NOVEMBER 2014 Volume 26 Number 11

Advancing Development & Manufacturing

PharmTech.com

QbD in
Parenterals
Addressing
Particulate
Contamination

MARKET REPORT TECHNICAL Q&A PEER-REVIEWED

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 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

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 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, wanjane@live.com.sg)
Pharmaceutical Development Jim Miller
asiew@advanstar.com Sean Milmo
GlaxoSmithKline R&D President,PharmSource
(Europe, smilmo@btconnect.com)
PharmTech Group Hellen Berger Reinhard Baumfalk Information Services
Editorial Director (Latin and South America, Vice-President, R&D Colin Minchom
Rita Peters hellen.berger@terra.com.br) Instrumentation & Control
rpeters@advanstar.com
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
shaigney@advanstar.com Publisher Boehringer Ingelheim GmbH BioInsights
Michael Tracey
Gabriele Betz Ian Pearson
Manufacturing Editor mtracey@advanstar.com
Jennifer Markarian
Department of Senior Design Team Leader,
jmarkarian@advanstar.com Sales Manager Pharmaceutical Sciences TSL Projects
Chris Lawson University of Basel, Switzerland
Tim Peterson
Science Editor Tel. +44 1244 629 324 Phil Borman
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Manager, GlaxoSmithKline Development Leader, Drug
rhernandez@advanstar.com
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aroberts@advanstar.com cjoinson@advanstar.com
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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
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Fax +44 1244 678 008 Technology, Hovione Beatriz San Martin
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Waste

4 Pharmaceutical Technology Europe November 2014 PharmTech.com

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 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
asiew@advanstar.com

6 Pharmaceutical Technology Europe November 2014 PharmTech.com

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 DRUG DEVELOPMENT: UKRAINE
Lana Sinichkina is
partner and head of Life
Sciences and Healthcare
Practice, and Leonid
Cherniavskyi is an
associate, both at Arzinger
Law Office,
http://arzinger.ua.
8 Pharmaceutical Technology Europe
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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.
T he pharmaceutical market of Ukraine is rapidly
developing in the light of a recently signed
Association Agreement with the European Union
and plan of actions regarding European integration
approved by the government. Harmonisation of
Ukrainian legislation in the field of pharmaceutical
manufacturing began in 2003 and is led by the State
Administration of Ukraine of Medicinal Products
(SAMP). Since then, the SAMP has been constantly
implementing the EU requirements of good
manufacturing practice (GMP), good distribution
practice (GDP), good storage practice (GSP) and
harmonised procedures of inspection of medicinal
products. GMP and GDP inspectorates successfully
operate within the SAMP.
Continuing harmonisation
with EU GMP standards
The implementation of GMP standards plays an ever
growing role in ensuring the quality of medicinal
products in Ukraine but also impacts operations
of foreign pharmaceutical companies. On 16 July
2014 the Ministry of Healthcare of Ukraine (MoH)
approved the new edition of the Good Manufacturing
Practice Standards (UA-GMP), which is mostly a
Ukrainian translation of the EU Guidelines for Good
Manufacturing Practice for Medicinal Products for
Human and Veterinary Use. The changes of the new
edition correspond with the respective changes in
the EU guidelines, which became effective on 16 Feb.
2014, and concern mainly the section “Definition
of Terms” and Section 2 “Personnel” of Part I (1).
The amendments were made following the needs
of Ukrainian pharmaceutical industry and took
into account the definitions of terms used in the
International Conference on Harmonisation (ICH) Q10
Pharmaceutical Quality System (2). Some of the
updates and amendments are listed in the following.
• To the general wording that the “manufacturer
should have an adequate number of personnel
with the necessary qualifications and practical
experience,” the MoH added clarification that
the ultimate responsibility for an effective quality
NOVEMBER 2014 PharmTech.com
ES522564_PTE1114_008.pgs 10.29.2014 21:05
management system and achievement of quality
objectives is borne by the senior management of
the company.
• The new edition (3) of UA-GMP clarifies situations
when, despite the ban on unexplained overlaps in
personnel responsibilities, certain functions may
be shared between the head of quality control
and head of production and/or the head of quality
assurance or head of the quality unit depending on
the size and structure of the company. Such shared
responsibilities relating to quality may include in
particular the design, effective implementation,
monitoring and maintenance of the quality
management system.
• The qualified person may now be relieved
from performing actions for ensuring that each
production batch imported from outside of Ukraine
has undergone, in Ukraine, a full qualitative
analysis, a quantitative analysis of at least all the
active substances and all the other tests or checks
necessary to ensure the quality of medicinal
products in accordance with the requirements of
the marketing authorisation (4). Such exception
may be allowed “in cases stipulated in Ukrainian
legislation (inter alia, where importation is made
from another state with which Ukraine concluded
an international treaty on measures concerning
compliance by medicinal products manufacturers
with GMP standards that are equivalent with the
provisions of UA-GMP and provided that necessary
control measures were applied in the exporting
country).” The new edition of UA-GMP requires that
a qualified person meet the criteria established in
Ukrainian legislation (5).
• Two more responsibilities were added to the list
of recommended responsibilities of the heads of
(Spotlight image) Image Source/Getty Images
production, quality control and, where relevant,
the head of quality assurance or head of quality
unit: participation in management reviews of
process performance, product quality, and of
the quality management system; advocating
continual improvement; and ensuring that
a timely and effective communication and
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 Drug Development
escalation process exists to raise
quality issues to the appropriate
levels of management (6).
• The new subsection regarding
external consultants was
introduced, requiring that such
consultants should have adequate
education, training and experience,
or any combination thereof, and
that records should be maintained
stating the name, address,
qualifications and type of service
provided by them (7).
Why foreign manufacturers
need to prove conformity
with UA-GMP standards
The Procedure on Conducting
Certification of Medicinal Products
Manufacture (Compliance
Confirmation Procedure) concerning
compliance with UA-GMP Standards
was approved by the MoH back in
2002 and is applied on a voluntary
basis. Although its new edition
(entered into force in February
2013) still stipulates that procedure
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of confirmation of compliance
with UA-GMP standards is applied
upon manufacturer’s will, in 2011,
amendments were introduced to
the Law of Ukraine “On Medicinal
Products” (Law on Medicines), which
required that companies obtain
the document confirming such
compliance.
In the end of 2011, the Law on
Medicines was complemented with
a new requirement to the procedure
of obtaining marketing authorisation
for medicinal products. According
to this amendment, the application
for marketing authorisation had to
be supported, inter alia, with the
document issued by the SAMP,
which confirms that the product
is produced at manufacturing
facilities that comply with UA-GMP
requirements. It should be noted
that such requirement referred only
to products produced by foreign
manufacturers due to the fact that
manufacturing license of local
Ukrainian producers was considered
ES522554_PTE1114_010.pgs 10.29.2014 21:03
to confirm the required compliance.
Furthermore, on 1 Jan. 2013,
the requirement to provide the
mentioned document confirming
compliance of manufacturing
conditions with UA-GMP standards
was implemented to the procedure
of state quality control for imported
medicinal products. This resulted in a
ban on import of medicinal products
in cases when such document could
not be provided.
Companies that could not obtain
the necessary GMP confirmation
from the SAMP for any reason (either
did not meet the deadlines or did
not pass the SAMP inspection) were
unable to import their products to
Ukraine until they managed to obtain
the necessary confirmation, or in
case of failure to obtain one, started
considering transfer of production to
other manufacturing sites including
local contract manufacturing. There
are several examples in 2013–2014
of companies deciding to choose
the second option in cases when
ADV
 Drug Development

their manufacturers failed to obtain
Ukrainian GMP approval. Such
companies, however, faced and
continue to face substantial gaps in
sales of products in Ukraine (which
may have been successful before
the ban) because they had not taken
timely measures to prepare for
the new requirements to UA-GMP
compliance confirmation.
Future amendments in
UA-GMP and procedure for
conformity confirmation
As of today, there is a working group
established under the auspices
of the SAMP that is dedicated to
developing GMP-related legislation.
On 10 Sept. 2014, the SAMP published
the draft of the amended procedure
for obtaining the document, which
confirms compliance with UA-GMP
requirements. The proposed
amendments mostly concern
the procedure of inspection of
manufacturing facilities, order of
adopting the decision to grant the
relevant UA-GMP confirmation
document by the SAMP, as well as
matters of controlling compliance
with UA-GMP requirements during
the term of validity of the named
document. The draft also provides
for extension of the terms of certain
stages of inspection, leading to
extension of the total time needed
to obtain the relevant confirmation
document. Another new requirement
is that only a Ukrainian resident may
represent a foreign company during
the procedure of confirmation of
UA-GMP compliance before the SAMP.
Following the developments
in Ukrainian GMP standards and
compliance, confirmation procedures
are important for pharmaceutical
companies supplying their products
to Ukraine. Failure to adapt
manufacturing facilities or to timely
get the necessary documents from
regulatory authorities may lead
to an inability to obtain marketing
authorisation for a new drug or to
import medicinal products harming
the reputation and revenues of the
company in Ukraine.
References
1. Part I, Guideline “Medicinal Products.
Good Manufacturing Practices,”
approved by the order of the MoH No.
497 dated 16 July 2014, http://ow.ly/
CIuV8, accessed 7 Oct. 2014.
2. ICH, Q10 Pharmaceutical Quality
System, Step 4 version (June 2008).
3. Paragraph 2.1–2.4 “General
Requirements” of Part I, Guideline
“Medicinal Products. Good
Manufacturing Practices.”
4. Paragraph 2.5 of Part I, Guideline
“Medicinal Products. Good
Manufacturing Practices.”
5. Paragraph 2.6 of Part I, Guideline
“Medicinal Products. Good
Manufacturing Practices.”
6. Paragraph 2.9 of Part I, Guideline
“Medicinal Products. Good
Manufacturing Practices.”
7. Paragraph 2.23 of Part I, Guideline
“Medicinal Products. Good
Manufacturing Practices.” PTE

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

York, from UCB Pharma; and Fareva
was able to acquire a manufacturing
and packaging facility with contracts in
Richmond, Virginia, from Pfizer in 2011.
It’s also worth noting that North
American companies have challenges
similar to the Europeans’ when
considering entry into Europe. A
common problem has been the failure
to realise that Europe is not a single
market—not even the European
Union—but rather a collection of
more than 20 countries with different
languages and cultures, and a wholly
different concept of distance. So, for
instance, North American companies
North American
companies have challenges
similar to the Europeans’
when considering entry
into Europe.
have established facilities in Ireland
intended to serve all of Europe, only
to learn that continental companies
view the Irish facilities as far away
and foreign.
As the bio/pharmaceutical
and contract services industries
consolidate, having a global network
of facilities, at least in North America
and Europe, has become increasingly
important for competitive success.
Mid-size European CDMOs and
contract labs must figure out how to
overcome the barriers to their entry
into North America if they intend to
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 · info@galenIQ.com · www.galenIQ.com

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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
with the issue at the production stage are being taken by the
manufacturers themselves. The European Medicines Agency
(EMA) and the variety of national competent authorities
(NCAs), such as licensing bodies and government ministries
responsible for drug supplies at the national level, seem
content to leave it to manufacturers to put forward proposals
for dealing with disruption of output at their production plants.
The industry has been
encouraged to develop
its own solutions to
prevent drug shortages
caused by manufacturing
and quality issues.
EMA believes that the industry’s risk management tends
to be “very reactive rather than proactive.” An agency official
told Pharmaceutical Technology Europe, “Sustained pressure
is needed to bring about a change in a manufacturer’s
approach to quality risk management and supply chain
security.” The agency’s policy has been to encourage “the
pharmaceutical industry to develop its own solutions
to address the prevention of drug shortages caused by
manufacturing and quality issues,” the official added.
Nevertheless, medicine manufacturers want more action
on the issue from the European Union and the governments
of the 28 member states. They reckon the problem has to be
resolved through a broader approach embracing
manufacturers, distributors, healthcare professionals and
even the patients themselves.
Recommendations from industry groups
A number of industry groups have been drawing up or
are close to finalising proposals for dealing with shortages
stemming from manufacturing disruptions. Patient
associations and management consultancies have also been
making recommendations.
The Drug Shortages Prevention Plan of the International
Society for Pharmaceutical Engineering (ISPE) was
discussed at a meeting in early October 2014, attended
by EMA representatives, national regulatory authorities,
14 Pharmaceutical Technology Europe NOVEMBER 2014 PharmTech.com
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Sean Milmo
is a freelance writer based in Essex,
UK, seanmilmo@btconnect.com.
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
quality systems, use metrics to identify and mitigate
risks, foster a corporate quality culture and for improved
communication with the authorities on potential shortages.
“We believe that the industry needs to adopt the proposals in
the ISPE plan,” John Berridge, ISPE advisor, told Pharmaceutical
Technology Europe. “We would like EMA and NCAs to help us
make manufacturers aware of the proposals by, for example,
putting details of them on their websites and by joining us in
training programmes.”
The Parenteral Drug Association (PDA) is planning to publish
a technical report on the prevention and management of drug
shortages. Among its suggestions will be the adoption of
concepts on the control of drug shortage risks based on the
criticality of the product and an overall product risk evaluation.
The European Federation of Pharmaceutical Industries
Associations (EPIA), the European Generic Medicines
Associations (EGA) along with two other pharmaceutical
associations for wholesalers and biopharmaceuticals
producers have been working on an improved process
for communications on shortages. This process would
relate to the way manufacturers inform regulatory
agencies of “meaningful interruptions of supply” (1).
EURORDIS, a rare disease patients group, together with
other patients organisations and professional associations,
including those representing community and hospital
pharmacists, have drawn up a set of proposals, in the form
of a Common Position, on medicines shortages (2). These
proposals include a requirement on drug approval applicants
to provide supply shortage risk assessment plans to regulatory
agencies before gaining marketing authorisation. Manufacturer
and/or marketing authorisation holders (MAH) would have to
inform the regulatory agencies as soon as a shortage becomes
possible. If a shortage occurs, a calendar of production until
the expected end of the shortage would have to be provided.
An unclear definition of drug shortages
Although there is broad agreement in the pharmaceutical
sector that the problem of shortages has been worsening in
recent years, groups differ in their judgement of the
GLOBE: ZOONAR RF/GETTY IMAGES
prevalence and severity of the problem, depending on their
position in the supply chain. The European Association of
Hospital Pharmacists (EAHP) told Pharmaceutical Technology
Europe that 87% of 600 hospital pharmacists it surveyed
considered it to be a problem, particularly with oncology drugs
and antibiotics. There is, however, a lack of consistent and
in-depth data on shortages mainly because it is collected by
national agencies, if at all, and there is no Europe agreement
ES522600_PTE1114_014.pgs 10.29.2014 21:06 ADV
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 on the definition of a “shortage.” Some NCAs have turned
down a request from EMA for the drawing-up of catalogues of
drug shortages in their countries because what was meant by
the term was unclear, especially since the term can have
different connotations in different languages.
“We cannot agree on a definition of shortages,” says
Marten Forrest, spokesperson for the Swedish Medical
Products Agency (MPA), explaining why his agency had
not created a shortages list. “For example, there is the
question of what sort of supply difficulties can be referred
to as a ‘shortage’ and whether these difficulties are global,
European or national,” he continues. “It is difficult to draw
up a list of medicines shortages without a definition.”
There is the question
of what sort of supply
difficulties can be referred
to as a shortage.
This lack of clarity about what are shortages can lead to
gaps in the reporting of them or of manufacturing disruptions
that could cause shortages. “Not all manufacturers are
notifying us about problems they are having which are or
could cause shortages,” said Forrest. “One of the important
signals of existing shortages is phone calls or email messages
from pharmacists asking for more information about a
shortage of a particular medicine we don’t know about.”
Underlying reasons and root causes
The industry now wants much more research into the causes
of shortages, particularly into incidents linking them with
manufacturing difficulties. “We don’t know what are the
amount of shortages arising from manufacturing problems,”
says Berridge. Some governments see the influence of
globalisation on patterns of pharmaceutical manufacturing as
being a major cause of shortages. “The globalisation of the
pharmaceutical industry means that medicines are often
manufactured in just a few sites worldwide,” explains a
spokesman for the UK Department of Health, which is
responsible for drug supplies in the country. “Production
schedules have to be planned months in advance and this
along with the move to ‘just-in-time’ manufacture to reduce
the cost of stockholdings means that there is little flexibility in
the system when problems do arise,” she adds.
In a recent report on medicines shortages in Europe,
birgli AG, a Swiss-based management consultancy linked
government-initiated price-curbs on medicines and legislative
support for parallel trading to reductions in manufacturing
sites and the use of ‘just-in-time’ supply chains.
“Before shortages can be reduced, the underlying
reasons and root causes of shortages should be well
understood,” explained Julie Marechal-Jamil, EGA’s senior
manager quality and regulatory affairs, in an interview
16 Pharmaceutical Technology Europe NOVEMBER 2014 PharmTech.com
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with Pharmaceutical Technology Europe. For quality and
manufacturing-related issues to be tackled properly in
relation to shortages, a combination of measures had to be
taken, Marechal-Jamil added. In addition to the initiation of
shortage-prevention plans at the corporate level, she said
there had to be a harmonised definition of drug shortage,
a harmonised shortages reporting process with identical
trigger points, triaging procedures and timelines, as well as
an improved flow of information along the supply chains.
One key issue yet to be resolved and upon which
there are divergent views even among the regulators is
the relation between GMP rules and supply disruptions
caused by weaknesses in quality control systems, which
could lead ultimately to medicine shortages. “Quality
defects are usually caused by some kind of GMP
failure but not always,” says the EMA official.
However, a different view is taken by some national
agencies that believe they can deal with production
deficiencies causing supply disruptions without reference to
GMP rules. “The obligation to ensure the continuous supply
of medicines so that the needs of patients in the UK are met
is a condition of a manufacturer’s licence [so] this is not a
GMP matter,” says a spokesperson for the Medicines and
Healthcare products Regulatory Agency (MHRA). “MHRA
routinely inspect manufacturers for compliance with the
conditions of their licence and with EU guidance on GMP,”
he continues. “To date there has been no occasions where
MHRA has needed to take action against a manufacturer in
relation to this obligation (in respect of its licence conditions).”
Nonetheless, ISPE reckons there is a close enough
connection between GMP standards and those underpinning
systems preventing supply disruption and procedures for
reporting potential shortages to the authorities. “Since the
EU’s revised GMP guidance will say that manufacturers must
notify competent authorities about impending interruptions
in supplies due to quality issues, GMP inspectors would seem
to be in a position to ask for details about what steps are
being taken in manufacturing plants to avoid disruptions,”
says Berridge “[They will also be able to ask] for details of the
company’s procedure for making notifications of disruptions
to the authorities.” The issue of medicines shortages in
Europe will clearly require a lot of dialogue between the
industry and regulators before significant progress is
made in resolving it. More communication between the
industry regulators is required to resolve the problem.
References
1. Birgitte Holst, Novo Nordisk A/S, “Communications Principles
in cases of Q and Manufacturing driven supply disruptions,”
presentation at the PDA Drug Shortage Workshop (Washington
DC, September 2014).
2. EURORDIS and six other organisations, “Common position
between patients’, consumers’ and healthcare professionals’
organisations involved in the activities of the European
Medicines Agency on supply shortage of medicines,”
www.geneticalliance.org.uk/docs/final_common_position_
supply_shortages_signatures.pdf, accessed 15 Oct. 2014. PTE
ES522611_PTE1114_016.pgs 10.29.2014 21:07 ADV
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Germany Post AMNOG:
Insights for BioPharma
The authors take a look at some of the recent developments
in the German pharmaceutical market.
Jill E. Sackman,
DVM, PhD, is a senior
consultant, and Michael
Kuchenreuther, PhD,
is a research analyst, both
at Numerof & Associates,
Inc., St. Louis, MO,
www.nai-consulting.com.
18 Pharmaceutical Technology Europe
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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
quality of life, and are outlined in
the IQWiG methodology paper (2).
Originally, the law was written to
include the possibility that patented
products already on the market
would have to undergo retrospective
benefit assessments; however,
manufacturers were recently spared
from this potential headache (3).
Once the G-BA reaches a final
conclusion, pricing negotiations begin
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–
from one country to another. While emerging markets continue to Spitzenverband), which negotiates
represent a new channel of demand for pharmaceutical products, on behalf of all SHIs and also private
manufacturers have quickly realised that significant attention must still sickness funds in Germany. It is
be given to more established markets, such as Germany. It’s no longer important to highlight that the ACT
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
November 2014 PharmTech.com
ES522583_PTE1114_018.pgs 10.29.2014 21:05 ADV
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 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
As of May 2014, 79 products have
been assessed by the G-BA within
169 patient subpopulations. More
than 50% of these early benefit
assessments have led to ‘no added
benefit’ rulings by the G-BA (see
Table II) (5).
resembled IQWiG’s recommendations
with a few notable exceptions (e.g.,
belimumab, cabazitaxel, eribulin) (6).
Reasons the G-BA has offered for
‘no proven added benefit’ include
inadequate comparator, lack of a
relevant study to back claims of
benefit, lack of data on potential
served as the published list price for
other markets. This approach is no
longer the case. Since April 2014, the
newly negotiated reimbursement
amounts are published as visible
ex-factory prices, effectively replacing
the original list prices as source for
referencing. Drugmakers fear the

20 Pharmaceutical Technology Europe November 2014 PharmTech.com

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 European Market Report

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
pricing framework within Europe (and
globally) either causing a downward
spiral in reimbursement across the
region or heavy parallel exports
from Germany to other countries.
If this new law is not overturned, it
poses a significant risk to profits in
the industry, especially considering
that price discounts have been
as high as 70% following G-BA’s
benefit assessment and range on
average between 16–30% (10). More
broadly, the new rule reinforces
the importance of manufacturers
understanding the nuances of this
market and having strategies in-place
to achieve successful market access.
Recommendations
for manufacturers
While Germany is certainly not the
only market that is enforcing more
stringent pricing and reimbursement
policies for new therapeutic products,
it is perhaps scrutinising the quality
and appropriateness of clinical data
more so than any other country.
Taken together with the fact that
other markets look to Germany to
determine pricing, manufacturers
should place a greater emphasis
on G-BA’s recommendations when
structuring clinical studies. To date,
the majority of AMNOG submissions
did not have much guiding input
from the G-BA prior to clinical
study design and were based on
evidence generated on a pre-AMNOG
world. Moving forward, proactively
consulting with the G-BA to define
the comparator(s), clinical endpoints
and patient cohorts will be essential.
Manufacturers need to do this early
in product development, especially
prior to starting Phase III trials.
Internally, manufacturers should also
enhance communication between
regulatory and market access teams
to strategically plan for both market
authorisation requirements and
G-BA’s requirements.
Even before G-BA consultations,
manufacturers need to give greater
consideration to the product’s
indication. While the indication
does not determine how the
benefit assessment is conducted,
completed assessments indicate
that it can influence the G-BA’s
comparator choice and a pivotal
trial’s relevance. For products with
broad indications, IQWiG and the
G-BA are demanding clinical data
for multiple patient subpopulations
and against multiple ACTs. For
example, these commissioning bodies
recently distinguished between
four subpopulations and ACTs for
Roche’s Kadcyla (see Figure 2) (11).
Manufacturers that have failed to
anticipate and include such data
are seeing a significant reduction
in the overall level of added benefit
granted to their products (e.g., Pixuvri
and Inlyta) (12). Moving forward,
manufacturers will need to ensure
that all relevant subpopulations have
robust and statistically significant
clinical endpoints to support
reimbursement, with increasing
demand for quality of life data. If
the resources required to study
multiple populations using multiple
comparators are too great, pursuing
a narrower indication for a clearly
defined patient population and
against a single comparator serves as
a viable alternative.
Manufacturers will also have
to keep in mind that every new
indication for a product will trigger
another round of benefit assessment
and a new price negotiation. Here,
attempts to negotiate a higher
price with subsequent indications
may be met with resistance by the
GKV-SV and prove to be a significant
challenge for manufacturers. Thus,
drugmakers should give greater
consideration to the trade-off
between a fast product launch and
the highest value launch.
Aside from data collection and
defining a product’s indication,
manufacturers must also develop
a solid pricing strategy earlier on in
the product development process
and have capabilities to better
predict a products negotiated
price. There is currently no formula

22 Pharmaceutical Technology Europe November 2014 PharmTech.com

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regarding the rebate amount the pharmaceutical
company has to grant on its retail price. Furthermore,
while evidence demonstrating added benefit is required
to avoid reference pricing, it is by no means the sole
determinant of pricing decisions. Rather, the extent to
which a product’s price will be marked down following
a positive benefit assessment is largely dependent
on its original launch price as well as the market size
and price of the appropriate clinical comparator. As
more products go through the product review and
pricing process and as more data become available,
manufacturers should consider developing algorithms
to forecast the benefit assessment outcomes and the
product’s final net price.
The first three years of the AMNOG reform have proven
that demonstrating added benefit is no small feat for
manufacturers, and while complaints continue to be
heard from pharmaceutical stakeholders, the law shows
no signs of slowing down. AMNOG has not only set new
rules for reimbursement and pricing of pharmaceuticals
in Germany, it also forces the industry to adapt at a
global level, rethinking how it brings new products to
market. Manufacturers that prepare thoroughly for benefit
assessment and the negotiation processes within it will
be best positioned for success.
Aknowledgement
The authors would like to thank Stefan Seliger, PhD, for his
review and insights.
SUPPORTING PHARMACEUTICAL
MANUFACTURERS
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European Market Report
References
1. German Pharmaceutical Industry Association/BPI, IMS World
Review 2012.
2. IQWiG, General Methods Version 4.1. (28 Nov. 2013).
3. G. Collier, A tweak or an outrage? Germany passes new
pricing law. 24 March 2014, www.scripintelligence.com/
home/A-tweak-or-an-outrage-Germany-passes-new-pricing-
law-350844, accessed 8 Aug. 2014.
4. IMS Consulting, Pricing and market Access outlook–2013 edition.
5. LEO Pharma Germany, It’s difficult to meet HTA criteria
according AMNOG—reason why? (10 June 2014).
6. J. Ruof, et al., eur J Health econ. 15, 577–589 (2014).
7. PRMA Insights, PrmA Insights Focus: Pricing and
reimbursement Success in Germany under AmNoG (2013).
8. F. Kermani, “Novartis Pulls Galvus From Germany After Failed
Price Negotiations,” The Pink Sheet Daily (19 June 2014).
9. L. Burger and T. Severin, “Germany’s stance on pricing
threatens drug firm profits,” http://uk.reuters.com/
article/2014/02/18/us-germany-drugs-analysis-idUK-
BREA1H09E20140218, accessed 14 Aug. 2014.
10. D. Bahr and T. Huelskoetter, “Comparing the Effectiveness
of Prescription Drugs: The German Experience,” www.ameri-
canprogress.org/issues/healthcare/report/2014/05/21/90120/
comparing-the-effectiveness-of-prescription-drugs-the-
german-experience/, accessed 14 Aug. 2014.
11. Institute for Quality and Efficiency in Health Care,
Trastuzumab emtansine–Benefit assessment according to
§35a Social Code Book V.
12. C. Henry, “Oncology drugs under AMNOG,” PmLive (7 May
2014). PTE
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Materials Development • Testing • Assurance
www.lucideon.com/pte
Pharmaceutical Technology Europe November 2014 23
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 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 parenteral manufacturing industry is taking action
to address particulate contamination issues.
Cynthia A. Challener, PhD, is a contributing editor
to Pharmaceutical Technology europe.
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
may collect in organs and cause damage
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
large quantities of parenteral therapies and
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

24 Pharmaceutical Technology Europe November 2014 PharmTech.com

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 QbD in Parenterals
particulates are generated from within
the glass vial such as glass flakes
that delaminate from the vial wall.
Inherent particulates are derived from
the formulation itself, such as when a
portion of it aggregates or crystallises.
There have been recent recalls
attributed to all three types of
particulates. In August 2014,
Particulate contamination in parenteral drugs packaged in
glass vials has created significant drug shortages recently.
Baxter voluntarily recalled in the
US two lots of Dianeal Low Calcium
Peritoneal Dialysis Solution due to
the presence of oxidised stainless
steel, garment fiber and polyvinyl
chloride particulate matter identified
during the manufacturing process (2).
Cephalon’s January 2012 voluntary
recall of Treanda (bendamustine
HCL) for Injection was based on the
identification of glass fragments in
a single vial (3). In December 2012,
Hospira issued a voluntary recall in the
US of three lots of carboplatin injection
due to presence of visible particulates
identified as carboplatin crystals (4).
In fact, particulate contamination
in parenteral drugs packaged in glass
vials has created significant drug
shortages recently, according to Perry.
He notes that according to the FDA
Office of Manufacturing and Product
Quality, from 2008–2012, the presence
of visible particles accounted for 22%
of all drug recalls (5).
Many contributing factors
Various industry players point to
many different reasons for the
increase in recalls due to particulates.
“Today, quality has never been higher,
but the manufacturing process is
more versatile and complex than
ever before,” states Wolfgang
Weikmann, senior vice-president of
quality for Vetter Pharma-Fertigung.
“As a result, there are numerous
individual process steps and a
multitude of single components (e.g.,
the glass barrel, stoppers, caps)
that serve as potential sources for
particulate contamination during
production,” says Weikmann. The
growing use of prefilled syringes is
another contributor to the increased
incidence of problems with visible
particulate matter, according to an
26 Pharmaceutical Technology Europe November 2014 PharmTech.com
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industry expert. The expert adds
that the continuing predominance
of protein therapeutic agents has
also resulted in more numerous
mechanisms by which particulates
can develop, because proteins are
known to interact with components
of the primary packaging system
under certain conditions.
As demand from customers and
regulatory authorities for ever-
higher quality continues to grow,
there is also a greater awareness
of the possibility of particulate
contamination, according to
Weikmann. “There is definitely a
heightened sensitivity in the industry
to particulates given the greater
understanding of their potential
safety implications, and that led to
a greater number of reports,” says
Fran L. DeGrazio, vice-president of
global R&D, strategic programme
management and technical customer
support for West Pharmaceutical
Services. In particular, according to
an industry expert, there is a growing
awareness of the importance of
subvisible particles with diameters in
the range from 2–10 microns, which
are currently below the “radar” of
compendial testing. “The number of
particles in that range is enormous
compared to the number of particles
with diameters above 10 microns,
and these colloidal particles can
aggregate over time, producing visible
particles,” the expert explains.
Industry understanding of the
physical and chemical mechanisms
of particulate formation is also
improving. For instance, shear
denaturation can produce visible
particles, according to an industry
expert. “There are instances where
the type of filling pump (piston vs.
peristaltic) makes an observable
difference in the development of
particulate matter in a drug product,”
the expert says.
Investigations of glass delamination
mechanisms are also providing
insights that are leading to new
glass manufacturing methods.
Glass delamination is normally
the result of chemical reactions
ES522555_PTE1114_026.pgs 10.29.2014 21:04
between the drug and the interior
surface of the glass container. “The
occurrence of these reactions is
the result of a complex interplay
of different variables, such as the
type of glass container, glass type
(composition), pH range, drug type
and/or drug formulation (chemistry
of the formulation). Importantly, a
change in a single variable can make
the difference between success
and failure,” observes Dan Haines,
scientific advisor, Pharma Services
with SCHOTT North America.
Additional risk factors have the
potential to influence the possibility
of delamination, including the storage
time and temperature, the container
manufacturing conditions and the
sterilisation process.
Taking action
The industry as a whole has tried to
bring more visability to the particulates
issue, according to DeGrazio.
“Parenteral manufacturers have
taken a number of actions to address
the issue, including optimisation of
comprehensive quality management
systems starting with supplier audits
through to final visual inspections,
as well as implementing permanent
process monitoring approaches that
are designed to detect potential
hazards,” Weikmann says.
One biopharmaceutical company,
for example, is focusing on
understanding shear effects on
particulate formation, particularly
from filling pumps, through
measurement of changes in
conformation that could eventually
lead to aggregation, and thus
particulate formation, according to
an industry expert. His company
is also using instruments such
as the FlowCAM (Fluid Imaging
Technologies) and Micro-Flow
Imaging (ProteinSimple) to investigate
subvisible particles.
Other activities at
biopharmaceutical companies include
making adjustments to fill and finish
processes and the development of
new material and system innovations,
such as polymers and special biotech
delivery systems, to reduce possible
particulate contamination. Glass
manufacturers are also responding by
adjusting manufacturing processes
and developing alternate methods
ADV

that minimise the types of issues that
have been seen in the marketplace,
according to DeGrazio.
Importantly, there is greater
sharing of knowledge between
all of the involved parties. “Closer
cooperation with suppliers, logistic
partners and technical engineering
supports the implementation of
corrective and preventive actions
along the supply chain,” notes
Weikmann. Collaborations with
critical external partners, such as
container producers that have shifted
the focus to quality instead of treating
glass vials as a commodity, are
helping drug companies understand
products and processes and improve
overall quality, according to Perry.
“By incorporating supplier expertise
up front and engaging in information
exchange from the beginning to the
end of the drug development process,
manufacturers can ensure that the
material is used in the correct way,”
he says. Perry also notes that new
guidance covering inspections is also
providing manufacturers with further
support to ensure quality.
Glass manufacturers are responding by adjusting
manufacturing processes and developing alternate methods.
Benefits of a QbD approach
Another approach that many
companies are taking to improve
quality, reduce the risk of particulate
contamination and avoid recalls
involves the implementation of
programmes such as Six Sigma, risk
management, right first time and
QbD, according to Perry. “The focus
is now on minimising the risk and
doing it right the first time. These
tools ensure that processes are
well managed by understanding the
key process parameters and risks
associated with those parameters,”
he explains.
“The very heart of the QbD concept
is that quality is built into a product
based on an in-depth understanding
of the compound and the process
by which it is developed and
manufactured. Critical steps in the
fill and finish process of parenteral
manufacturing that affect quality
are identified and their influence
evaluated. Matching the appropriate
processes to the actual needs of the
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product may help to identify potential
risks in the process including
possible sources for particulate
contamination,” says Weikmann.
For a CDMO like Vetter, he adds that
the QbD approach is an important
concept, primarily because of the
many advantages it offers to industry
stakeholders. “This approach enables
consistent and robust production of
high quality products and, therefore,
the reduction of batch failures and
stock-outs. It also offers the potential
for greater confidence in drug
quality and may reduce the need
for intensive oversight by regulatory
authorities,” Weikmann asserts.
For glass manufacturers, a
QbD approach ensures a good
understanding of which material and
process inputs have an impact on
glass particulates, as well as the ways
in which the process and material
interactions could lead to certain
glass characteristics that predispose
the glass to particulate formation,
according to DeGrazio.
The implementation and success of
QbD is also a way to help build long-
lasting relationships with customers
and key partners, according to
Perry. “By taking a global view of our
processes and products, we have
been able to shift our focus from
price-based discussions to total cost
of ownership and quality. With QbD,
we have adopted more of a risk-
based approach to production and
in the end have been able to look
further down the value chain to make
sure we are doing what is right for
patients,” he comments.
A variety of challenges
These numerous benefits of QbD
aren’t realised without significant
effort, however. QbD is essentially
a holistic, proactive, science-
and-risk-based approach to the
development and manufacturing of
drugs, and proper implementation
presents a variety of challenges for
the manufacturer. According to an
industry expert, the biggest issue
is the lack of a clear translation
from the broad principles of QbD to
ES522561_PTE1114_027.pgs 10.29.2014 21:04
QbD in Parenterals
specific implementation actions. “It
is definitely necessary to have the
right level of technical ability within
the organisation to understand and
implement QbD effectively,” Perry
states. In addition, the organisational
mindset must be aligned and willing
to take on such programmes and to
live by the relevant principles and
disciplines. “QbD cannot be seen as
the next fad and is most successful
when driven from the top of the
organisation,” adds Perry.
Time and cost are also issues.
“Incorporating QbD into a process
takes more time, and due to the need
for improved understanding and
greater testing, costs more money,”
DeGrazio says. She goes on to say,
however, that in the long run, use of
a QbD approach should reduce many
of the downstream issues that can
occur, and for those that do occur,
allow for better knowledge as to why.
As a result, QbD should ultimately
help the industry reduce costs.
Additional challenges can also
include finding the right business
partners that share the same
quality understanding and meeting
increasing regulatory requirements,
such as the FDA’s process validation
guidance, according to Weikmann.
References
1. S.E. Langille, PDA J. Pharm. Sci. and Tech.
67 (3) 186-200 (2013).
2. Baxter, “Baxter Voluntarily Initiates U.S.
Recall of Two Lots of Peritoneal Dialysis
Solution Due to Presence of Particulate
Matter,” Press Release, 13 Aug. 2014.
3. Cephalon, “Cephalon, Inc. issues a volun-
tary nationwide recall of Treanda (benda-
mustine HCL) for Injection 25mg/Vial Due
to Particulate Matter,” Press Release,
27 Jan. 2012.
4. Hospira, “Hospira Issues Voluntary
Nationwide Recall of Three Lots of
Carboplatin Injection Due to Visible
Particulate Matter,” Press Release,
Dec.14, 2012, www.fda.gov/Safety/
Recalls/ucm332353.htm, accessed
7 Oct. 2014.
5. John G. Shabushnig, Insight Pharma
Consulting, LLC, “Detection and
Control of Visible Particles in Injectable
Products,” www.pda.org/docs/default-
source/attendee-presentations/north-
america/2014/2014-pda-annual-meeting/
john-shabushnig-phd.pdf?sfvrsn=5,
accessed 30 Sept. 2014. PTE
Pharmaceutical Technology Europe November 2014 27
ADV
 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

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 Technical Q&A: Continuous Manufacturing

be mobile. Continuous manufacturing,
used in both OSD applications and
bioprocessing, will support the benefits
that can be gained from miniaturised
or small-volume production processes.
The PCMM consortium is exploiting
all these options to fully optimise
the efficiency and flexibility of future
production processes.
PTE: What scale is meant
by “miniature”?
O’Brien (Pfizer): We
expect to operate within
a range of 5 to 30 kg per hour, which
roughly translates to an annual
capacity of 0.5 to 1 billion uncoated
tablets per year.
Steiner (GEA): Comparing batch
processing with continuous systems is
difficult in terms of absolute numbers,
but the footprint or volume of such a
system could be up to 60–70% smaller
than a conventional installation. Being
continuous actually eliminates the
question of scale: the only factor is
time. The equipment is physically
smaller, but as it’s run continuously,
it’s easy to manufacture production-
scale volumes of product. There’s no
need for scale-up any more or long
product transfer times from R&D to
full-scale manufacturing.
Challenges
PTE: What do you see as
the biggest challenges in
employing the PCMM
model?
Steiner (GEA): From my perspective,
I would say that we’ve not really
encountered any insurmountable
hurdles. Regarding technical
challenges, the miniaturisation
aspect was challenging, but we
found solutions. Economically, we’ve
discovered that the system price for
the PCMM compares very well with
traditional models and actually offers
a lot of advantages, especially in
terms of its portability, flexibility and
productivity. The whole system was
put together with existing equipment,
including the commercialised CMT
continuous inline blending technology
from Pfizer. We didn’t have to invent
anything new; we’ve just put it together
in a smart new way.
O’Brien (Pfizer): There is a body
of work around achieving regulatory
understanding and ultimately their
acceptance of both the technology
and general paradigm. FDA and EMA
have expressed support for and seem
to expect broader implementation
on continuous manufacturing in the
pharmaceutical industry, but many
aspects will need to be worked
through in terms of what is required
for regulatory filings and routine
operation. Challenges also remain
in moving from the batch test
and release to a real-time release
paradigm. It is unclear whether
regulatory agencies in developing
markets will readily embrace the new
technology. We also anticipate that
workforce planning and retraining
will be crucial to the successful
implementation of this new paradigm.
Future of
continuous processing
PTE: Do you have
continuous manufacturing
projects outside of PCMM?
Steiner (GEA): GEA’s
ConsiGma is a multipurpose platform
for continuous manufacturing that has
been designed to transfer powder into
coated tablets in development, pilot,
clinical and production volumes in a
modular, compact unit. The system
can perform dosing and mixing of raw
materials, wet granulation, drying,
tableting or direct compression,
including online PAT quality control, all
in one system.
O’Brien (Pfizer): At Pfizer, we
have a number of ongoing projects in
various stages of development that
are investigating continuous and semi-
continuous processing technologies
for both API and other drug product
development and manufacturing
processes. It should be noted that we
are also working with global regulatory
bodies to ease the adoption of PCMM
and related advanced manufacturing
technologies.
PTE: What role do you
think continuous
manufacturing (PCMM or
other) will play in oral solid
dosage in the next five to 10 years?
O’Brien (Pfizer): From our vantage
point, it wouldn’t be a surprise
to see PCMM and other related
OSD continuous development and
manufacturing paradigms ultimately
become the new norm in the
pharmaceutical industry.
Jornitz (G-CON): Continuous
manufacturing will dominate facility
and process designs, as well as the
manufacturing modus.
Steiner (GEA): Continuous
manufacturing will continue to grow.
The pharmaceutical industry is facing
increasing demands for faster supply
chains, and continuous technology is
an enabler of more flexible and faster
routes to market. I reiterate the key
aspect that continuous manufacturing
is an enabler of miniaturisation; the
subsequent portability and modularity
lead to ‘process excellence,’ which in
turn, delivers ‘business excellence,’
saving both cost and time, improving
manufacturing efficiency and
enhancing the output quality of the
whole organisation. PTE

Process validation for continuous manufacturing processes

Although some aspects of process validation for continuous
processes are the same as those for traditional batch processes,
there are some unique considerations. Gretchen Allison, senior
director and team leader for Global Quality Validation, Pfizer
Global Supply, spoke with Pharmaceutical Technology Europe
about these issues.
“Key considerations for validating a continuous
manufacturing process rely on many of the established
principles of basic pharmaceutical process development,
guides and standards that the pharmaceutical industry
generally applies to validating traditional batch processes—
for example, the establishment of critical quality attributes
(CQAs), critical process parameters (CPPs) and corresponding
acceptance criteria for a given product and process,” explains
Allison. “Other process validation considerations that apply
to both traditional batch manufacturing and continuous
manufacturing are the use of quantitative statistical methods
(as appropriate) to evaluate the validation data and the
evaluation of intra-batch and inter-batch variation.”
To read the full interview, visit www.PharmTech.com/Allison.

Pharmaceutical Technology Europe NovEmbEr 2014 29

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 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
Berg’s team at Stanford University created the world’s
first recombinant DNA molecule. In 1976, Swanson
and Boyer founded Genentech. In 1982, Eli Lilly
launched Humulin, the first human insulin produced
using recombinant DNA technology, developed by
Genentech. Since the 1990s, biologic drugs have
been the centre of attention for the pharmaceutical
industry, both in terms of therapeutic opportunity and
Andy Fry is the founder of business activity.
of Team Consulting, andy. EvaluatePharma World Preview 2014 predicts that
fry@team-consulting.com. global sales of prescription drugs are expected to
exceed $1 trillion by 2020 (1) of which more than 50%
are expected to be biological products, dominated
by monoclonal antibodies. But just like insulin,
these protein-based drugs are rendered useless if
taken orally. A means of delivery other than a tablet
or capsule is, therefore, called for, and there are
challenges associated with it.
Size is important
People with diabetes have been successfully injecting
themselves with insulin, often several times each
day, for more than 90 years. It might be expected
that self-injection of any other drug should be as
straightforward. However, it is not quite that simple.
Insulin, with a molecular weight of 5.8 kDa, is a rather
large molecule when compared with drugs such as
aspirin (at 180 Da) or even penicillin (at around 335 Da).
Now consider Humira, a hugely successful product
used to treat a range of autoimmune conditions,
including rheumatoid arthritis, ankylosing spondylitis
30 Pharmaceutical Technology Europe NovEmbEr 2014 PharmTech.com
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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
is anything but simple. The high mg per mL
concentrations of these macromolecule drugs result
in high enough viscosities of the injectable product to
cause problems for device designers, manufacturers,
primary container suppliers and patients.
What are the practical options?
The cost and convenience drivers for self-administered
therapies, especially for chronic conditions, result in
regular but infrequent injections of relatively large
payloads of molecules, injected weekly, possibly
fortnightly, or even quarterly. Injection of 1 mL in a
single, self-administered dose has historically been
regarded as the upper threshold of acceptability,
but single injected doses of up to 2.5 mL are now
being actively explored. Discomfort or pain are major
considerations, but time also forms a part of the
equation. In general, patients don’t want to hold an
autoinjector (an increasingly common delivery device
format for biological drugs) in place for more than 15
seconds, a time window that includes needle insertion
as well as the actual injection.
Syringeability
Syringeability refers to the force required to inject
a given solution at a given rate via a chosen needle
ADAM GAULT/SPL/Getty Images
length and gauge. Flow through a hollow needle is
characterised by the Hagen-Poiseuille equation:
128QµLA
F= (Eq. 1)
πD4
ADV
 F = syringe stopper (plunger) force
Q = volumetric flow rate
μ = dynamic viscosity
L = needle length
D = needle bore diameter
A = syringe plunger area
Although syringe plunger friction
and tissue resistance at the needle
tip will add to syringe plunger force,
viscous resistance within the needle
is particularly relevant as larger
molecules and higher mg/mL
concentrations result in higher
viscosity formulations. Needle gauge
is key; although a finer needle means
easier and less painful insertion, it
also has a smaller bore. Equation 1
shows that plunger force varies with
D4. If an injector device is fitted with a
27 G needle (bore size 0.191 mm) and
the needle is changed to a 30 G (bore
size 0.140 mm) of the same length,
the plunger force needed to give the
same flow rate (Q) (and therefore
the same injection duration) has to
increase by 350%.
For a spring-powered autoinjector,
the spring must provide adequate
force at the end of stroke (as the last
drop of drug is delivered). However,
the stiffness or rate of a traditional
coil spring dictates that at the start
of delivery, the spring force will
be significantly higher. Add on the
syringe plunger friction and tissue
resistance, plus a safety margin to
allow for tolerances, and it becomes
apparent that some surprisingly high
forces have to be handled by the
injector mechanism and, specifically,
reacted through the prefilled syringe
(usually of type 1 borosilicate glass)
at the heart of the autoinjector. Not
surprisingly, breakages, failures and
malfunctions are among the problems
faced by autoinjectors delivering
higher viscosity biologic drugs.
At this point, it should be
emphasised that the rules of fluid
dynamics cited, though applicable
for a great many situations, are only
Figure 1 is courtesy of Zogenix.
strictly valid for Newtonian fluids (i.e.,
those for which shear rate is directly
proportional to flow rate). So-called
“ideal fluids” exhibit zero stress
under any flow conditions. At the
opposite extreme, ideal solids do not
flow under any conditions. Between
gavni/Getty Images
these two extremes, Newtonian
fluids, exhibiting a neat, straight-line
relationship are joined by other, non-
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Figure 1: Viscous formulation delivery by DosePro needle-free injector
(Courtesy of Zogenix)
60
58
Typical viscous
Injection time (milliseconds)
56
protein formulations
54
52
50
48
46
44
42
40
0 1000
Newtonian fluids that exhibit non-
linear behaviours:
• ‘Dilatant’ fluids exhibit shear-
thickening behaviour, for example,
cornflour mixed with water goes
from liquid to solid when trying to
stir the mix.
• ‘Pseudoplastic’ or shear-thinning
fluids, such as tomato ketchup,
become mobile and free-flowing
when shaken. This group includes
blood and high concentration
formulations of high molecular
weight drugs.
Andrea Allmendinger of Hoffman-La
Roche presented a paper (2) looking
into this topic with regard to high-
concentration, large-payload
macromolecule drugs at the Parenteral
Drug Association Universe of Prefilled
syringes in Basel, November 2013. This
paper illustrated how complex the
subject can be, but made interesting
reading. The statistician George Box
once stated “Essentially, all models
are wrong, but some are useful,” and
this view has strong resonance when
exploring viscous product delivery
with a syringe and needle.
Although there may be some
rheological assistance due to shear
thinning during injection for some
products, a variety of approaches to
reduce delivery challenges are actively
being pursued. These approaches
include thin-walled or tapered needles
to reduce viscous resistance and
minimise pain; constant force springs
ES522954_PTE1114_031.pgs 10.29.2014 23:38
2000 3000 4000 5000 6000
Viscosity (cP)
and dampers to minimise peak forces;
precisely moulded cyclic polyolefin
syringes, which are more robust than
glass; and reduced friction stoppers
and syringes. But why not just change
the approach to injected delivery and
side-step some of these challenges?
Large-volume injectors
If we treat injection time as an
opportunity, not a challenge, it presents
an interesting device scenario. When
applying the Hagen-Poiseuille equation
for an autoinjector, the flow rate (Q) in
Equation 1 of 1 mL or 2 mL in perhaps
10 seconds is driven largely by the
acceptable operating time for the
patient. But if the injection device could
be worn for 15 minutes during delivery,
then the flow rate for the same
injection size reduces by 9000%—and
Equation 1 tells us that the plunger
force would reduce in the same ratio.
In fact, the drug formulation could be
less concentrated (and less viscous),
though of larger volume (e.g., 5 mL),
while the flow rate and force to deliver
would remain manageable. This is the
operating territory for the large-volume
injector (LVI) or bolus delivery device.
A number of devices of this type
are in development, which use a
variety of primary containers (glass,
plastic, flexible, rigid, traditional
and novel variants) and a range
of mechanisms, power sources
and control systems (mechanical,
electrical, electronic, hybrid). The LVI
Pharmaceutical Technology Europe NovEmbEr 2014 31
ADV
 addresses some of the key challenges
confronting the autoinjector and
much effort is being devoted to the
technical, pharmaceutical and user-
related aspects of LVI devices.
Needle-free delivery uses a fine, high velocity jet generated
by driving liquid through an orifice at high pressure to pierce
the skin and underlying tissue.
Needle-free delivery
Needle-free delivery has been a
reality since the late 1940s, and
several technologies are now
available. Needle-free delivery uses
a fine, high velocity jet generated
by driving liquid through an orifice
at high pressure to pierce the
skin and underlying tissue. The
governing equation (by Bernoulli)
can be rearranged as shown in
Equation 2.
4Q 2
F = 2ρA ( C π D2 ) (Eq. 2)
f life device. Nevertheless, although
F = plunger force
Q = volumetric flow rate
ρ = fluid density
Cf = orifice flow coefficient
(0.95 for a practical, round-
edged orifice)
D = orifice diameter
A = syringe plunger area
Comparing this with Equation 1,
the only fluid property in the Bernoulli
equation is ρ (density) and there
is no viscosity term. Because drug
formulations generally have densities
close to that of water, the implication
is that a needle-free device will
deliver the same volume, at the same
rate, using the same energy, largely
irrespective of viscosity.
Strictly speaking, this holds true
for orifice plates of zero length and
hence is not the only governing
relationship for a practical, real-
practical orifii do have a finite length
and do exhibit some viscous loss,
needle-free devices are largely
unaffected by product viscosity in
the practical range of interest, as
Figure 1 illustrates.
Which to choose?
All three injection technologies
discussed have their place, but
selection is often left until late in the
development of the drug product,
which can mean that opportunities
can be missed. Early exploration of
formulation options together with
the increasingly wide range of real,
practical options for parenteral
delivery can provide significant
benefits to everyone from the
pharmaceutical company to the
patient.
References
1. EvaluatePharma World Preview 2014,
Outlook to 2020, www.evaluategroup.
com/public/Reports/EvaluatePharma-
World-Preview-2014.aspx, accessed
2 October 2014.
2. Andrea Allmendinger, “Injection forces
during subcutaneous drug administra-
tion,” presentation at the PDA Universe
of Prefilled Syringes (Basel, November
2013). PTE

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Considerations in Developing
Sublingual Tablets—An Overview
Muhammad Ashraf and Vilayat A. Sayeed
The rich blood supply and the relative thinness
of the sublingual mucous membrane provide a
unique opportunity for systemic delivery of certain
drugs. This route of administration offers distinct
advantages, such as rapid onset of action and
improved patient compliance, particularly in geriatric,
psychiatric, and paediatric patients. This review
highlights relevant physicochemical drug properties
and formulation design considerations critical to
quality and performance of sublingual tablets. It also
highlights commonly used technology platforms and
critical-to-quality drug development elements that
need to be addressed in regulatory submissions.
Disclaimer: The views and opinions presented in this article
are those of the authors and do not necessarily reflect views or
policies of the Food and Drug Administration.
Muhammad Ashraf, PhD, is a senior quality reviewer and
*Vilayat A. Sayeed, PhD, is director, Division of Chemistry III,
Office of Pharmaceutical Science, CDER, FDA, Vilayat.Sayeed@
FDA.HHS.GOV.
*To whom all correspondence should be addressed.
Submitted: 23 Jan. 2014. Accepted: 23 Feb. 2014.
CITATION: When referring to this article, please cite it as M. Ashraf
and V. Sayeed, “Considerations in Developing Sublingual Tablets—
An Overview,” Pharmaceutical Technology 38 (11) 2014.
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PEER-REVIEWED
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
this review is on the latter two points, as an understanding
of these elements enables the selection of drug candidates
suitable for oral mucosal delivery and optimises drug delivery.
Anatomical structure of the oral mucosa
The oral cavity has four distinct regions that can absorb drugs—
the sublingual, buccal, gingival, and palatal regions. These
regions differ from one another in histological structure and
biochemical composition of the mucosal membrane, and their
ability to retain the dosage form long enough to allow com-
plete drug absorption. The sublingual membrane on the floor of
the mouth under the tongue and the buccal membrane lining
the cheeks are commonly used for systemic drug delivery.
The mucosal lining consists of three distinct layers. The
outermost layer is the epithelial membrane, which
consists of stratified squamous epithelial cells and has a
protective barrier function. The innermost layer of the
epithelial membrane is called the basement membrane
that replenishes the epithelium. Below the epithelium lies
the lamina propria followed by the submucosa. The lamina
propria is a hydrated and less dense layer of connective
tissue containing collagen and elastic fibers. The oral
ANTHONY BRADSHAW/GETTY IMAGES
submucosa is also richly supplied with blood vessels.
Following absorption through the mucous membrane
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
drains via the internal jugular vein, the subclavian vein, and
the brachiocephalic vein directly into the superior vena
cava (2, 3). Thus, venous return from these regions enters
Pharmaceutical Technology Europe November 2014 33
ES522614_PTE1114_033.pgs 10.29.2014 21:07 ADV
 Sublingual Formulations
Table I: Drugs available as sublingual tablets.
Drug Manufacturer
Nitroglycerin (Nitrostat) Pfizer
Isosorbide dinitrate Multiple manufacturers
Fentanyl citrate (Abstral) Galena Biopharma
Buprenorphine hydrochloride Multiple manufacturers
Ergotamine tartrate (Ergomar) Rosedale Therapeutic
Ergoloid mesylates Watson
Asenapine (Saphris) Merck Sharp & Dohme
Buprenorphine hydrochloride
Multiple manufacturers
and naloxone hydrochloride
Zolpidem tartrate
Purdue Pharma
(Intermezzo)
the systemic circulation, bypassing the pre-systemic drug
elimination, unlike in oral administration. Direct drainage
into systemic circulation results in immediate systemic
availability of the drug and rapid onset of action. It should
be noted that smoking, which causes vasoconstriction, may
affect drug absorption.
Permeability of the oral mucosa and drug absorption
The salivary glands present in the oral cavity secrete saliva that
has a pH of 5.5–7.0. Saliva consists of proteins and carbohydrate
complexes called mucus and enzymes such as amylase and
carboxylesterase. Mucus is negatively charged at the physi-
ological pH, forming a cohesive gelatinous film on all oral cavity
surfaces. This cohesiveness permits mucoadhesion of the drug
to the epithelial tissue leading to drug absorption (4, 5).
The epithelial membrane is 100 –200 µm thick in the
sublingual region and 500–600 µm thick in the buccal region (6).
The epithelial membrane in both regions is non-keratinised. The
permeability of the mucosa varies from region to region in the
oral cavity depending on thickness and degree of keratinisation
of the epithelial membrane (7).
Membrane-coating granules deposited at the apical surfaces
of the epithelial cells and neutral lipids, such as ceramides
and acylceramides, impart a barrier function to keratinised
epithelium resulting in decreased permeability. Conversely,
cholesterol, cholesterol esters, and glucosyl ceramides in the
non-keratinised epithelial cells of the sublingual and buccal
regions render it permeable to drug absorption (8).
The profuse blood supply, combined with the relative
thinness and higher permeability of the sublingual mucosa,
permits rapid absorption and desirable bioavailability of certain
drugs following sublingual administration. Thus, the sublingual
mucosa is a suitable site for achieving a clinically effective drug
concentration in a shorter period of time when rapid onset of
action is desired. For this reason, rapidly dissolving sublingual
tablets are highly effective for the emergency treatment of
angina, breakthrough cancer pain, or migraine.
It should be noted that the sublingual region is constantly
washed by saliva and by movements of the tongue, and
thus is not suitable for the prolonged retention of a drug
34 Pharmaceutical Technology Europe November 2014 PharmTech.com
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delivery system. On the other hand, the buccal mucosa is not
continuously affected by saliva or by tongue movements and
is suitable for prolonged retention of dosage forms such as
mucoadhesive sustained drug delivery systems.
Commercially available sublingual tablets
Presently, a small number of commercially available drugs use
the sublingual mucosa for drug administration. These drugs
are used for the emergency treatment of angina pectoris,
hypertensive crises, breakthrough cancer pain, and migraine.
The buccal route has been exploited for hormone replace-
ment therapy. Table I lists some of the approved drugs that
are available as sublingual tablets (9).
Potential drug candidates for oromucosal delivery
The literature is full of studies that have demonstrated the
enhanced potential of several drugs when administered via
oromucosal route. However, this potential has not been fully
utilised commercially in developing drugs for oromucosal
delivery. The following examples illustrate superior therapeutic
management when drugs were administered via the oromu-
cosal route as compared to oral administration.
In a comparative effectiveness study of sublingual
captopril, nifedipine, and prazosin, it was reported that
sublingual captopril may be a better alternative to sublingual
nifedipine in treating hypertensive emergencies based
on less side effects (10). Another study has shown that
sublingually administered captopril and nifedipine are
effective in the treatment of hypertensive emergencies;
however, for severe forms of hypertension, this study
recommends sublingual nifedipine (11).
Sublingual administration of verapamil has exhibited
significantly higher maximum plasma concentration of the
drug (Cmax), a faster absorption rate, and greater bioavailability
as compared to its oral administration (12). It has also been
shown to produce a rapid and significant reduction in
ventricular rate (13). Sublingual administration of furosemide
was shown to offer a therapeutic advantage over the oral route
of administration (14).
Oromucosal administration of midazolam was compared
with the rectal administration of diazepam for the emergency
treatment of acute febrile and afebrile (epileptic) seizures in
children (15). Oromucosal midazolam was found to be more
effective than the rectal diazepam.
The sublingual tablets of buprenorphine and naloxone have
shown useful results for the treatment of opiate addiction (16).
The study has proposed office-based treatment of addiction
using sublingual administration of these drugs.
Zolmitriptan is used for the treatment of migraine and cluster
headaches. A sublingual formulation of zolmitriptan exhibited
faster absorption and higher drug exposure as compared to
subcutaneous injection and is expected to be highly efficient
for the emergency treatment of these conditions (17).
In a randomised, double-blind clinical trial, comparing
40 mg of sublingual piroxicam with a 75 mg intramuscular
injection of diclofenac for the emergency treatment of acute
ES522620_PTE1114_034.pgs 10.29.2014 21:08 ADV

Table II: Physicochemical properties of sublingually administered drugs.
Drug Molecular weight Largest dose**
Nitroglycerin 227 0.6 mg
Fentanyl citrate 336* 0.8 mg
Buprenorphine 467.6 2–8 mg
Asenapine maleate 285.8* 10 mg
Nicotine 162.234 4 mg
Ergotamine tartrate 583.68* 2 mg
* Molecular weight of the base.
**Largest dose for sublingual tablet.
renal colic, sublingual piroxicam was found as effective as the
intramuscular diclofenac (18).
Self-injected epinephrine is used for the treatment of
anaphylaxis. In a study, sublingual epinephrine resulted in
rapid absorption and higher peak plasma concentration in
animal models when compared to self-injected epinephrine.
The study proposed sublingual epinephrine as an alternative
to self-injected epinephrine (19, 20).
Estrogens in menopausal women with cardiovascular
disease have been shown to produce coronar y and
peripheral vasodilation, reduction of vascular resistance,
and improvement of endothelial function. Sublingual
estrogens have exhibited faster drug absorption (i.e., shorter
Tmax higher Cmax) than orally administered forms (21, 22).
The sublingual administration of vaccines may be used
against various infectious diseases. Preclinical studies have
found that sublingual vaccines can be highly immunogenic
and may protect against influenza virus and Helicobacter
pylori (23–25).
Development of sublingual tablet formulations
For optimal sublingual formulation development, it is neces-
sary to understand the mechanism of drug absorption, physi-
cochemical and mechanical properties of the drug, function
of the excipients in the formulation, and taste-masking tech-
niques for better patient compliance.
Mechanism of mucosal drug absorption. Following
sublingual administration, the drugs are absorbed across the
mucous membrane by one of the following mechanisms:
• Passive diffusion
• Active or carrier-mediated transport
• Endocytosis.
Although the process of passive diffusion is spontaneous,
the rate of diffusion is dependent on the molecular weight and
solubility of the drug, concentration gradient, temperature,
the surface area of the membrane, and the proximity of
the molecule to the membrane. When a drug exists in its
unionised form in saliva, it is absorbed by passive diffusion.
Physical models have been proposed to describe drug
absorption from saliva through the lipid bilayer of the mucous
membrane into systemic circulation (26–29). The rate of drug
absorption across the mucous membrane is directly related
to its partition coefficient (30). Some compounds, such as
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Sublingual Formulations
Water solubility pKa Log P
1.8 mg/mL -5.6 0.94
0.025 mg/mL (citrate) 8.4 2.9
Insoluble in water 8.24, 10.0 4.9
3.7 mg/mL 8.6 4.9
Slightly soluble 8.21 0.99
Insoluble in water 6.3 2.4
glutamic acid, L-ascorbic acid, nicotinic acid, and thiamine, are
transported via a carrier-mediated process (31–34).
Lipids present in the oral mucous membrane offer the main
barrier to the permeability of hydrophilic drugs. On the other
hand, well-hydrated connective tissues provide resistance
to lipophilic drugs. Thus, the potential transport path across
the oral mucous membrane may be either polar or non-
polar. Non-polar molecules cross through the lipid regions
of the epithelium, while polar molecules travel through ionic
channels present in the intercellular spaces of the epithelium,
or aqueous pores present in the epithelial cells. For this reason,
an understanding of a drug’s lipophilic or hydrophilic nature
during the developmental stage of the drug product appears
to be the most useful index for evaluating its suitability for
absorption across the oral mucosa.
Physicochemical properties of drugs. Table II lists the
physicochemical properties of some commercially available
drugs administered sublingually. These properties of the drugs
facilitate their absorption by passive diffusion through the
oral mucosa. Partition coefficients and ionisation constants of
several drugs are described in the literature (35–38).
For efficient absorption through the oral mucosa, the drug
must be hydrophobic enough to partition into the lipid bilayer,
but not so hydrophobic such that once it is in the bilayer, it
will not partition out again. Satisfactory oral absorption of
drugs has been observed over a wide range of log P (octanol/
water partition coefficient) values of 1 to 5. As the log P
value increases beyond 5, the solubility in saliva is usually
not enough to provide adequate concentration for diffusion
through the lipid bilayer (39). According to the diffusive model
of absorption, the flux across the lipid bilayer is directly
proportional to the concentration gradient. Therefore, lower
solubility in saliva results in lower absorption rates and vice
versa. In general, a drug formulated for sublingual or buccal
administration should have a molecular weight of less than
500 (as free base) to facilitate its diffusion (39).
Because drugs diffuse through the lipid bilayer in the
unionised form, based on the pH-partition theory, the pKa of
drugs also plays a crucial role in drug transport across the
oral mucous membrane. It is important to note that the oral
cavity, unlike the gastrointestinal tract, has a narrow range
of pH, usually from 5.6 to 7.6. Thus, a basic drug administered
as a salt, predominantly exists as a free unionised base if
Pharmaceutical Technology Europe November 2014 35
ES522612_PTE1114_035.pgs 10.29.2014 21:07 ADV
 Sublingual Formulations
the pH is raised above its pKa value and this increase in
the unionised fraction of a drug increases its bioavailability
(40). For this reason, the inclusion of a suitable buffer in the
formulation of an ionisable drug makes it possible to control
the pH of aqueous saliva in a range most appropriate for the
optimal absorption of such drugs. Drugs that do not contain
ionisable groups are not affected by changes in pH.
Unlike the gastrointestinal tract, the absorptive surface of
the oral cavity is much smaller; therefore, large doses cannot
be administered via this route. Thus, only potent drugs, which
require small doses to obtain the desired therapeutic effect,
can be administered from this route. In addition to these
critical drug attributes, it is highly desired that drugs for
oromucosal delivery be adequately taste masked. Otherwise,
it is difficult to achieve patient compliance.
Characteristics of sublingual tablets. In view of the
short residence time in the mouth, rapid disintegration
and dissolution is crucial for drug absorption following
administration of sublingual tablets. For this reason,
sublingual tablet formulations should be designed to
disintegrate and dissolve rapidly in saliva, without the aid of
water to achieve this objective.
The physical and mechanical characteristics of a tablet,
such as size, hardness, porosity, and wettability, affect its
disintegration time. A smaller tablet size, with low hardness
and high porosity, disintegrates more rapidly than a larger or
harder tablet. However, a tablet with a high porosity and low
hardness is more friable, and this presents problems in tablet
packaging and handling. During development, all approaches
to increase the mechanical strength of tablets should be
studied, without compromising disintegration and dissolution.
The amount and type of disintegrants also play a significant
role in achieving rapid disintegration. Effervescent agents
have been used to facilitate disintegration (41). The inclusion
of water-soluble excipients, such as saccharides, helps in
achieving rapid dissolution by enhancing the wettability of
the tablet matrix. Moreover, the manufacturing process and
critical process parameters also affect disintegration and
dissolution of sublingual tablets.
Following sublingual administration, the patient is advised
to abstain from swallowing the tablet and avoid eating,
drinking, or chewing to facilitate drug absorption through
the oral mucosa. Even swallowing saliva is to be avoided, to
prevent ingestion through the gastrointestinal tract where
drug absorption may be inefficient. Because these aspects
pose some inconvenience to the patient, they should be
taken into account at the product development stage to
improve patient compliance.
Some drugs may have a bitter or unpleasant taste. When
such drugs are dissolved in the saliva for mucosal absorption,
they may also interact with the taste buds in the mouth
and produce the bitter, unpleasant taste, and may not be
acceptable to patients. Patient acceptability of formulations
is improved by various physicochemical approaches that
prevent the interaction of drugs with taste buds and thus
eliminate the negative sensory response (42Ð46). Sweeteners,
36 Pharmaceutical Technology Europe November 2014 PharmTech.com
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flavours, and other taste-masking agents are essential
components for formulations containing drugs with an
unpleasant taste. Sugar-based excipients quickly dissolve
in saliva and produce endothermic heat of dissolution. They
create a pleasant feeling in the mouth and are most suitable
for sublingual tablets along with other flavours. The coating of
bitter drugs is not an option for drugs to be dissolved in saliva.
Sublingual tablets promote rapid absorption and higher
bioavailability with an almost instant onset of action. If
the dissolution of the drug is incomplete, contact time is
short, and/or permeation is too low, part of the dose may be
swallowed and consequently not absorbed through the oral
mucosa, with subsequent effects on bioavailability. Many
sublingual tablets may be compromised by the possibility
of the patient swallowing the active drug substance before
it has been released and absorbed via the oral mucosa into
the systemic circulation.
A sublingual tablet designed to promote the retention
of the active drug substance under the tongue, to prevent
its swallowing, and to minimise inter and intra individual
variability, has been reported. This approach made use of
ordered mixtures of fine drug particles and bio-adhesive
material attached to coarser excipient carrier particles.
Tablets composed of these units have the potential to
rapidly disintegrate and release the units, which adhere to
the sublingual mucosa, and thus prolong the contact time at
the absorption site (47Ð48). Directly compressible sublingual
tablets developed using this approach led to the bio-adhesive
retention of the drug in the oral cavity and optimal exposure
of drug substance to the dissolving fluids in the mouth, which
resulted in complete and rapid sublingual absorption.
Manufacturing sublingual tablets—
Technology platforms
Although several technologies are available to manufacture
sublingual tablets, usually compression molding, direct com-
pression, and freeze drying have been commonly used for com-
mercial manufacture of sublingual tablets. The compression
molding process has been used since the early nineteenth cen-
tury for the preparation of nitroglycerin tablets. Presently, the
direct compression and freeze-drying methods are commonly
exploited for commercial manufacture of sublingual tablets.
Compression molding. Tablets manufactured by the
compression molding process exhibit rapid disintegration
and dissolution, which is usually within 5Ð10 seconds. These
tablets pose special challenges during handling and shipping,
because of the poor mechanical strength, and may require
special packaging (49, 50). Alternatively, the mechanical
strength of the tablets may be enhanced by employing a
suitable binder. However, the binder level should be
optimised to avoid any deleterious effects on disintegration
and dissolution of the tablets.
The formulations for the compression molding process
typically contain soluble excipients to impart quick and
complete dissolution, and taste modifiers for patient
compliance (51). Molded tablets have also been prepared
ES522610_PTE1114_036.pgs 10.29.2014 21:07 ADV
 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
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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 sbarschdorf@advanstar.com

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 Sublingual Formulations
directly from a molten matrix, in which the drug is dissolved
or dispersed (heat molding), or by evaporating the solvent
from a drug solution or suspension at room pressure (no
vacuum lyophilisation) (52).
The compression molding process involves moistening of
the formulation blend with a solvent (usually hydro-alcoholic),
followed by molding into tablets under low pressure. The moist
tablets are finally dried (53). The lower compression pressure
employed for molding and drying of the moist tablet produces
a highly porous tablet structure with enhanced dissolution.
The choice, ratio, and amount of granulating solvents are
critical to the physicochemical characteristics, performance,
and stability of the tablets, and should be optimised (54, 55).
Several patented technologies are also available for commercial
manufacture of compression molded tablets.
Takeda (Osaka, Japan) has developed a mixture containing
a combination of starches and sugars. This mixture, after
blending with the drug and wetting with a suitable amount of
water, can be compression molded. The tablets manufactured
from this proprietary mixture are reported to have sufficient
mechanical strength and exhibit rapid disintegration (56).
Novartis Consumer Health (Basel, Switzerland) has filed
a patent application for tablets prepared by dispensing the
drug solution or suspension into molds, evaporating the
solvent from the molds by heating under reduced pressure,
or microwave radiation, and then sealing the dried units
directly in the mold (57).
Nippon Shinyaku (Kyoto, Japan) compression-molds and dries
a kneaded mixture containing drug and a water-soluble sugar.
This process is claimed to impart sufficient physicochemical
stability to the tablet, good appearance, and dissolution time of
less than 30 seconds in the oral cavity (58).
Direct compression. The direct compression method is
commonly used for commercial manufacture of sublingual
tablets. It is a simple and cost-effective process, as it
employs ingredients that can be mixed well and do not
require further granulation steps prior to lubrication and
compression. Sublingual tablets manufactured by the direct
compression method exhibit good mechanical strength and
acceptably fast disintegration (59).
The directly compressible sublingual tablet formulation
contains directly compressible soluble excipients, a super
disintegrant, and lubricant. It may also contain microcrystalline
cellulose, dry binder, buffers, surface-active agents, sweeteners,
and flavours. Sugar-based excipients are widely used as bulking
agents because of their high aqueous solubility, sweetness,
pleasant feeling in the mouth, and good taste-masking. Nearly
all sublingual formulations incorporate some saccharide-
based material (60). The choice of a suitable disintegrant and
its amount are critical for achieving a fast disintegration and
dissolution rate. Sometimes effervescent agents are used to
increase disintegration and dissolution of sublingual tablets.
Several novel approaches of incorporating disintegrants
and other soluble and/or insoluble excipients to obtain
rapid dissolution and adequate mechanical strength are
reported. One example is the Flashtab technolog y of
38 Pharmaceutical Technology Europe November 2014 PharmTech.com
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multiparticulate actives (coated crystals and uncoated
or coated microgranules) (61). In these tablet s, the
simultaneous presence of a disintegrant with a high swelling
or disintegrating force, defined as “disintegrating agent,”
and a substance with a low swelling force (starch, cellulose,
and direct-compression sugar), defined as “swelling agent,”
was claimed as the key factor for the rapid disintegration
of a tablet. The tablet manufactured by this technology is
reported to have adequate mechanical strength (62).
Daiichi (Tokyo, Japan) developed a fast disintegrating
composition of moderate strength, using a combination of
starch or cellulose, and one or more water-soluble saccharides
(63). Erythritol was found to be the best sugar for this type of
formulation, showing rapid disintegration that was negligibly
affected by tablet hardness, good tolerability and sweetening,
and a refreshing mouth sensation because of its endothermic
heat of dissolution.
Freeze dr ying. The process of freeze dr ying
(lyophilisation) is expensive, time-consuming, and produces
tablets of poor mechanical strength. For these reasons, it
is not commonly used to manufacture sublingual tablets.
However, it does have advantages over the other processes,
as the tablets made by this process have high porosity, and
when placed under the tongue disintegrate and dissolve
instantly. It is a process of choice for products that are
unstable or are heat sensitive.
The process involves lowering the temperature of
the product in an aqueous medium to below freezing,
followed by applying a high-pressure vacuum. To extract
the water in the form of a vapour, which is collected as
ice on a condenser, a gradual temperature rise is applied
during the drying process. The product temperature at
the ice sublimation interface and the formulation collapse
temperature are critical to obtain a freeze-dried cake of
quality structure. This process retains the physical structure
and preserves the material for storage or transport.
The resulting tablets are usually light and have highly porous
structures that allow rapid dissolution or disintegration.
The freeze-drying process may result in a product with an
amorphous structure, leading to an enhanced dissolution rate.
However, tablets manufactured by freeze drying process have
poor stability at a higher temperature and humidity (64).
Considerations critical to product quality
To develop a sublingual tablet that can elicit the desired
physicochemical and mechanical properties of the drug
product at the site of absorption, it is important to under-
stand, control, and monitor the following critical to quality
attributes: particle size of the API, wetting time, disinte-
gration and dissolution, content uniformity, hardness, fri-
ability, size and weight variation, stability, texture and taste
masking, etc.
Most of these tests are universal quality determinants of
conventional tablet dosage forms and are equally relevant
for sublingual tablets. However, the disease management
and conditions of use for sublingual tablets require a
ES522616_PTE1114_038.pgs 10.29.2014 21:08 ADV

very short residence time in the oral cavity. This critical
determinant particularly calls for very rapid disintegration,
dissolution, and absorption of the product resulting in quick
onset of action.
The drugs that are administered sublingually generally
have low solubility. Therefore, to enhance dissolution, it is
crucial to reduce and control the particle size of the API.
This attribute is important in the case of all drugs with low
solubility. However, a tighter control on particle size of API
is desirable in sublingual drug products to maintain the
reproducible quality and performance of the drug product in
view of the limited window of dissolution and absorption time.
The conditions prevailing in the oral cavit y for
disintegration and dis solution of sublingual t ablet s
are markedly different from the tablets that are orally
ingested. For this reason, the compendial disintegration
and dissolution test methods are not suitable for testing
sublingual tablets. It is important to note that compendial
methods for disintegration and dissolution tests were
developed to test the in-vitro performance of tablets
developed for disintegration and dissolution in the stomach
following oral ingestion. Other specialised tablets, such as
modified-release or enteric-coated tablets, may also partly
release the drug in the stomach. In contrast, sublingual
tablets are designed to completely disintegrate and dissolve
in the oral cavity under the tongue.
To address this critical difference, researchers have
proposed various approaches to test disintegration and
dissolution of sublingual tablets. These approaches employ
physiological conditions of the oral cavity as a guide in
testing disintegration and dissolution of sublingual tablets.
One such disintegration method employs a 10 -cm
diameter Petri dish filled with 10 mL of water that contains
eosin, a water-soluble dye. A 10-cm diameter circular tissue
paper is placed in the Petri dish. The tablet is carefully
placed in the centre of the dish and the time for the tablet
to completely disintegrate into fine particles is noted as the
disintegration time (65). This method has been used widely
to test the ability of the sublingual tablets to disintegrate
and dissolve in a minimal amount of water, which is
more representative of the moisture available under the
conditions of use.
Another popular in-vitro method involves a texture
analyser (TA) instrument to accurately determine the
disintegration time. In this method, a tablet under constant
force is immersed in a defined volume of water. The time
for the tablet to disintegrate is determined by measuring
the distance the probe travels into the tablet. The time–
distance profiles generated by the TA software enable the
calculation of the beginning and end of disintegration time.
The influences of the applied force, the volume of water, and
water temperature were found to be critical experimental
conditions (66–68).
The wet ting test, designed by Bi et al., compares
favourably with the conditions prevailing in the sublingual
region of humans and animals (69). Other authors employed
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Sublingual Formulations
physiological conditions of the oral cavity by using different
pieces of equipment (70–72).
The palatability of a sublingual formulation, especially those
containing APIs that have an unpleasant taste, is another
critical factor for patient compliance as the drug product
disintegrates, dissolves, and is absorbed in the oral cavity.
Various taste-modifying techniques are reported in the
literature including sweeteners, flavouring agents, inclusion
and molecular complexes, granulation, salt formation, pro-
drug, viscosity modifiers, solid dispersions, and the use of
lipoproteins among others (73).
To address this critical patient compliance concern,
suitable taste-masking strategies should be studied in
the product development stage and incorporated in the
product design. The technologies that are reported in the
literature for the evaluation of taste include the electronic
tongue, measurement of frog taste nerve response, the
spectrophotometric method, and a human taste panel (74–76).
Conclusion
The scientific principles employed and the knowledge gained
during the product and process development for the manu-
facture of a sublingual drug product that is fit for its intended
use should be provided in the appropriate quality section of
ICH M4Q (R1) of the application submitted to FDA (77). As the
quality of the drug product cannot be adequately ensured
merely by in-process and finished-product testing, critical
to quality controls for raw material, process and equipment,
packaging, fitness of test method, and risk analysis should
be discussed following the principle highlighted in ICH Q8 (R2),
Q9, and Q10 and presented in the submission to FDA. The
proposed specification to ensure the quality of the sublingual
tablet should be based on the ICH quality guidances, with
adequate justification and supportive data (78).
Where applicable, qualification data should be provided
in the application to support the use of excipients not used
previously in the FDA-approved product. The objective of
the drug product is to ensure that the drug available to the
consumer is not only safe and effective, but has also been
properly manufactured and packaged to meet the established
quality target product profile over its intended shelf life. A
well-developed product will effectively address these issues
by including appropriate control strategies and establishing
the functional relationships of the material attributes, critical
process parameters and patient needs to meet the tablet
quality attributes as discussed in the article.
In conclusion, this review demonstrates that there are a
number of commercially available sublingual formulations
manufactured using various technologies. The publically
available information on sublingual tablets implies that this
dosage form has good potential to enhance drug delivery in
treating a number of indications. In most reported cases, it has
been shown that the sublingual dosage form not only improves
the patient’s compliance, but also reduces the time for the
onset of the drug action, and increases the bioavailability of
drugs as compared to conventional tablets.
Pharmaceutical Technology Europe November 2014 39
ES522615_PTE1114_039.pgs 10.29.2014 21:07 ADV
 Sublingual Formulations

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

40 Pharmaceutical Technology Europe November 2014 PharmTech.com

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 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
in processes from API production to secondary
packaging equipment and at every process in
between. Proper monitoring of compressed airflow
and consumption can tell operations personnel much
about the health of the system and provide specific
and crucial diagnostic information before larger
problems occur. Monitoring also provides necessary
data to ensure that long-term energy costs in the
plant do not mysteriously increase.
Flow sensors provide
crucial diagnostic information.
Most applications or skids used in pharmaceutical
production and packaging have an air preparation
assembly on the front end (see Figure 1) to regulate
pressure, filter the air to cleanliness levels required
by the US Food and Drug Administration, provide a
manual on/off valve and monitor the system pressure.
The pressure sensor in this assembly will alert the
control system if there is a pressure drop that will
cause actuation components to not perform properly
or a pressure spike that can result in component or
instrument damage.
Figure 1: A control cabinet in an API manufacturing
process contains an air-preparation assembly.
DANLEAP/GETTY IMAGES
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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,
proper volume of air must be supplied to reach and craig.correia@us.festo.com.
maintain the pressure. Volumetric flow, however, is
seldom measured in pharmaceutical plants today.
A leaking seal inside an actuator or a broken tube
might not be enough to cause a pressure drop and
can easily go undetected. Without a flow sensor,
the problem may not be realised until there is a
further or complete failure of the component and a
downstream process fails. A pharmaceutical plant
can have as many as 5000 pneumatic solenoid valve
controlling processes and more than five miles of
tubing, so there is a lot of opportunity to improve
this analysis.
Flow sensor function
Flow sensors are available as stand-alone products
that can be mounted inline in an existing tube or pipe
(see Figure 2a) or integrated into an air-preparation
assembly with the filter and regulator (see Figure 2b).
The flow sensor will send digital and analog signals
back to the controller for analysis, data collection
or display on a touch screen. Most are freely
programmable to set threshold values, window
comparators and hysteresis directly on the sensor.
Flow sensors measure flow rates and/or volumetric
air consumption. Flow sensors for compressed air are
also suitable for use with nitrogen, thus allowing them
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.
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
Pharmaceutical Technology Europe November 2014 41
ES522559_PTE1114_041.pgs 10.29.2014 21:04 ADV
 Troubleshooting
Figure 2: Flow sensors can be mounted (a) in-line (Festo, SFE3) or (b) embedded
in an air preparation unit (Festo, SFAM).
(a)
Figure 3: Flow meters with high
capacity are typically installed at the
front end of equipment (Festo, SFAM).
the controller, where it can be locally
analysed, displayed, maintained in a
data log, used to create an alert or
passed on through the supervisory-
control and data-acquisition system
for further analysis.
An increase in compressed
air consumption can be an early
indication of:
• Leaking seals at a quarter-turn
actuator or pneumatic-linear
actuator
• Early-stage cracks in piping or
welds
• Failing flexible tubing or fittings
• Solenoid valves not closing
properly
• Failing pneumatic pumps
• Problems with a nitrogen air
blanket
• Faulty vessel seals.
Investigating the source of this
consumption increase early on and
correcting the problem will improve
the performance and uptime of all
automated plant equipment.
42 Pharmaceutical Technology Europe November 2014 PharmTech.com
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(b)
Benchmarking efficiency
Industry is increasingly considering
energy efficiency, and compressed
air is recognised as a critical energy
resource. Large companies are
putting reduction targets into project
objectives, which impacts equipment
selection. Equipment manufacturers
desire to quantify how new models
have gained efficiency.
Flow sensors make air
consumption transparent. Using the
cumulative air consumption operating
mode, the sensor works like a meter
and it is possible to measure the
volume of air consumption for a given
process or over time. If, for example,
a process is consuming 15% more
compressed air compared to two
years prior, the plant has gained a
critical piece of diagnostic information
that can help guide corrective and
energy-savings actions.
Selecting a flow meter
When selecting and integrating a
flow sensor, several points should be
considered, as follows:
• Determine where in the process
you want to measure the airflow
or consumption to help determine
whether it should be integrated into
an air preparation unit or mounted
in-line downstream. To measure
flow into equipment, a flow meter
with high capacity, such as the flow
meter shown in Figure 3 (Festo,
SFAM), is typically installed inline.
• Calculate the range of flow that will
be measured. Flow sensors have
different ranges, and selecting a
sensor with wide band will impact
data accuracy.
• Decide if local display is required.
ES522563_PTE1114_042.pgs 10.29.2014 21:04
• Define why and how the flow
data will be used and select a
sensor capable of providing flow
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
a functional description of how the
sensor will be used and what type
of analysis is expected so changes
can be made at the control and
programming level. Looking ahead,
once this analysis is available, set up a
plan on how it will be used. Data can
be reviewed as part of preventative
maintenance programmes. Certain
alerts can force operations personnel
to investigate further.
Particularly with the energy
conservation effort, once the
information is available, the question
shifts to “What do we do with this
information?” and “How do we
implement the solutions?” Until these
steps are completed, the benefit of
the flow sensor is not fully realised.
Costs of compressed air in North
America are about $0.30 per 1000
scf. This means a single leak can cost
more than $3000 in annual electricity
cost. A single flow sensor and a
successful preventive maintenance
programme can have a payback
period of a few weeks.
Conclusion
Whether designing a single piece
of equipment or a complete facility,
proper use of a flow sensor to monitor
compressed air consumption can
provide crucial data to increase uptime,
improve troubleshooting of the process
and help manage long-term energy
costs. Although it is easier to integrate
flow sensors when equipment is initially
All figures are courtesy of the author.
designed, these components can be
easily added to existing installations. To
achieve the maximum benefit, a strong
emphasis must be placed on follow
through and preventative maintenance
based on the data. PTE
ADV
 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 kmoore@advanstar.com.

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 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
event but also a place where innovations thrive. With
more than 2500 exhibitors gathered at Paris Nord
Villepinte, France on 7–9 Oct. 2014, visitors had the
opportunity to learn more about the various products
and services offered across the entire pharmaceutical
manufacturing supply chain.
Excipients
Beneo-Palatinit showcased its multifunctional excipient,
GalenIQ, for oral solid dosage forms, including tablets,
capsules, lozenges, granules and pellets. This non-
hygroscopic, physically and chemically stable excipient
is available in a variety of particle sizes, morphologies
and solubility, and serves as an anti-caking agent, anti-
humectant agent, stabiliser and taste-masking agent
among its various functions.
Cafosa showcased its Health in Gum, an excipient
used in medicated chewing gum. The directly
compressible powder gum, which consists of gum
base, sweeteners and polyols, was created to simplify
the manufacturing process of compressed and
medicated chewing gum. The API can be added to the
ready-to-use powder.
Croda’s range of excipients for oral, parenteral,
topical and ophthalmic formulations are produced
using the company’s proprietary super refining
process to offer the highest level of purity. The flash
chromatographic process removes polar and oxidative
impurities from the excipients without altering their
fundamental structure (1). Croda’s super refined range
include polyethylene glycols (PEFs), polysorbates,
oleic acid, oleyl alcohol, isopropyl myristate and
dimethyl isosorbide, as well as medical-grade lanolins,
poloxamers and omega-3 fatty acid concentrates.
The Dow–Colorcon Alliance presented the next
generation hydroxypropyl methylcellulose (HPMC)
excipient, METHOCEL DC2, which provides an alternative
to wet granulation in matrix tablet production. The
improved flow properties and process capability of
powder blends delivered by METHOCEL DC2 helps to
reduce waste, shorten development time and lower
manufacturing costs by up to 60% (2).
Dow has also expanded its AFFINISOL solubility-
44 Pharmaceutical Technology Europe November 2014 PharmTech.com
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enhancement portfolio. Developed in collaboration with
Bend Research, the AFFINISOL HPMCAS (hydroxypropyl
methylcellulose acetate succinate) polymers help
maintain stable solid dispersions and inhibit API
crystallisation. Dow has also designed a novel cellulosic
polymer with improved thermal properties for hot-melt
extrusion (HME) applications. AFFINISOL HPMC HME can
be readily extruded over a wide range of temperatures
without the need to add plasticisers. Studies with
itraconazole and griseofulvin, which are BCS Class II
drugs, show that AFFINISOL HPMC HME offers a greater
processing window as well as achieves and maintains
supersaturation with multiple release profiles (3).
PROSOLV EASYtab SP from JRS Pharma is an all-
in-one, ready-to-use, high functionality, excipient
composite that combines binder/filler, glidant,
superdisintegrant and lubricant for rapid formulation
development and convenient tablet manufacture.
Roquette showcased its capsule filling solutions.
Lycatab C-LM is a low-moisture partially pregelatinised
maize starch, used as a hard capsule filler for
moisture-sensitive APIs. The company’s new directly
compressible polyols—mannitol, maltitol, xylitol and
sorbitol—can be used to create a variety of tastes and
textures for all types of tablets.
Formulation
Capsugel’s proprietary lipid multiparticulate (LMP)
technology brings together the advantages of lipid-
based technology and multiparticulate formulations.
Applications include taste-masking, controlled release
and bioavailability enhancement. Complementing the
LMP technology is the company’s Coni-Snap sprinkle
capsules that are easy to open, enabling the contents
to be sprinkled into soft food for patients who have
swallowing difficulties.
Catalent Pharma Solutions continues to expand its
technology offering in biologics, following the acquisition
of Redwood Bioscience and the SMARTag antibody
drug conjugate (ADC) technology platform. SMARTag
enables the production of homogenous bioconjugates
with improved performance and ease of manufacturing.
ADCs generated using this novel site-specific technology
demonstrated better toxicity profiles in vivo (4).
Hermes Pharma, specialist in the development and
manufacturing of user-friendly solid oral dosage forms,
ADV

showcased its effervescent dosages,
chewable tablets, orally disintegrating
granules, lozenges and instant drinks.
PSL presented its microsphere
refiner technology, which enables
downstream processing of
microsphere formulations in one
step with more than 97% recovery of
the final product (5). Microparticles
are filtered, washed and dried in the
microsphere refiner, and this process
can be efficiently scaled up from R&D
to commercial manufacturing. PSL also
showcased its Mini Lab Glass Filter
Dryer, designed for filtration and drying
of microsphere drug-delivery systems
on a laboratory scale, as well as it’s
new pilot plant filter dryer, the Simple
Filter Dryer for filtration, washing and
drying of API and intermediates.
Packaging and
drug-delivery systems
Locked4Kids is a child-resistant carton
that is easily opened by seniors. The
innovation, which was launched at
CPhI and won the CPhI Pharma Award
in the packaging category, consists
of a tray that locks into the carton
when fully inserted. The packaging
has “push points,” placed diagonally
across at a distance that is easily
managed by adults, but not young
children. Available in a range of sizes,
Locked4Kids meets European and
American standards for reclosable
child-resistant packaging and is
suitable for mass production.
Gerresheimer showcased its
innovative glass and plastic packaging
solutions for the pharmaceutical
industry, with products ranging from
pharmaceutical vials to complex
drug-delivery systems. Nemera’s
portfolio, on the other hand, include its
preservative-free multidose eyedropper
(Novelia); a fully passive safety device
for prefilled syringes (Safe’n’Sound);
and the company’s precision metering
valves for pressurised metered dose
inhalers (Inhalia).
Stiplastics’ innovative granule and
tablet dispenser has the ability to
deliver the precise number of granule
or tablet required, without the
medication getting jammed inside the
system. The novel one-push system
supports variations in pill size and
shape.
One of the displays at the SCHOTT
booth was adaptiQ, a new system
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for ready-to-use pharmaceutical
vials, consisting of a nest and tub
configuration that allows for direct
filling, freeze-drying, weighing and
closing inside the nest. SCHOTT
also showcased its break-resistant,
lightweight and transparent TopPac
polymer syringes, which are designed
to administer highly viscous drugs and
infusion therapy with large-volume
syringes via infusion pumps. The
company’s syriQ InJentle prefilled
syringes for highly sensitive biotech
drugs offers improved drug stability
through its unique design and features
an innovative tamper-evident seal.
Another highlight was West
Pharma’s portfolio of drug packaging
and delivery solutions. The company
exhibited packaging solutions such
as the West Ready Pack system, a
convenient, one-stop solution for
sterile vials, stoppers, seals and vial
adapters; NovaPure component;
Westar RU steam-sterilized plungers
and Westar RS/RU cartridge
components. Drug-delivery offerings
include the Daikyo Crystal Zenith
prefilled syringe system and West’s
self-administration solutions—the
SmartDose electronic wearable
injector, the ConfiDose autoinjector
and the SelfDose injector.
Process development
DSM Sinochem Pharmaceuticals
(DSP) introduced a new generation of
eco-friendly super-statins, produced
using the company’s fully backward
integrated process, which involves
a highly efficient enzymatic step.
This unique proprietary technology
yields APIs with higher purity at a
lower carbon footprint (6). The super-
statins are the latest addition to DSP’s
portfolio of PureActives drugs.
Equipment
Bosch Packaging Technology
showcased its compact laboratory
systems, including equipment from
its Hüttlin and Manesty range for
processing of pharmaceutical liquid
and solid dosage forms. The smallest
high-shear mixer granulator in the
laboratory equipment range, Hüttlin
Mycromix, offers homogeneous mixing
for granulation applications with short
drying times. The company’s compact
and mobile tablet press, Manesty
Xpress 100, with its data acquisition
ES522560_PTE1114_045.pgs 10.29.2014 21:04
CPhI Roundup
software, enables evaluation of new
tablet formulations.
Micro-Macinazione SA showcased its
advanced micronisation services and
equipment. The company specialises in
the design and manufacturing of spiral
and opposed jet mills, containment
systems, rigid and flexible glove box
isolators and pneumatic conveyors.
Micro-Macinazione’s cGMP jet mills
cater for different capacities from API
batches of a few grams to full tons.
Analytical technologies
Rigaku Raman Technologies introduced
its new handheld Raman analyser for
raw material identification. Progeny
eliminates issues of fluorescence
interference with the use of a 1064 nm
excitation laser and enables the
measurement of materials through
thick, coloured bottles as well as
other materials known to cause
fluorescence interference, such as
sodium carboxy methyl cellulose,
alginic acid and cell culture media used
in biopharmaceutical manufacturing (7).
References
1. Croda, “Super Refined,” www.
crodahealthcare.com/home.
aspx?s=149&r=344&p=2257, accessed
20 Oct. 2014.
2. Dow, Colorcon, “Dow-Colorcon
Alliance will Commercialise Next-
Generation HPMC Excipient by
Year-End, to Help Lower tablet
Manufacturing Costs by up to 60
Percent,” Press Release, 7 Oct. 2014.
3. Dow, “Dow Continues to Strengthen
its AFFINISOL Portfolio to Help Pharma
Solve the Insoluble,” Press Release,
7 Oct. 2014.
4. Catalent, “Catalent Expands Its
Technology Offerings In Biologics,
Acquires Redwood Bioscience Inc. and
the SMARTag Technology Platform,”
Press Release, 2 Oct. 2014.
5. PSL, “PSL launch two new innovations
at CPhI-PMEC worldwide in Paris,” Press
Release, 29 Sept. 2014.
6. DSM Sinochem Pharmaceuticals, “DSM
Sinochem Pharmaceuticals creates new
generation of eco-friendly super-statins,”
Press Release, 10 Oct. 2014.
7. Rigaku Raman Technologies, “Rigaku
Raman Technologies to Showcase
World’s First Customisable Handheld
Raman Analyser for Accurate and
Comprehensive Raw Material ID at CPhI
2014,” Press Release, 14 Aug. 2014. PTE
Pharmaceutical Technology Europe November 2014 45
ADV
 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 : dds@mmm.com
Website : www.3M.com/dds

46 Pharmaceutical Technology Europe NOVEMBER 2014 PharmTech.com P h a r mTe c h . c o m

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 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
Email : pha@lancasterlabs.com
Website : www.eurofins.com/Biopharma

Pharmaceutical Technology Europe NOVEMBER 2014 47

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 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
Email : West.Pharmaceutical.Services@westpharma.com
Website : www.westpharma.com

48 Pharmaceutical Technology Europe NOVEMBER 2014 PharmTech.com P h a r mTe c h . c o m

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 PHARMA CONVERSATION & COMMUNITY
HEADLINES ON PHARMTECH.COM/NEWS
• The European Medicines Agency (EMA) has stated that
it intends to work with global regulatory agencies in
assisting the World Health Organisation (WHO) to develop,
evaluate and approve drugs to fight the Ebola virus.
The agency is establishing a group of experts in the field
of vaccines, infectious diseases and clinical trial design.
EMA also plans to review information on Ebola treatments
currently under development to assist health authorities
with decision-making. Companies have been asked
to send the agency all their quality, preclinical and
clinical data for drugs currently under development.
• GSK is working with WHO, regulators and other partners to
accelerate development of its investigational Ebola vaccine
and to ramp up production as quickly as possible. GSK
acquired the Ebola vaccine candidate through the
acquisition of a biotechnology company, Okairos, in
May 2013 and has since been working with the
National Institutes of Health to develop this vaccine
candidate in response to the Ebola threat.
• Johnson & Johnson has committed up to $200 million to
accelerate and significantly expand the production of an
Ebola vaccine in development at its Janssen Pharmaceutical
Companies. The company is closely collaborating with WHO,
the National Institute of Allergy and Infectious Diseases
and other key stakeholders, governments and public
health authorities on the clinical testing, development,
production and distribution of the vaccine regimen.
• A new European initiative, DRIVE–AB (Driving Reinvestment
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
is to define a standard for the responsible use of the
dwindling reserve of effective antibiotics, and to develop,
test and recommend new economic models for
pharmaceutical investment in new drug candidates.
• The International Society for Pharmaceutical Engineering
(ISPE) has released its Drug Shortages Prevention Plan.
Based on ISPE’s 2013 ISPE Drug Shortages Survey, the plan
was created by industry experts and regulatory agencies
in the US and Europe. In the plan, ISPE suggests that
companies investigate root causes for drug shortages and
create a quality culture to ensure a reliable supply of drugs.
The plan lays out a holistic approach for identifying root
causes of drug shortages on technical, quality systems
and management levels.
50 Pharmaceutical Technology Europe NOVEMBER 2014 PharmTech.com
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MOST TWEETED
• Demand for new Ebola therapies and vaccines spotlights
production challenges. http://bit.ly/ZwgJP1
• AbbVie and Shire deal officially off. Shire receives $1.635
billion in break-up fees. http://bit.ly/1r9NKIp
FACILITY NEWS
• Roche has announced plans to expand its Basel site.
The company will invest 3 billion Swiss francs in the
construction of a modern R&D infrastructure, attractive
workplaces and sustainable site development.
• IDT Biologika has completed and certified the construction
of a large-scale production facility dedicated to the filling
and lyophilisation of biologics and vaccine products. The
facility in Dessau, Germany uses a sterile liquid-filling line
engineered to handle up to 24,000 vials per hour.
EVENTS
ICH Q7 Compliance for APIs Manufactured by
Chemical Synthesis or Cell Culture/Fermentation
1–3 December 2014
Berlin, Germany
PDA Europe Conference
Outsourcing/Contract Manufacturing
2–3 December 2014
Berlin, Germany
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COMPANY PAGE
3M Drug Delivery Systems ................................................................. 46, 51
BASF............................................................................................................. 37
Beneo GmbH ...............................................................................................13
Catalent Pharma Solutions ....................................................................... 52
Dow Europe GmbH ...................................................................................... 2
Eurofins Lanacaster Laboratories .......................................................17, 47
ITT Engineered Valves ............................................................................... 21
Lucideon ..................................................................................................... 23
Meggle........................................................................................................... 9
Merck Millipore......................................................................................10–11
Nemera ........................................................................................................ 6
Patheon ....................................................................................................... 43
Pet Flavors Inc ............................................................................................ 25
Sensitech .....................................................................................................19
Shimadzu Europe ......................................................................................... 5
Veltek Associates......................................................................................... 7
West Pharmaceutical Services .......................................................... 15, 48
ES522557_PTE1114_050.pgs 10.29.2014 21:03 ADV
 3M DRUG DELIVERY SYSTEMS
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INHALATION SYSTEMS
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!
Watch the contract manufacturing video: go.3M.com/Inhalation
EXPERTS AT COMMERCIALIZING INNOVATION
ES522762_PTE1114_CV3_FP.pgs 10.29.2014 22:18 ADV
 best technologies.
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