operating conservation effort, once the
mode, the sensor works like a meter information is available, the question
and it is possible to measure the shifts to “What do we do with this
volume of air consumption for a given information?” and “How do we
process or over time. If, for example, implement the solutions?” Until these
a process is consuming 15% more steps are completed, the benefit of
the controller, where it can be locally compressed air compared to two the flow sensor is not fully realised.
analysed, displayed, maintained in a years prior, the plant has gained a Costs of compressed air in North
data log, used to create an alert or critical piece of diagnostic information America are about $0.30 per 1000
passed on through the supervisory- that can help guide corrective and scf. This means a single leak can cost
control and data-acquisition system energy-savings actions. more than $3000 in annual electricity
for further analysis. cost. A single flow sensor and a
An increase in compressed Selecting a flow meter successful preventive maintenance
air consumption can be an early When selecting and integrating a programme can have a payback
indication of: flow sensor, several points should be period of a few weeks.
• Leaking seals at a quarter-turn considered, as follows:
actuator or pneumatic-linear • Determine where in the process Conclusion
actuator you want to measure the airflow Whether designing a single piece
• Early-stage cracks in piping or or consumption to help determine of equipment or a complete facility,
welds whether it should be integrated into proper use of a flow sensor to monitor
• Failing flexible tubing or fittings an air preparation unit or mounted compressed air consumption can
• Solenoid valves not closing in-line downstream. To measure provide crucial data to increase uptime,
properly flow into equipment, a flow meter improve troubleshooting of the process
• Failing pneumatic pumps with high capacity, such as the flow and help manage long-term energy
• Problems with a nitrogen air meter shown in Figure 3 (Festo, costs. Although it is easier to integrate
blanket SFAM), is typically installed inline. flow sensors when equipment is initially
All figures are courtesy of the author.
• Faulty vessel seals. • Calculate the range of flow that will designed, these components can be
Investigating the source of this be measured. Flow sensors have easily added to existing installations. To
consumption increase early on and different ranges, and selecting a achieve the maximum benefit, a strong
correcting the problem will improve sensor with wide band will impact emphasis must be placed on follow
the performance and uptime of all data accuracy. through and preventative maintenance
automated plant equipment. • Decide if local display is required. based on the data. PTE
magenta
cyan
yellow
Systematic and Efficient Analytical
Method Development for A Speedy
Clinical Product Development
ON-DEMAND WEBCAST
REGISTER FREE AT www.pharmtech.com/Efficient
EVENT OVERVIEW
This webinar will present strategies for fast, efficient, and effective analyti- PRESENTERS
cal method development for preclinical and early clinical development ANDREW LEASON
programs. In most cases, development and qualification of analytical Analytical Development
methods is rate-limiting for drug candidates moving rapidly from discov- Scientist
ery to first-in-man studies. The key to success is to balance the tasks of Patheon
performing sufficient method development to ensure safety in the clinical
programs; building a base of scientific knowledge to support develop- RICHARD R. GOODIN
ment; and meeting development timelines with available resources. Pre- Senior Analytical Chemist,
sentations will include discussions and case studies for: Early Development,
Pharmaceutical
• Rapid chromatographic method development
Development Services
for preclinical drug programs
Patheon
• Analytical method problem solving for early
clinical development formulations
MODERATOR
RITA PETERS
KEY LEARNING OBJECTIVES Editorial Director
• Understand how to rapidly develop analytical Pharmaceutical Technology
methods for preclinical drug programs
• Identify and solve problems with analytical
methods for early clinical formulations
• Understand trade-offs between available scientific Sonsored by:
knowledge and project deadlines from an analytical
method development perspective
WHO SHOULD ATTEND

• Analytical development scientists responsible for Presented by:
development and validation of test methods for preclinical
and early clinical development programs
• Project managers responsible for coordination of
preclinical and early clinical development program
• Regulatory CMC specialists involved with preparation
of IND/CTX documentation for first-in-man studies FOR QUESTIONS, CONTACT
• Formulation scientists involved with early-stage formulation Kristen Moore at
for toxicology and Phase I clinical studies [email protected].
magenta
cyan
yellow
CPhI RounduP
CPhI 2014 at a Glance—

So Much to See, So Little Time…
From APIs and excipients to custom manufacturing, finished formulations and pharmaceutical
packaging, CPhI features products and services spanning the entire pharmaceutical supply chain.
Adeline Siew, Phd

O nce again, CPhI Worldwide together with its
colocated events—ICSE, P-MEC and InnoPack—
has proven that it is not only a networking and sourcing
enhancement portfolio. Developed in collaboration with
Bend Research, the AFFINISOL HPMCAS (hydroxypropyl
methylcellulose acetate succinate) polymers help
event but also a place where innovations thrive. With maintain stable solid dispersions and inhibit API
more than 2500 exhibitors gathered at Paris Nord crystallisation. Dow has also designed a novel cellulosic
Villepinte, France on 7–9 Oct. 2014, visitors had the polymer with improved thermal properties for hot-melt
opportunity to learn more about the various products extrusion (HME) applications. AFFINISOL HPMC HME can
and services offered across the entire pharmaceutical be readily extruded over a wide range of temperatures
manufacturing supply chain. without the need to add plasticisers. Studies with
itraconazole and griseofulvin, which are BCS Class II
Excipients drugs, show that AFFINISOL HPMC HME offers a greater
Beneo-Palatinit showcased its multifunctional excipient, processing window as well as achieves and maintains
GalenIQ, for oral solid dosage forms, including tablets, supersaturation with multiple release profiles (3).
capsules, lozenges, granules and pellets. This non- PROSOLV EASYtab SP from JRS Pharma is an all-
hygroscopic, physically and chemically stable excipient in-one, ready-to-use, high functionality, excipient
is available in a variety of particle sizes, morphologies composite that combines binder/filler, glidant,
and solubility, and serves as an anti-caking agent, anti- superdisintegrant and lubricant for rapid formulation
humectant agent, stabiliser and taste-masking agent development and convenient tablet manufacture.
among its various functions. Roquette showcased its capsule filling solutions.
Cafosa showcased its Health in Gum, an excipient Lycatab C-LM is a low-moisture partially pregelatinised
used in medicated chewing gum. The directly maize starch, used as a hard capsule filler for
compressible powder gum, which consists of gum moisture-sensitive APIs. The company’s new directly
base, sweeteners and polyols, was created to simplify compressible polyols—mannitol, maltitol, xylitol and
the manufacturing process of compressed and sorbitol—can be used to create a variety of tastes and
medicated chewing gum. The API can be added to the textures for all types of tablets.
ready-to-use powder.
Croda’s range of excipients for oral, parenteral, Formulation
topical and ophthalmic formulations are produced Capsugel’s proprietary lipid multiparticulate (LMP)
using the company’s proprietary super refining technology brings together the advantages of lipid-
process to offer the highest level of purity. The flash based technology and multiparticulate formulations.
chromatographic process removes polar and oxidative Applications include taste-masking, controlled release
impurities from the excipients without altering their and bioavailability enhancement. Complementing the
fundamental structure (1). Croda’s super refined range LMP technology is the company’s Coni-Snap sprinkle
include polyethylene glycols (PEFs), polysorbates, capsules that are easy to open, enabling the contents
oleic acid, oleyl alcohol, isopropyl myristate and to be sprinkled into soft food for patients who have
dimethyl isosorbide, as well as medical-grade lanolins, swallowing difficulties.
poloxamers and omega-3 fatty acid concentrates. Catalent Pharma Solutions continues to expand its
The Dow–Colorcon Alliance presented the next technology offering in biologics, following the acquisition
generation hydroxypropyl methylcellulose (HPMC) of Redwood Bioscience and the SMARTag antibody
excipient, METHOCEL DC2, which provides an alternative drug conjugate (ADC) technology platform. SMARTag
to wet granulation in matrix tablet production. The enables the production of homogenous bioconjugates
improved flow properties and process capability of with improved performance and ease of manufacturing.
powder blends delivered by METHOCEL DC2 helps to ADCs generated using this novel site-specific technology
reduce waste, shorten development time and lower demonstrated better toxicity profiles in vivo (4).
manufacturing costs by up to 60% (2). Hermes Pharma, specialist in the development and
Dow has also expanded its AFFINISOL solubility- manufacturing of user-friendly solid oral dosage forms,
cyan
yellow
CPhI Roundup
showcased its effervescent dosages, for ready-to-use pharmaceutical software, enables evaluation of new
chewable tablets, orally disintegrating vials, consisting of a nest and tub tablet formulations.
granules, lozenges and instant drinks. configuration that allows for direct Micro-Macinazione SA showcased its
PSL presented its microsphere filling, freeze-drying, weighing and advanced micronisation services and
refiner technology, which enables closing inside the nest. SCHOTT equipment. The company specialises in
downstream processing of also showcased its break-resistant, the design and manufacturing of spiral
microsphere formulations in one lightweight and transparent TopPac and opposed jet mills, containment
step with more than 97% recovery of polymer syringes, which are designed systems, rigid and flexible glove box
the final product (5). Microparticles to administer highly viscous drugs and isolators and pneumatic conveyors.
are filtered, washed and dried in the infusion therapy with large-volume Micro-Macinazione’s cGMP jet mills
microsphere refiner, and this process syringes via infusion pumps. The cater for different capacities from API
can be efficiently scaled up from R&D company’s syriQ InJentle prefilled batches of a few grams to full tons.
to commercial manufacturing. PSL also syringes for highly sensitive biotech
showcased its Mini Lab Glass Filter drugs offers improved drug stability Analytical technologies
Dryer, designed for filtration and drying through its unique design and features Rigaku Raman Technologies introduced
of microsphere drug-delivery systems an innovative tamper-evident seal. its new handheld Raman analyser for
on a laboratory scale, as well as it’s Another highlight was West raw material identification. Progeny
new pilot plant filter dryer, the Simple Pharma’s portfolio of drug packaging eliminates issues of fluorescence
Filter Dryer for filtration, washing and and delivery solutions. The company interference with the use of a 1064 nm
drying of API and intermediates. exhibited packaging solutions such excitation laser and enables the
as the West Ready Pack system, a measurement of materials through
Packaging and convenient, one-stop solution for thick, coloured bottles as well as
drug-delivery systems sterile vials, stoppers, seals and vial other materials known to cause
Locked4Kids is a child-resistant carton adapters; NovaPure component; fluorescence interference, such as
that is easily opened by seniors. The Westar RU steam-sterilized plungers sodium carboxy methyl cellulose,
innovation, which was launched at and Westar RS/RU cartridge alginic acid and cell culture media used
CPhI and won the CPhI Pharma Award components. Drug-delivery offerings in biopharmaceutical manufacturing (7).
in the packaging category, consists include the Daikyo Crystal Zenith
of a tray that locks into the carton prefilled syringe system and West’s References
when fully inserted. The packaging self-administration solutions—the 1. Croda, “Super Refined,” www.
has “push points,” placed diagonally SmartDose electronic wearable crodahealthcare.com/home.
across at a distance that is easily injector, the ConfiDose autoinjector aspx?s=149&r=344&p=2257, accessed
managed by adults, but not young and the SelfDose injector. 20 Oct. 2014.
children. Available in a range of sizes, 2. Dow, Colorcon, “Dow-Colorcon
Locked4Kids meets European and Process development Alliance will Commercialise Next-
American standards for reclosable DSM Sinochem Pharmaceuticals Generation HPMC Excipient by
child-resistant packaging and is (DSP) introduced a new generation of Year-End, to Help Lower tablet
suitable for mass production. eco-friendly super-statins, produced Manufacturing Costs by up to 60
Gerresheimer showcased its using the company’s fully backward Percent,” Press Release, 7 Oct. 2014.
innovative glass and plastic packaging integrated process, which involves 3. Dow, “Dow Continues to Strengthen
solutions for the pharmaceutical a highly efficient enzymatic step. its AFFINISOL Portfolio to Help Pharma
industry, with products ranging from This unique proprietary technology Solve the Insoluble,” Press Release,
pharmaceutical vials to complex yields APIs with higher purity at a 7 Oct. 2014.
drug-delivery systems. Nemera’s lower carbon footprint (6). The super- 4. Catalent, “Catalent Expands Its
portfolio, on the other hand, include its statins are the latest addition to DSP’s Technology Offerings In Biologics,
preservative-free multidose eyedropper portfolio of PureActives drugs. Acquires Redwood Bioscience Inc. and
(Novelia); a fully passive safety device the SMARTag Technology Platform,”
for prefilled syringes (Safe’n’Sound); Equipment Press Release, 2 Oct. 2014.
and the company’s precision metering Bosch Packaging Technology 5. PSL, “PSL launch two new innovations
valves for pressurised metered dose showcased its compact laboratory at CPhI-PMEC worldwide in Paris,” Press
inhalers (Inhalia). systems, including equipment from Release, 29 Sept. 2014.
Stiplastics’ innovative granule and its Hüttlin and Manesty range for 6. DSM Sinochem Pharmaceuticals, “DSM
tablet dispenser has the ability to processing of pharmaceutical liquid Sinochem Pharmaceuticals creates new
deliver the precise number of granule and solid dosage forms. The smallest generation of eco-friendly super-statins,”
or tablet required, without the high-shear mixer granulator in the Press Release, 10 Oct. 2014.
medication getting jammed inside the laboratory equipment range, Hüttlin 7. Rigaku Raman Technologies, “Rigaku
system. The novel one-push system Mycromix, offers homogeneous mixing Raman Technologies to Showcase
supports variations in pill size and for granulation applications with short World’s First Customisable Handheld
shape. drying times. The company’s compact Raman Analyser for Accurate and
One of the displays at the SCHOTT and mobile tablet press, Manesty Comprehensive Raw Material ID at CPhI
booth was adaptiQ, a new system Xpress 100, with its data acquisition 2014,” Press Release, 14 Aug. 2014. PTE
cyan
yellow
3M DRUG DELIVERY SYSTEMS SPONSORED CONTENT
Ingrid Blair
Business Vice President
3M Drug Delivery Systems
PARTNER WITH 3M IN DRUG DELIVERY

TECHNOLOGIES AND CONTRACT
MANUFACTURING SERVICES
An increasing emphasis on patient compliance and preference has
been a driving force behind pharmaceutical development recently.
Regulators want to see that human factors have been taken into
account for new products, and patients want solutions that align
well with their lifestyles and diagnoses. Innovation in drug delivery
can help satisfy both needs.
By looking to alternative drug delivery methods or even adding simple features to current products,
manufacturers can give patients tools that will help them stay compliant. For example, adding the
3M™ Integrated Dose by Dose Counter to a metered dose inhaler can help patients keep track of how
much medication they have remaining. The counter provides visual confirmation that the dose has
been dispensed, helping patients feel confident and reducing the chance that they will unexpectedly
run out of medication.
Alternative drug delivery methods can also be very valuable in building patient preference. For instance,
many patients experience difficultly swallowing pills. For these patients, the option of a transdermal
patch may be ideal, as it offers virtually painless administration, as well as visual proof that a dose has
been administered. It’s also caregiver-friendly and may offer efficacy benefits, as transdermal delivery
can avoid first past metabolism and help maintain a steady blood level of medication.
These examples illustrate how manufacturers can gain patient preference and help patients stay in
compliance by incorporating patient-friendly delivery features. Development of these features is driven
not only by the needs of pharmaceutical companies, but by paying careful attention to the voice of the
end-user. 3M Drug Delivery Systems maintains ongoing dialogues with regulators, payers, healthcare
professionals and patients to stay informed of their needs and continue creating new solutions.
ABOUT INGRID BLAIR

Ingrid Blair is Business Vice President in the Drug Delivery Systems Division of 3M and has spent
more than 25 years at 3M in positions of increasing responsibility in technology development,
laboratory management and global business leadership.
ABOUT 3M DRUG DELIVERY SYSTEMS

3M Drug Delivery Systems provides customers with proven inhalation, transdermal, oral and topical
manufacturing expertise, while ensuring the highest standards of manufactured product delivery from
feasibility to market.
Company Name : 3M Drug Delivery Systems

Phone : 1-800-643-8086
Email : [email protected]
Website : www.3M.com/dds
46 Pharmaceutical Technology Europe NOVEMBER 2014 PharmTech.com P h a r mTe c h . c o m
magenta
cyan
yellow
EUROFINS BIOPHARMA PRODUCT TESTING SPONSORED CONTENT
Michael McDowell
Vice President, Business Development
and Project Management
Eurofins BioPharma Product Testing
STRATEGICALLY ENGAGING CLIENTS

TO MEET THEIR UNIQUE OUTSOURCING &
INSOURCING NEEDS
As with any industry, over the course of time, there are a myriad
of factors that influence the ebb and flow of a business segment’s
market demand. Currently, two prime factors are affecting the
demand for biopharmaceutical contract services. These factors
include a shift toward a reduction of fixed costs for large bio/pharma
companies and favourable funding conditions for small/virtual and midsize biotechs. For a contract
testing service provider, flexibility and tailoring quality service solutions to a vastly different set of drug
development and manufacturing challenges combined with the ability to quickly add capacity are
paramount. As the largest global network of harmonised biopharma GMP product testing laboratories,
Eurofins BioPharma Product Testing strategically engages clients to meet their unique outsourcing and
insourcing needs by helping them effectively allocate their research and manufacturing expenditures.
Over the past five years, most big biopharma companies have embraced outsourcing to help achieve
their strategic objective of reduced fixed costs. Biopharma product testing is one area where we can
help large drug developers and manufacturers achieve this goal. To better accommodate specific testing
requirements, clients choose from our multiple service models. If it is best to keep the testing on site, work
is insourced through our award-winning Professional Scientific Staffing solution. If dedicated resources are
needed, a team of scientists is contracted through our full time equivalent (FTE) model. These options, in
addition to the traditional fee-for-service model, provide flexibility resulting in increased outsourcing. Having
the harmonisation, capacity and capabilities to manage projects of any size at our global facilities as well as
the qualified staff to perform testing at our clients’ global sites have been valued service benefits.
The second factor that is fueling outsourcing is the fact that small/virtual and midsize biotech companies
are well-financed due to extremely favourable funding markets. Ninety-seven life-science companies
raised $6.7 billion through IPOs last year (Bloomberg Businessweek, March 2014). Our research shows
that a combination of all external funding and global partnerships raised an estimated total of $38 billion for
this sector in 2013. Confidence in the ability to get funding has accelerated the development of proprietary
molecules, which has resulted in an unprecedented demand for global cGMP product testing services.
Fortunately, we have a financially strong, strategic, parent company, Eurofins Scientific, with 200 locations
in 36 countries, supplying the resources we need to grow and support our clients’ innovative technologies.
For the past 50 years, whether our clients have had outsourcing or insourcing needs, they trust
us as the industry gold standard to deliver a stellar work ethic, highest standards of quality testing
and data, and dedication to project satisfaction. Partnering with our clients to help them navigate a
challenge into a success is always the optimum goal.
ABOUT MICHAEL J. MCDOWELL

Michael J. McDowell, B.A., is Executive Vice President of BioPharmaceutical Business Development,
Marketing & Communications, and Project Management at Eurofins Lancaster Laboratories, part of
Eurofins BioPharma Product Testing. Mr. McDowell began his career with the company in 1995.
ABOUT EUROFINS BIOPHARMA PRODUCT TESTING

The largest network of harmonised bio/pharmaceutical GMP product testing labs worldwide, Eurofins
BioPharma Product Testing enables companies to advance candidates from development through
commercialisation while ensuring regulatory compliance, cost effectiveness and achievement of timelines.
Company Name : Eurofins BioPharma Product Testing

Phone : +001 717-656-2300
Website : www.eurofins.com/Biopharma
Pharmaceutical Technology Europe NOVEMBER 2014 47
magenta
cyan
yellow
WEST PHARMACEUTICAL SERVICES, INC. SPONSORED CONTENT
Mike Schaefers
Vice President, Global Marketing
West Pharmaceutical Services, Inc.
CHALLENGES AFFECTING
PHARMACEUTICAL DEVELOPMENT
While Western markets, such as North America and Europe, show
moderate demand increases for pharmaceutical packaging, there
is tremendous growth in emerging markets such as China, India,
Brazil, Middle East and North Africa (MENA) as well as Eastern
Europe. These markets are gaining importance rapidly. However,
every market in the emerging economies has unique characteristics
that have to be managed in terms of product and quality
requirements, product registration requirements, local competition
and more. Nonetheless, emerging markets demand good product quality at an affordable price.
In Western markets increasing regulatory and quality requirements, such as low defect rates, quality-
by-design requirements, more stringent requirements for combination products, stronger focus on
patient safety along with an increasing pressure on costs, have challenged the pharmaceutical packaging
industry to produce high-quality packaging components that meet the needs of the drug product, but
also match requirements for combination products to ensure ease of use by the patient.
Glass has been the global standard for many years for parenteral products and certainly will play a
major role in the future. However, other materials, especially high-quality polymer container made of
cyclic olefin copolymers (COC) or cyclic olefin polymers (COP), are gaining importance in the industry
as alternative packaging materials because they address many industry needs. Containers made
from COC or COP will capture more market share, as the materials provide benefits such as break
resistance, reduced particle burden, design flexibility and more.
In addition, as the trend towards self-administration continues, prefilled syringes and cartridges,
especially in combination with injection devices, will see significant increase in demand. Again,
prefilled syringes and cartridges made of COP such as the Daikyo Crystal Zenith® polymer, offer
unique benefits as they provide a silicone-free, tungsten-free solution that can be customised and
tailored to the injection device.
Based on the trends mentioned previously, pharmaceutical companies need to provide solutions
that address increased quality expectations in the market and optimise the total cost of ownership.
In addition, with the increased need for product differentiation as well as higher expectations to meet
patient needs, delivery devices will gain importance. As a result, packaging materials need to enable
the use of delivery devices. Finally, solutions for anti-counterfeiting, serialisation and track and trace
will play a major role in the pharmaceutical packaging market.
At West, we work side-by-side with our healthcare partners from concept to the patient designing
and manufacturing packaging, diagnostic and delivery systems that promote efficiency, reliability and
safety. Talk to West today to determine how we can help you design and manufacture a packaging
and delivery system that is right for your drug product and its users.
ABOUT MIKE SCHAEFERS

As Vice President Global Marketing, Mike is responsible for the global marketing activities of West’s
Pharmaceutical Packaging System Division.
ABOUT WEST PHARMACEUTICAL SERVICES, INC.

West leads the way with cutting-edge technologies and quality systems, a thorough understanding of
regulatory compliance and an unmatched knowledge of pharmaceutical product testing, development
and packaging. Visit us a www.westpharma.com to learn more.
Company Name : West Pharmaceutical Services, Inc.

Phone : +49 2403 7960
Website : www.westpharma.com
48 Pharmaceutical Technology Europe NOVEMBER 2014 PharmTech.com P h a r mTe c h . c o m
magenta
cyan
yellow
START OR RENEW YOUR SUBSCRIPTION TODAY!
 Go to www.pharmtech.com — click on ‘Subscribe’ and scroll down to Pharm
Tech Europe, or
FREE
 Mail form to Pharmaceutical Technology Europe, Advanstar, Bridgegate Pavilion,
Chester Business Park, Wrexham Road, Chester CH4 9QH, United Kingdom, or
 Photocopy this form — complete all sections — fax it back
Fax back on (00)1-218-740-6417 or (00)1-218-740-6437
Answer all questions by flling in the circles ●
1. What is your company’s primary business? (Fill in ONE only) 3. Would you also be interested in Pharmaceutical
100 ◯ Pharmaceutical Manufacturing Technology Europe’s weekly e-newsletter?
110 ◯ Biopharmaceutical Manufacturing (Your Email address is required below.) Y ◯ Yes
150 ◯ Ingredients (e.g. Raw Materials, APIs, excipients,
chemicals, water) 4. Do you recommend, specify, or authorise the purchase of
141 ◯ Contract Services services, equipment, and supplies? Y ◯ Yes N ◯ No
160 ◯ Drug Delivery/Medical Product and Device
Manufacturing (e.g. inhalers) 5. Do you plan to purchase any of the following in the future?
105 ◯ Engineering/Facilities/Construction (Fill in ALL that apply)
80 ◯ University/Academia/Education A ◯ Raw Materials
90 ◯ Government (including regulatory agencies and bodies) B ◯ Processing/Manufacturing Equipment
C ◯ Drug Delivery
2. What is your function? (Fill in ONE only) D ◯ Packaging
10 ◯ Research/Development/Formulation E ◯ Cleanrooms & Contamination Control
20 ◯ QA/QC/Validation/Regulatory Affairs F ◯ Laboratory & Analytical Equipment
33 ◯ Supply Chain G ◯ Process Automation & Control
44 ◯ Manufacturing/Processing H ◯ Outsourced Services
45 ◯ Information Technology I ◯ Compliance & Validation/QA/QC
60 ◯ Engineering
80 ◯ Corporate Management
90 ◯ Project/Purchasing/Procurement/Contract Management
95 ◯ Education Professional
Advanstar Communications provides certain customer contact data (such as customers’ names, addresses,
phone numbers and e-mail addresses) to third parties who wish to promote relevant products, services and
other opportunities which may be of interest to you. If you do not want Advanstar Communications to make
your contact information available to third parties for marketing purposes, please contact us by emailing
[email protected] or by mail at Advanstar, Bridgegate Pavilion, Chester Business Park, Wrexham Road,
Chester CH4 9QH, United Kingdom.
Which version of Pharmaceutical Technology Europe would you like to receive?

◯ Digital ◯ Print ◯ Both
Sign here if you wish to receive (continue to receive) Pharmaceutical Technology Europe FREE
Signature Date
Print your name and address
Mr/Mrs/Ms First name Family name

Please quote your reference
Job Title number if you have it:
Company
Address
PROMO CODE: PTEAD2
*Free to qualifying readers in Europe
Postcode City Country
Please let us have your email address – so we can keep our renewal costs down
E-Mail
Tel.
Fax
magenta
cyan
yellow
PHARMA CONVERSATION & COMMUNITY
HEADLINES ON PHARMTECH.COM/NEWS MOST TWEETED
• The European Medicines Agency (EMA) has stated that • Demand for new Ebola therapies and vaccines spotlights
it intends to work with global regulatory agencies in production challenges. http://bit.ly/ZwgJP1
assisting the World Health Organisation (WHO) to develop, • AbbVie and Shire deal officially off. Shire receives $1.635
evaluate and approve drugs to fight the Ebola virus. billion in break-up fees. http://bit.ly/1r9NKIp
The agency is establishing a group of experts in the field
of vaccines, infectious diseases and clinical trial design.
FACILITY NEWS
EMA also plans to review information on Ebola treatments
currently under development to assist health authorities • Roche has announced plans to expand its Basel site.
with decision-making. Companies have been asked The company will invest 3 billion Swiss francs in the
to send the agency all their quality, preclinical and construction of a modern R&D infrastructure, attractive
clinical data for drugs currently under development. workplaces and sustainable site development.
• IDT Biologika has completed and certified the construction

• GSK is working with WHO, regulators and other partners to of a large-scale production facility dedicated to the filling
accelerate development of its investigational Ebola vaccine and lyophilisation of biologics and vaccine products. The
and to ramp up production as quickly as possible. GSK facility in Dessau, Germany uses a sterile liquid-filling line
acquired the Ebola vaccine candidate through the engineered to handle up to 24,000 vials per hour.
acquisition of a biotechnology company, Okairos, in
May 2013 and has since been working with the EVENTS
National Institutes of Health to develop this vaccine
candidate in response to the Ebola threat. ICH Q7 Compliance for APIs Manufactured by
Chemical Synthesis or Cell Culture/Fermentation
1–3 December 2014
• Johnson & Johnson has committed up to $200 million to
Berlin, Germany
accelerate and significantly expand the production of an
Ebola vaccine in development at its Janssen Pharmaceutical PDA Europe Conference
Companies. The company is closely collaborating with WHO, Outsourcing/Contract Manufacturing
the National Institute of Allergy and Infectious Diseases 2–3 December 2014
Berlin, Germany
and other key stakeholders, governments and public
health authorities on the clinical testing, development,
production and distribution of the vaccine regimen. Join our online community
www.PharmTech.com/LinkedIn
• A new European initiative, DRIVE–AB (Driving Reinvestment http://twitter.com/pharmtechgroup
in R&D and Responsible Antibiotic Use), has been launched
to address the growing threat of antibiotic resistance.
DRIVE–AB is a €9.4 million public-private consortium,
funded by the EU Innovative Medicines Initiative. Its aim
Ad Index
is to define a standard for the responsible use of the COMPANY PAGE
dwindling reserve of effective antibiotics, and to develop, 3M Drug Delivery Systems ................................................................. 46, 51
test and recommend new economic models for BASF............................................................................................................. 37
pharmaceutical investment in new drug candidates. Beneo GmbH ...............................................................................................13
Catalent Pharma Solutions ....................................................................... 52
Dow Europe GmbH ...................................................................................... 2
• The International Society for Pharmaceutical Engineering Eurofins Lanacaster Laboratories .......................................................17, 47
(ISPE) has released its Drug Shortages Prevention Plan. ITT Engineered Valves ............................................................................... 21
Based on ISPE’s 2013 ISPE Drug Shortages Survey, the plan Lucideon ..................................................................................................... 23
was created by industry experts and regulatory agencies Meggle........................................................................................................... 9
Merck Millipore......................................................................................10–11
in the US and Europe. In the plan, ISPE suggests that Nemera ........................................................................................................ 6
companies investigate root causes for drug shortages and Patheon ....................................................................................................... 43
create a quality culture to ensure a reliable supply of drugs. Pet Flavors Inc ............................................................................................ 25
Sensitech .....................................................................................................19
The plan lays out a holistic approach for identifying root
Shimadzu Europe ......................................................................................... 5
causes of drug shortages on technical, quality systems Veltek Associates......................................................................................... 7
and management levels. West Pharmaceutical Services .......................................................... 15, 48
magenta
cyan
yellow
3M DRUG DELIVERY SYSTEMS INHALATION SYSTEMS
Just because we make it

look easy doesn’t mean it is
A contract manufacturer that can navigate

complexity to commercialize your innovation
• Gain a competitive edge by selecting a partner with experience and expertise
• 3M developed the first Metered Dose Inhaler (MDI)
• FDA approval of six new MDI products in six years, in conjunction with our partners
• Pressure-fill and cold-fill systems technology and the people with the skills to
use it properly
• Expertise at commercializing innovation that will get your product ready for
market faster
Visit 3M’s stand (#45) at DDL to discuss your inhalation needs!
US: (1) 800 643 8086 Watch the contract manufacturing video: go.3M.com/Inhalation
UK: (44) 1509 613626
ASIA: (65) 6450 8888
©3M 2014. All Rights Reserved.
3M is a trademark of 3M Company. EXPERTS AT COMMERCIALIZING INNOVATION
magenta
cyan
yellow
best technologies.
broadest expertise.
faster development.
rp scherer softgel technologies

controlled release technologies
optimelt™ hme technology
OSDrC is a registered trademark of Sanwa Kagaku Kenkyusho Co.
osdrc® optidose™ technology
Our 18 R&D teams in 10 countries are now

ʺ 2014 Catalent Pharma Solutions. All rights reserved.
zydis® fast-dissolve technologies

working on 500+ projects, applying multiple
World’s best orally dissolvable tablet
proven and innovative drug delivery technologies – about 3 seconds. Uniquely delivers
to help you deliver optimal release profiles, small or large molecules. 20 Rx and
technology OTC products in 50 markets. NEW
enhanced bioavailability and better dose spotlight taste-masking and higher dose options.
forms—preferred by patients and payers.
Catalent. More products. Better treatments. Reliably supplied.™

us +
+ 11 888
888SOLUTION
SOLUTION eu8846)
(765 eu 00800
00800 8855 8855
6178 6178 [email protected]
solutions catalent.com
@catalent.com catalent.com
TECHNOlOGy SElECTION & ApplICATION  FORMulATION & ANAlyTICAl SERVICES  ClINICAl & COMMERCIAl Supply  TAIlORED OR END-TO-END SOluTIONS
magenta
cyan
yellow

I Am Chemical Engineer - Magazine

Uploaded by

Copyright:

Available Formats

I Am Chemical Engineer - Magazine

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

I Am Chemical Engineer - Magazine

Uploaded by

Copyright:

Available Formats

NOVEMBER 2014 Volume 26 Number 11

Advancing Development & Manufacturing

MARKET REPORT TECHNICAL Q&A PEER-REVIEWED

LOOKING TO IMPROVE YOUR

Want to learn more how METHOCEL™ DC2

Colorcon works together with Dow Pharma & Food

®�Trademark of The Dow Chemical Company ÅDowÆ or an afÑliated company of Dow.

source of peer-reviewed research and expert analyses for

development, manufacturing, formulation and drug

Features Columns and Regulars

Pharmaceutical Technology Europe November 2014 3

4 Pharmaceutical Technology Europe November 2014 PharmTech.com

• Complete solution package

Ebola and the

Adeline Siew, PhD

6 Pharmaceutical Technology Europe November 2014 PharmTech.com

LEARN MORE AT WWW.STERILE.COM

8 Pharmaceutical Technology Europe NOVEMBER 2014 PharmTech.com

RetaLac® the HPMC/lactose co-processed ex- – 50 parts HPMC (K4M) and

RetaLac® from MEGGLE:

MEGGLE HEAD OFFICE GERMANY

Sterility testing made reliable

Sterility testing made easy

A t the 2014 CPhI trade show, held 7–9 Oct. in Paris,

12 Pharmaceutical Technology Europe NOvemBeR 2014 PharmTech.com

Pfizer Ireland Plant

The International Society for

BENEO-Palatinit GmbH · Phone: +49 621 421-150 · [email protected] · www.galenIQ.com

Tackling Drug Shortages

I ncidents of drug shortages in Europe have been increasing

The industry has been training programmes.”

encouraged to develop a technical report on the prevention and management of drug

prevent drug shortages The European Federation of Pharmaceutical Industries

caused by manufacturing Associations (EGA) along with two other pharmaceutical

and quality issues. producers have been working on an improved process

Patient safety should be driving your

Contact West today.

Right In Your Backyard.

With the largest network of harmonized bio/pharmaceutical

While delivering a true local lab experience, our

Germany Post AMNOG: quality of life, and are outlined in

Insights for BioPharma include the possibility that patented

18 Pharmaceutical Technology Europe November 2014 PharmTech.com

One trusted partner for end-to-end temperature

Learn how Sensitech can help protect your products—

Amsterdam Bangalore Boston Hong Kong Melbourne Santiago Shanghai

harms and omission of data for

20 Pharmaceutical Technology Europe November 2014 PharmTech.com

Meet the revolutionary new valve,

Cam-Line® Cam-Tite® Dia-Flo® Fabri-Valve® Pure-Flo® Skotch®

Figure 2: Case summary of IQWiG’s benefit assessment of Kadcyla.

Drug Kadcyla (trastuzumab emtansine, Roche)

22 Pharmaceutical Technology Europe November 2014 PharmTech.com

regarding the rebate amount the pharmaceutical References

Materials Development • Testing • Assurance

Pharmaceutical Technology Europe November 2014 23

Consequences of particulate matter

Parenterals, litres of intravenous fluids are administered

Particulates and death have occurred as a result of the

and Quality concern for the pharmaceutical industry.

®�Trademark of The Dow Chemical Company ÅDowÆ or an afÑliated company of Dow.