Pharmaceutical Technology Europe
APRIL 2016 Volume 28 Number 4
Advances for
Bio/Pharma
Analytical
Laboratories
FORMULATION
PEER-REVIEWED
Container Selection for
Biologic Formulations
Establishing an Eco-Friendly
Facility in Malta
QUALITY
FMEA for Filter
Integrity Testing
2 CHEERS
2 COINS IN A FOUNTAIN
2 FRENCH HENS
2 LITTLE PIGS
GOLDILOCKS AND THE 2 BEARS
2 PIECE SUIT
2 STOOGES
2 BLIND MICE
2 DIMENSIONAL
2 MUSKETEERS
2 TENORS
3 CHANGES EVERYTHING.
That’s why we’ve added Celsis®. to our family of industry-leading brands. Customers have long trusted our Endosafe®
endotoxin testing and Accugenix® microbial identification solutions to bring their products to market safely and efficiently.
Celsis® now rounds out the trio, offering rapid microbial detection systems that make us unmatched in our ability to support
your micro QC programs, every step of the way, learn more at www.criver.com/celsis.
April 2016
Pharmaceutical Technology Europe is the authoritative
source of peer-reviewed research and expert analyses for
scientists, engineers, and managers engaged in process
development, manufacturing, formulation and drug
delivery, API synthesis, analytical technology and testing,
packaging, IT, outsourcing, and regulatory compliance
in the pharmaceutical and biotechnology industries.
Advances for Bio/Pharma Analytical Laboratories
Today’s analytical laboratory equipment reflects the
realities of downsizing, outsourcing,and the need for
speed.
Container Selection for Biologic Formulations
Choosing the right container and container
closure system is crucial for ensuring product
quality, safety, and efficacy of a biologic formulation.
Headspace Moisture Analysis for Determination of
Residual Moisture Content in Lyophilized Pharmaceutical Products
Headspace moisture analysis is a rapid non-destructive
analytical method that may potentially address the
limitations of traditional methods used for residual
moisture determination.
Failure Mode Effects Analysis
for Filter Integrity Testing
Understanding the risks associated
with FMEA is crucial in lot release testing.
Advancing Development & Manufacturing
PharmTech.com
Cover: Resolution Productions/
Getty Images
Art direction: Dan Ward
Concept Design for Establishing an Eco-Friendly
Pharmaceutical Production Facility in Malta
The authors discuss the concept design of a
versatile, sustainable, small-scale facility in Malta.
Ruggedness of Visible Residue Limits for Cleaning
Validation, Part IV: Defining Visible Residue Limits
to be Practical, Achievable, and Verifiable
Visible residue limits have been shown to be a
valuable tool in a validated cleaning validation
programme.
Editor’s Comment
The Repercussions of Data Integrity Violations
Outsourcing Review
CMC Development is Hot
European Regulatory Watch
Europe Moves Forward on Anticounterfeiting Measures
US Regulatory Watch
Vaccine Development Faces Urgency and Challenges
API Synthesis & Manufacturing
Conjugation Chemistry with Highly Potent Compounds
Packaging Forum
Blister Pack Optimization
Troubleshooting
Understanding Measurement Uncertainty in Weighing
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Pharmaceutical Technology Europe
APRIL 2016
3
EDITORIAL ADVISORY BOARD
PharmTech Europe
Editor
Adeline Siew, PhD
asiew@advanstar.com
PharmTech Group
Editorial Director
Rita Peters
rpeters@advanstar.com
Senior Editor
Agnes Shanley
ashanley@advanstar.com
Managing Editor
Susan Haigney
shaigney@advanstar.com
Manufacturing Editor
Jennifer Markarian
jmarkarian@advanstar.com
Science Editor
Randi Hernandez
rhernandez@advanstar.com
Community Editor
Caroline Hroncich
chroncich@advanstar.com
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Chief Operating Oficer
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EVP & Managing Director, UBM
Medica
Georgiann DeCenzo
EVP, Strategy & Business
Development
Mike Alic
Contributing Editor
Cynthia A. Challener, PhD
Reinhard Baumfalk
Global Correspondent
Sean Milmo
(Europe, smilmo@btconnect.com)
Art Director
Dan Ward
Innovation
Sartorius AG
King’s College London
Rafael Beerbohm
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Boehringer Ingelheim GmbH
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Jim Miller
Phil Borman
President,PharmSource
Manager, GlaxoSmithKline
Information Services
Rory Budihandojo
Colin Minchom
Director, Quality and EHS Audit
Senior Director
Boehringer-Ingelheim
Pharmaceutical Sciences
Christopher Burgess
Shire Pharmaceuticals
Managing Director
Clifford S. Mintz
Burgess Analytical Consultancy
President and Founder
Ryan F. Donnelly
BioInsights
Professor
Tim Peterson
VP & Managing Director, Pharm/
Science Group
Dave Esola
Queens University Belfast
Transdermal Product
Tim Freeman
Development Leader, Drug
VP & Managing Director, CBI/IVT
Johanna Morse
Managing Director
Delivery Systems Division, 3M
Freeman Technology
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Technical Director
VP & Managing Director,
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VP, Marketing & Audience
Development
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VP, Media Operations
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Chief Financial Oficer
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Chairman
Dame Helen Alexander
Editorial: All submissions will be handled with reasonable care, but the publisher assumes no responsibility for safety of
artwork, photographs, or manuscripts. Every precaution is taken to ensure accuracy, but the publisher cannot accept
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Chair of Pharmaceutical
Instrumentation & Control
Director of Quality Systems
Publisher
Michael Tracey
mtracey@advanstar.com
Luigi G. Martini
Vice-President, R&D
Pharmaceutical Technology Europe
APRIL 2016
10% Post
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Vice-President, R&D
Philips Respironics
Hovione
Thomas Rades
Sharon Grimster
Professor, Research Chair in
ReNeuron
Formulation Desgin and Drug De-
Anne Marie Healy
livery, University of Copenhagen
Professor in Pharmaceutics and
Rodolfo Romañach
Pharmaceutical Technology
Professor of Chemistry
Trinity College Dublin, Ireland
University of Puerto Rico,
Deirdre Hurley
Puerto Rico
Senior Director, Plant
Siegfried Schmitt
Helsinn Birex
Principal Consultant
Pharmaceuticals Ltd.
PAREXEL
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Independent Consultant
Professor
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University of Ljubljana, Slovenia
CEO, Senior Consultant,
Griet Van Vaerenbergh
Genau & More A/S
GEA Process Engineering
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Tablets Technology Cell, GMS
Arlenda
GlaxoSmithKline
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Roberto Margarita
Managing Director
Platform Director
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Corden Pharma
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2016
The Parenteral Drug Association presents:
st
1 PDA Europe
Annual Meeting
T H E F U T U R E I N I N J EC TA B L E S
30 June - 1 July
Root Cause
Investigation
30 June - 1 July
Development of a
Pre-Filled Syringe
30 June
Test Methods for
Pre-Filled Syringes
30 June
Cleaning and
Disinfection
30 June
How to Find the Right
GMP for APIs
28-29 June 2016
Estrel Hotel Berlin
Berlin | Germany
europe.pda.org/AnnualMeeting2016
EDITOR’S COMMENT
The Repercussions of
Data Integrity Violations
P
harma has huge
responsibilities
resting on its shoulders
to deliver safe and
effective medicine.
As the push for
transparency heightens,
the industry finds itself
increasingly being
scrutinized in many
areas, from drug pricing and the reporting
of all clinical trial results to business ethics,
sales and marketing activities, and quality
control of manufacturing operations. But
how well is Pharma managing regulatory
compliance? A PwC report (1) in March
2016 noted a rise in the number of
pharmaceutical companies being issued
warning letters by the United States Food
and Drug Administration for GMP violations
related to data integrity deficiencies.
The three most common data integrity
issues cited by FDA for inspections from
2013 to 2015 were the lack of controls to
prevent alterations of data by staff, failure
to maintain records of accurate data, and
delayed reporting of data.
Data integrity is fundamental in
pharmaceutical manufacturing. It enables
traceability of a batch to its origin and,
more importantly, ensures that drugs are
6
Pharmaceutical Technology Europe
made and tested according to the required
quality standards. It is, therefore, crucial
that data records are accurate, complete,
legible, attributable, intact, and maintained
within their original context, including their
relationship to secondary data records.
Non-compliance does not only result in
revenue loss for the violator due to facility
shutdown, product recalls, import bans, and
delayed or denied drug approvals, but it also
tarnishes the company’s reputation and
provides competitors with an opportunity
to increase their market share. In addition,
warning letters divert the attention of
workers from their daily activities to
corrective and preventive actions, which
cost significant time and money.
According to Ernst & Young (2), one the
key root causes of data integrity issues is
staff shortage combined with excessive
workload that lead to inaccurate and
incomplete documentation; the emphasis
on quantity over quality forces workers to
compromise on quality so that production
targets and dispatch timelines can be met.
The lack of awareness among employees
and ineffective training are also known to
result in data integrity problems.
Regulators worldwide are increasingly
focusing on data integrity in their
enforcement efforts. Despite recent reports
APRIL 2016
PharmTech.com
of Indian and Chinese companies receiving
warning letters for data integrity violations,
the problem is, in reality, a global one. The
solution for the industry does not only
involve changing its approach from reactive
to proactive but embracing a culture of
quality so that regulatory compliance
becomes second nature in every company.
References
1. PwC, Health Research Institute Regulatory
Spotlight, Data Integrity Problems A Growing
Risk to Global Pharma Companies (March
2016), http://pwchealth.com/cgi-local/hregister.cgi/reg/pwc-data-integrity-spotlight.pdf,
accessed 1 Apr. 2016.
2. Ernst & Young, Analyzing the State of
Data Integrity Compliance in the Indian
Pharmaceutical Industry (June 2015),
www.ey.com/Publication/vwLUAssets/
ey-data-integrity-compliance-in-thepharma-industry/$FILE/ey-data-integritycompliance-in-the-pharma-industry.pdf,
accessed 1 Apr. 2016.
Adeline Siew, PhD
Editor of Pharmaceutical Technology Europe
asiew@advanstar.com
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OUTSOURCING REVIEW
CMC Development is Hot
Demand is driving expansion and consolidation
of formulation and clinical trial materials services.
Jim Miller is president of
PharmSource Information
Services, Inc., and publisher
of Bio/Pharmaceutical
Outsourcing Report,
tel. 703.383.4903,
Twitter@JimPharmSource,
info@pharmsource.com,
www.pharmsource.com.
arly development services are not the most
glamorous segment of the contract development
and manufacturing organization (CDMO) industry, but
these days they may be the hottest. Booming market
demand is driving record growth, expansion, and
acquisition activity.
Formulation development and manufacturing of
early-phase clinical trial materials (CTM) historically
have been some of the least attractive segments
of the contract services industry from a business
standpoint. Typically, price points were low relative to
larger-scale manufacturing services, and client churn
was high because projects were generally one-off
engagements for emerging bio/pharma companies
with short pipelines and limited funding. Further, the
business had low barriers to entry and there were few
economies of scale, so the industry remained highly
fragmented.
Market and technical trends in recent years
have drastically changed the significance and
attractiveness of early development services. The
serious formulation work is done in Phase II after
proof-of-concept is demonstrated, and at that
point, scale up and tech transfer to the commercial
manufacturer is a much greater consideration.
Commercial-scale contract manufacturing
organizations (CMOs) have a strong interest in
capturing the client at that point because they
have the opportunity to retain the business as the
product works through the development stages
to commercialization. Clients have an interest
in having the commercial CMO develop the
formulation because they expect it will facilitate
tech transfer with minimal need to change the
formulation as it is scaled up.
Formulation development services
Formulation development has also taken on greater
significance as delivery challenges have increased.
For instance, today’s highly potent APIs often present
major challenges for solubility and bioavailability
that require more sophisticated formulations such
as amorphous solid dispersions produced with
advanced technologies such as spray drying or
hot-melt extrusion. Advanced expertise is needed
to select the most appropriate formulation and
processing technology. Specialized knowhow may
8
Pharmaceutical Technology Europe
APRIL 2016
PharmTech.com
also be required as bio/pharma companies seek novel
presentations that can differentiate their products in
the market (e.g., taste-masked or controlled-release
formulations).
The demand for formulation and
other development services is
driving both capacity expansions
and new investor interest.
Development services have also been beneficiaries
of the boost in drug development activity fed by
record amounts of external fundraising. Total nondebt fundraising increased by approximately 50% to
US$31.5 billion (€27.68 billion), compared to US$21.5
billion (€18.9 billion) in 2014, according to data from
the PharmSource Lead Sheet. With ample funding,
clinical trial activity has been on the upswing.
According to data from clinicaltrials.gov, Phase I and
Phase II trial registrations declined from 2008 through
2013 when external funding was difficult to obtain,
but registrations have been trending upward in the
past two years.
Company investments
The increased demand for development services is
showing up in the financial results of the few CDMOs
that reveal them publicly. Catalent, Patheon, and the
Metrics Contract Services unit of Mayne Pharma have
all reported revenue growth of 20% or more for their
development services businesses in the past year.
Anecdotally, CDMOs report record levels of business
and tight capacity that in many cases is forcing clients
to wait six months for a project slot.
Not surprisingly the demand for formulation and
other development services is driving both capacity
expansions and new investor interest. For instance,
Patheon has established a new development services
unit at its Greenville, North Carolina, US, facility, while
Catalent invested in its Kansas City, Missouri, US, facility
as its centre for solid-dose development. Injectables
capacity is a particular focus, owing to the growth of
biologics: Alcami has announced expanded capacity at
its Charleston, South Carolina, US, injectables operation,
while Piramal Pharma Solutions has announced a US$10
million (€8.79 million) expansion of its Coldstream
Laboratories facility in Lexington, Kentucky, US.
(Spotlight image) Stockbyte/GettyImages
E
Lonza’s entry into the market is strong confirmation of
the opportunity for formulation and other development
services. The company will launch formulation and analytical
development in the fourth quarter of 2016; preclinical and
GMP-compliant clinical supplies manufacturing will begin
in 2017. The new drug product services offering will focus
on parenteral dosage forms and will include specialized
analytical services, such as particulate identification,
characterization, extractables and leachables, and container/
closure integrity testing.
Adding clinical-scale drug product development and
manufacture gives Lonza a more complete offering to help
customers get into the clinic and makes the company more
competitive with other biologics CDMOs. Its strategy for the
business is to lead with strong technical capabilities, which
will distinguish it from those fill/finish CDMOs that have no or
limited pre-formulation and formulation capabilities.
Acquisition activity has picked up in the development
services space in response to improved demand. At the end of
2015, Capsugel acquired Xcelience (Tampa, Florida, US) and its
Powdersize micronization unit (Quakertown, Pennsylvania, US).
They have become part of Capsugel’s Dosage Form Solutions
(DFS) business unit, which includes Bend Research (Bend,
Oregon, US) and Encap Drug Delivery (Livingston, UK).
The acquisition builds out the Capsugel DFS by adding
micronization to DFS’s portfolio of solubility- and bioavailabilityenhancing technologies, which already include spray drying,
hot-melt extrusion, liquid-filled hard capsules, and softgels.
Further, it bolsters Capsugel’s capabilities and capacity in
analytical testing, formulation, and CTM manufacture of soliddose products.
Other recent deals in the early development arena include
AMRI’s acquisition of Whitehouse Laboratories, a provider of
analytical testing services; and Amatsigroup’s (Fontenilles,
France) acquisition of Q Biologicals (Zwijnaarde, Belgium).
Amatsigroup is a private equity-backed French CDMO that has
rolled up some smaller operations in France and Belgium. It
is under the radar of most US-based companies but has now
reached revenues of more than US$33 million (€30 million),
which is decent for a standalone development services
company.
One situation worth watching is whether preclinical
contract research organization (CRO) Charles River
Laboratories decides to ramp up its presence in the
pharmaceutics arena. Charles River, which has revenues
of US$1.4 billion (€1.23 million), recently announced plans
to acquire WIL Research, whose QS Pharma unit provides
formulation, analytical, and CTM manufacturing with
revenues of more than US$50 million (€43.94 million) for
those businesses. Charles River already has a major position
in analytical testing for large-molecule analytical testing
and CEO James Foster indicated at January’s JP Morgan
Healthcare Conference that CMC services could be a new
growth avenue for Charles River.
So the formulation and CTM services space is very much in
play as its participants experience high double-digit growth.
There are only a few independent service providers left in this
segment of the industry so there aren’t many significant deals
left to be done, but it is a part of the industry that is rapidly
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Europe Moves Forward on
Anticounterfeiting Measures
The European Commission publishes regulations on mandatory packaging safety features to fight counterfeiting.
he European Commission (EC) has finally published a regulation on mandatory safety features for medicines packaging
to combat counterfeiting of pharmaceuticals. Publication of
the regulation means that a deadline of 9 Feb., 2019 has been
set for implementation of European Union (EU) rules on unique
identifier barcodes and anti-tamper devices for single-pack
medicines, many years after the rules were first suggested. The
three-year transition period, however, has already been questioned by information technology (IT) specialists as to whether
it will be long enough to allow time for the proper testing of
systems for authentication of the unique identification data.
The packaging safety features scheme will be an end-to-end
system under which the serialization and other data on each
pack will be fed by packaging units into a repositories network
so that it can be verified by a pharmacist with a scanner at the
dispensing point.
The EC, the Brussels-based EU executive, formally approved
the regulation in October 2015, after the European Parliament
and the European Council, representing the EU’s 28 member
states, delegated it with the task of drawing up detailed rules
on the single-pack serialization codes and their verification.
The packaging regulation is one part of the 2011 Falsified
Medicines Directive (FMD) of the EU, which was based on
legislative proposals first made by the EC in 2008. Sections
of the FMD, including those covering packaging, were drawn
up to strengthen rules first outlined in a 2001 directive on
medicines.
The regulation, which mostly applies to prescription
medicines, has taken so long to work out after many years of
consultation and bring to the stage of implementation because
of the complexity of serialization systems. Of the many pieces
of EU legislation on medicines, the packaging regulation
could turn out to be the one with the biggest impact on the
European pharmaceutical sector because of the broad range
of groups that it affects.
Medicine manufacturers and packaging contractors,
wholesalers and other distributors, and hospit al and
communit y pharmacists all have to be linked to a new
digitalized supply-chain system based on a network of data
repositories containing the serialization and other data on
each individual pack. In Germany alone, Europe’s largest
pharmaceuticals market, there are approximately 20,000
pharmacists to be connected to the system.
The difficulties of setting up the safety features scheme
within three years stem from the necessity to establish it
on two levels—one on the manufacturing side and the other
within a repositories network.
10
Pharmaceutical Technology Europe
APRIL 2016
PharmTech.com
Implications for manufacturers
The manufacturers or their packaging contractors are having
to reorganize and upgrade their packaging lines for the production of packs which, under the regulation, will be required
to have a 2D matrix serialization barcode containing a product
code, serial and batch numbers, and expiry date. The pack
will also have to have an anti-tamper device (ATD), the specifications for which are not laid down by the regulation, except
that it should not interfere with the verification process at
the dispensing point. In most cases, manufacturers and packaging companies will have to rely on the outside expertise of
software and equipment vendors, the most efficient of which
already have full order books.
A survey in 2015 by Domino Printing Sciences, Cambridge,
England, a specialist in packaging coding systems, found
that approximately 35% of companies investing in packaging
improvements to comply with the regulation were upgrading
100 or more packaging lines. Another 15% were converting
between 50 and 99 lines (1).
Around two-thirds of companies had allocated serialization
budgets of more than £2 million (US$3 million). However, 25%
had not fixed a budget, while around a quarter were also
expecting that preparation for serialization would taken them
longer than three years, according to the survey.
“A high number of smaller companies are still not even
aware of the regulation so it is likely a lot of them will not
make the deadline,” says Craig Stobie, head of Domino’s global
life-sciences team. “On the other hand many of the larger
and more proactive companies have been preparing for the
regulation for some time.”
Creating a repositories network
Parallel with the preparation work being carried out by the
manufacturers and their packaging partners is the creation of
a repositories network. This network will be run by National
Medicines Verification Organizations (NMVOs) in each of the
EU’s 28 member states and a central European Medicines
Verification Organization (EMVO) with a European Hub connecting all the national systems to ensure their interoperability.
The Hub will link the pharmacists authenticating the data on
packs with the national schemes.
Under the regulation, authentication is the responsibility
of manufacturers, distributors, and pharmacists so
the verification organizations are being formed by the
stakeholders, with much of the funding being provided by the
manufacturers. The NMVOs will be supervised by national
medicines authorities.
GLOBE: ZOONAR RF/GETTY IMAGES
T
The EMVO and the Hub has already
been set up. Of the EU member states,
only Germany has so far established an
NMVO, but its authentication system
is still in the pilot stage. Most of the
rest are well advanced in the process
of creating verification organizations
so that they should be ready to sign
contracts with authentication software
providers later this year.
“It will be challenging (set ting up
NMVOs on time), and for some countries
it will be more challenging than others,”
says Anci Kvarnstroem, a consultant at
PhQConsulting in Sweden. “But they will
all be able to meet the deadline. A lot of
countries had already started preparing
to implement the regulation even before
it was finally published.”
Testing the system
“The most challenging task will not be the
establishment of the NMVOs but putting
in place and testing the actual authentication systems in each country,” she continued. “[These will have to have] secure
connections to the European Hub and to
all stakeholders that are obliged to verify
and decommission the individual packs
by the deadline in February 2019.”
T h e r e i s a g row in g v i e w a m o n g
IT experts and groups involved in the
creation of the NMVOs that a key issue
is the time needed to test new systems.
T h u s b o t h t h e m a n u f a c t u re r s a n d
packaging companies and the NMVOs
will have to allow for a sufficiently long
testing period before the deadline of
February 2019.
“This is a huge change-management
project,” said Graham Smith, commercial
d i r e c t o r a t A e g a t e , a U K- b a s e d
a u t h e n t i c a t i o n s e r v i c e s p r o v i d e r.
“Before the re gulation comes into
effect in February 2019, we need to
make sure everything works properly.
Manufacturers need not only to serialize
medicines, but also to test that these
codes can be loaded into the database
and that the codes can be read by
wholesalers and pharmacists. It seems to
make sense that once an authentication
system is in place there should be
sufficient time allowed for testing.”
Some stakeholder groups are aiming
to leave as long as 18 months for testing
by set ting up NMVOs as quickly as
possible and appointing authentication
service providers to establish
verification systems by the end of 2016.
In the UK, for example, stakeholders are
expecting to have a verification system
at least at the pilot stage by mid-2017 so
that manufacturers will then be able to
start testing their serialization systems
on it.
“We believe that the testing period
needs to be a lengthy one,” says Rick
Greville, responsible for the implementation of FMD legislation at the Association
of the British Pharmaceutical Industry
(ABPI), representing UK manufacturers.
“We are advising manufacturers that they
should allow a minimum of six months
before the February 2019 deadline for
testing,” he says.
Experts have warned that manufacturers need to ensure that all their lines
upgraded for serialization are properly
tested. “The temptation is to concentrate on testing the better equipped lines
while it is the lines held in reserve which
will be causing problems,” says Stobie.
Opinion is nonetheless divided about
the amount and application of the data
provided by the new safety features
system. The Brussels-based Medicines
for Europe—formerly European Generic
and Biosimilar medicines Association
(EGA)—is, for example, urging medicines
agencies to allow the application of the
unique identifier data to be broadened
to applications like pharmacovigilance.
“The FMD legislation allows national
competent authorities to extend the
scope of the safet y features,” says
Maarten Van Baelen, the association’s
market access director.
However, others believe that the priority
should be ensuring that the serialization
system as laid down by the regulation is
operating by the February 2019 deadline.
“The potential for other data management
s c h e m e s i s v e r y a l l u r i n g ,” s a y s
Kvarnstroem. “We must remain focused
on the implementation of the serialization
system to comply with the regulation. If
we start to widen the scope of the project,
we won’t be able to get it ready on time.”
Reference
1. C. Stobie. “Compliance Waits for No
One!,” presentation at Pharmapack conference (Paris, February 2016). PTE
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APRIL 2016
11
Jill Wechsler is Pharmaceutical Technology
Europe’s Washington editor, tel. +1 301.656.4634,
jwechsler@advanstar.com.
Vaccine Development Faces
Urgency and Challenges
Global outbreaks energize vaccine R&D and drive production modernization.
he Ebola outbreak in 2015 and the current stampede to develop
a new vaccine to combat the Zika virus illustrate the increasingly important role of vaccines in advancing public health. Public
and private funding for vaccine development and production has
grown noticeably, from US$822 million (€722 million) in 2000 to
US$3.6 billion (€3.16 billion) in 2014, spurred by the “Decade of
Vaccines” (2011–2020) initiative launched by the Bill & Melinda
Gates Foundation and the global health community five years ago.
The campaign has helped move more vaccine candidates through
clinical testing to market approval, according to an analysis in
the February 2016 special issue on vaccines in the journal Health
Affairs (1). And it has prompted manufacturers to expand and modernize vaccine production facilities to be able to meet the global
demand for treatments and to avoid product shortages.
The urgent need for new treatments to combat Zika and
related birth defects also illustrates the inadequacies in the
current world health infrastructure to combat epidemic and
pandemic diseases. Experts seek to improve public health
infrastructure and to reach global agreement on clinical
trial design and regulator y decision making to support
rapid development of needed therapies. At a Ministerial
Conference on Immunization in Africa in February 2016,
officials emphasized the need for greater funding of national
immunization programmes, including expanded regional
capacity for vaccine development and production; they also
demanded increased price transparency to facilitate access to
affordable vaccines.
Scientific advances
To achieve these goals, scientists in academia, government, and
industry are moving to tap new genomics technology to reduce
the long R&D process and help modernize vaccine development
and production. The design of new antigens based on molecular
structure and advances in synthetic biology will help deliver
new vaccines to patients, noted GlaxoSmithKline (GSK) Chief
Scientist Rino Rappuoli at the PDA/FDA Vaccines conference in
December 2015.
Such strategies may accelerate development of a vaccine
for Zika, which is similar to that for dengue, East Nile virus, and
yellow fever. Sanofi hopes to build on its success in producing a
vaccine against dengue fever, which was approved in December
2015 in Mexico, Brazil, and the Philippines (2). GSK, Pfizer, Merck,
Johnson & Johnson, and Takeda, as well as several smaller
biotech firms, are examining vaccine research portfolios for
potential candidates to combat Zika.
Anthony Fauci, director of the National Institute of Allergy
and Infectious Diseases (NIAID), has explained at several
Congressional hearings that he hopes to begin Phase I studies
12
Pharmaceutical Technology Europe
APRIL 2016
PharmTech.com
on a Zika virus vaccine in a few months, building on a DNAbased vaccine for West Nile virus already under development.
Positive early results could lead to larger trials more quickly
than usual, but a fully tested and approved Zika vaccine still will
take several years.
Scientists are moving
to tap new genomics
technology to reduce the
long R&D process and
help modernize vaccine
development.
Meanwhile, testing continues on Ebola vaccine candidates
that have produced evidence of safety and efficacy from
“emergency use” and initial clinical studies. Merck announced
advanced clinical trials for its vaccine developed with NewLink
Genetics in January 2016, plus a deal with GAVI, the Vaccine
Alliance, for coverage and distribution by the end of 2017 (3).
Vaccines for other widespread infectious diseases also are
moving forward. Researchers recently reported progress in
combating Middle East Respiratory Syndrome (MERS), and
US investment in research to protect against bioterrorism
has led to a new vaccine to treat anthrax exposure. Efforts
to establish more reliable and efficient supplies of seasonal
influenza vaccine in the United States, moreover, have led
to development and US Food and Drug Administration (FDA)
approval of the first US adjuvant flu vaccine.
President Obama has asked Congress for US$1.9 billion
(€1.67 billion) in emergency funding to tackle Zika, much
of that designated for the Centers for Disease Control and
Prevention (CDC) to track the disease and prevent its spread,
and to the National Institutes of Health (NIH) to fund R&D on
vaccines and antiviral therapeutics. FDA would get US$10
million (€8.78 million) to support oversight of vaccines and
diagnostics, as well as assays to screen blood for the Zika virus.
Additional resources would help the US Department of Health
and Human Services’ (HHS) Biomedical Advanced Research
and Development Authority (BARDA) further the development
and manufacturing of new Zika vaccine candidates and other
innovative vaccine platform technologies. BARDA already is
GLOBE: ZOONAR RF/GETTY IMAGES
T
working with Brazilian agencies to
develop a Zika vaccine and to build
commercial-scale manufacturing.
Manufacturing challenges
In addition to support for innovation to
achieve a sustainable and profitable vaccine industry, manufacturers hope to gain
more streamlined vaccine development
requirements and clearer reimbursement
and coverage programmes. Despite the
proven effectiveness and value of vaccines, health agencies and insurers want
lower prices, while conflicting regulations
add to manufacturing costs.
For example, the transfer of
production of a long-used vaccine
adjuvant to a new facilit y at GSK’s
Marburg, Germany, production site took
five years and involved 15,000 pages
of nearly 300 documents, reported
GSK officials Hans-Joachim Mai and
Jutta Ochs at the 2015 PDA vaccines
conference. The extensive process was
needed to document unchanged quality
attributes of the adjuvant under a new
automated quality control system.
Similarly, Wilson Forsyth, director
of quality control at AstraZeneca (AZ)
Biologics Global Operations, described
a complex two-year process for shifting
a vaccine quality control operation
from California to the UK as part of a
consolidation of quality control and
vaccine R&D at AZ’s Liverpool facility. The
transfer process involved multiple work
streams and was complicated by different
time zones and the need to continue
production of seasonal influenza vaccine.
More modern vaccine production
aims to avoid supply shortages, which
regularly plague flu vaccine makers
due to tight production timelines. In
2015, AZ’s MedImmune experienced
production “challenges” that delayed
shipment of millions of doses to the
US of its FluMist nasal spray. Vaccine
shortages are difficult to resolve because
the cost of building and operating highquality vaccine production facilities limits
availability of alternate sources and the
ability to outsource production.
Costs and coverage
Vaccine shortages may be most common
with low-cost products because manu-
facturers are more likely to close a plant
that experiences vaccine quality production issues or to exit that market rather
than invest in improvements, according
to a recent analysis of the relationship
between vaccine prices and shortages by
David Ridley and colleagues at the Duke
University Fuqua School of Business (4).
The analysts found that most vaccine
shortages involved older, low-cost products, and fewer problems with newer
products, particularly innovative combination vaccines. Government health programmes and other payers want to avoid
over-paying for vaccines, Ridley noted, but
higher-priced products encourage R&D
in new vaccines and in high-quality and
high-capacity manufacturing facilities.
Co-pays and coverage limits by insurers
also can block access to vaccines, as
seen with Medicare beneficiaries who
have to pay more out-of-pocket for
vaccines, according to a recent study by
Avalere Health for GSK (5).
References
1. Health Affairs 35 (2) (February 2016), http://
content.healthaffairs.org/content/35/2.toc
2. Sanofi Pasteur, “Sanofi Pasteur’s Dengue
Vaccine Approved in the Philippines,”
Press Release, 22 Dec., 2015, http://hugin.
info/152918/R/1975412/722908.pdf
3. Gavi, “Ebola vaccine purchasing commitment from Gavi to prepare for future outbreaks,” Press Release, 20 Jan., 2016, www.
gavi.org/Library/News/Press-releases/2016/
Ebola-vaccine-purchasing-commitmentfrom-Gavi-to-prepare-for-future-outbreaks/
4. D. Ridley, X. Bei, E. Liebman, Health Affairs 35 (2) (February 2016), http://content.
healthaffairs.org/content/35/2/235.abstract
5. Avalere, “Medicare Has the Potential to
Avoid Preventable Illnesses by Encouraging Broader Coverage for Adult Vaccines,”
Press Release, 18 Feb., 2016, http://avalerehealth-production.s3.amazonaws.com/uploads/pdfs/1455800241_20160217_Part_D_
vaccine_coverage_release.pdf PTE
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Pharmaceutical Technology Europe
APRIL 2016
13
Advances for
Bio/Pharma
Analytical
Laboratories
Agnes Shanley
14
ime travelers from the 1980s would not recognize
the typical pharmaceutical laboratory of
2016. Large spaces filled with dedicated tabletop
instruments have disappeared, as pharmaceutical
companies have shut down facilities, downsized, and
are outsourcing more analytical laboratory work to
contract analytical service providers.
As pharmaceutical facilities become modular and
more flexible, instruments are shrinking. Portable
devices bring more data to the warehouse, plant
floor, and the lab, while wireless operation and use
of radiofrequency identification (RFID) tags are being
used to reduce operator error.
Data manipulation has been simplified in
more user-friendly chemometrics and statistical
analysis software. In addition, procedures such as
chromatography have become easier and more
powerful, while workhorse methods are gaining
ground as “first-pass” alternatives to expensive and
complex analytical methods.
To wrest value from every procedure and
instrument, laboratories are embracing some of the
basic concepts of lean manufacturing and optimizing
workflow to reduce waste and improve efficiency.
“With a move toward outsourcing and greater
focus on biotherapeutics, customers are asking for
more and better workflow solutions,” says John
Rontree, senior director, chromatography and mass
spectrometry at Thermo Fisher Scientific. “These
solutions simplify tasks for outsourcing vendors, and
reduce the complexity that comes with analyzing
biologics,” he says.
Pharmaceutical Technology Europe
APRIL 2016
PharmTech.com
A growing number of pharmaceutical companies are
outsourcing most, if not all of their analytical work.
Today, stability testing, dissolution, and method
development are typically outsourced, says Keith
Moore, vice-president of analytical services at Metrics
Contract Services.
Standard processes include high-performance
liquid chromatography (HPLC) assays, dissolution
testing by either HPLC or ultra violet (UV), and
Karl Fischer testing procedures, says Moore.
Pharmaceutical manufacturers are also outsourcing
operations that require specialized equipment and
highly trained users, such as mass spectrometry,
X-ray powder diffraction (XRPD), and nuclear magnetic
resonance (NMR) spectroscopy, he says.
Pharmaceutical manufacturers either outsource
directly to contract laboratory companies or
to larger contract manufacturing organizations
(CMOs) that have acquired analytical capabilities.
Metrics, for example, is a contract development and
manufacturing organization (CDMO) with analytical
testing capabilities.
According to Industry Standard Research’s
reports on the state of pharma outsourcing, lab
services are the seventh most widely outsourced
function for small molecules and the sixth largest for
biopharmaceuticals. It’s also an area that is seeing
more mergers and acquisitions. Eurofins, for instance,
which bought Lancaster Labs in 2011, acquired
Sinensis Life Sciences, an analytical services company
in the Netherlands, in 2016. At the end of December
Resolution Productions/Getty Images
Today’s analytical laboratory equipment reflects the
realities of downsizing,
outsourcing, and the need for speed.
Lab Procedures
2015, AMRI bought Whitehouse
Analytical, a major analytical services
company.
Both pharmaceutical sponsors and
their contract partners benefit from
more powerful analytical methods.
The workhorse method, HPLC,
still dominates pharma labs, but
alternatives such as UHPLC (ultra-high
pressure liquid chromatography),
offered by leading chromatography
vendors, including Waters, Varian,
Perkin Elmer, and Thermo Scientific,
are gaining users.
UHPLC, which uses smallerdiameter resin particles to improve
resolution, speed, and sensitivity,
allows more samples to be
analyzed faster than with other
methods. In addition, it reduces
solvent requirements and waste for
disposal, and requires less space,
hood space, and storage.
UHPLC for analytics has been likened
to continuous processing in the
manufacturing world. “If continuous
processing reduces the cost of
goods sold, UHPLC lowers the cost
of analysis,” notes Emil Ciurczak, NIR
spectroscopist who published the
industry’s first papers on the use of
process analytical technology (PAT) in
pharmaceutical manufacturing when
he worked at Sandoz in the 1980s.
“With UHPLC, less material is
required, and less time is needed
for preparation,” Ciurczak says. “So,
if, for example, you move sampling
from 40 mLs to 1–2 mLs per run,
you also save the cost of buying,
storing, and disposing of materials,”
he says. “The throughput increases
are especially remarkable, with one
instrument capable, in some cases,
of doing the work of six conventional
HPLCs,” he adds.
For bioseparations, notoriously
difficult to achieve efficiently, vendors
such as BIA Separations, Diosynth,
Biorad, Agilent, and Merck Millipore
have developed monolithic columns
that improve mass transfer and
reduce purification times.
Continuous and simulated moving
bed (SMB) chromatography, which
allows several columns to be run in
parallel, has also been developed
by companies that include Novasep,
GE Healthcare, Tarpon Biosystems,
Knauer, ChromaCon, and Semba
Biosciences. Vendors claim that this
approach can improve productivity by
a factor of up to six, and reduce the
use of resin and buffer by 75% (1).
For dissolution testing, Moore
says, UV spectroscopy is often the
first choice, even before HPLC,
because it provides immediate data
for trending and saves solvent,
disposal, and other costs. It also
uses one value, absorbance, to
analyze data, so there is no need to
transfer samples to vials.
In some situations, FourierTransform infrared (FTIR) and Raman
spectroscopy are being used to
evaluate polymorphism, instead of
the more challenging x-ray powder
diffraction.
In general, chemical imaging is
becoming more important, says
Ciurczak, and vendors such as
Innopharma, which developed
a real-time particle size imaging
platform with Glatt in 2015, as well
as Chemimage, Malvern, Bruker, and
Perkin-Elmer, are improving their
offerings in this segment.
Use of ion mobility spectroscopy is
also increasing for some applications.
“It’s becoming the poor man’s mass
spectrometer,” he says. Originally
used in airport security applications,
the technique, offered by vendors
that include Smith’s Detection, Water,
SelexION, and SCIEX, found its first
pharma applications in cleaning
validation back in the late 1990s.
Today, it is finding increased use in
some lower-end mass spectromet
Advances for
Bio/Pharma
Analytical
Laboratories
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Pharmaceutical Technology Europe is the authoritative
source of peer-reviewed research and expert analyses for
scientists, engineers, and managers engaged in process
development, manufacturing, formulation and drug
delivery, API synthesis, analytical technology and testing,
packaging, IT, outsourcing, and regulatory compliance
in the pharmaceutical and biotechnology industries.
Advances for Bio/Pharma Analytical Laboratories
Today’s analytical laboratory equipment reflects the
realities of downsizing, outsourcing,and the need for
speed.
Container Selection for Biologic Formulations
Choosing the right container and container
closure system is crucial for ensuring product
quality, safety, and efficacy of a biologic formulation.
Headspace Moisture Analysis for Determination of
Residual Moisture Content in Lyophilized Pharmaceutical Products
Headspace moisture analysis is a rapid non-destructive
analytical method that may potentially address the
limitations of traditional methods used for residual
moisture determination.
Failure Mode Effects Analysis
for Filter Integrity Testing
Understanding the risks associated
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Advancing Development & Manufacturing
PharmTech.com
Cover: Resolution Productions/
Getty Images
Art direction: Dan Ward
Concept Design for Establishing an Eco-Friendly
Pharmaceutical Production Facility in Malta
The authors discuss the concept design of a
versatile, sustainable, small-scale facility in Malta.
Ruggedness of Visible Residue Limits for Cleaning
Validation, Part IV: Defining Visible Residue Limits
to be Practical, Achievable, and Verifiable
Visible residue limits have been shown to be a
valuable tool in a validated cleaning validation
programme.
Editor’s Comment
The Repercussions of Data Integrity Violations
Outsourcing Review
CMC Development is Hot
European Regulatory Watch
Europe Moves Forward on Anticounterfeiting Measures
US Regulatory Watch
Vaccine Development Faces Urgency and Challenges
API Synthesis & Manufacturing
Conjugation Chemistry with Highly Potent Compounds
Packaging Forum
Blister Pack Optimization
Troubleshooting
Understanding Measurement Uncertainty in Weighing
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APRIL 2016
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EDITORIAL ADVISORY BOARD
PharmTech Europe
Editor
Adeline Siew, PhD
asiew@advanstar.com
PharmTech Group
Editorial Director
Rita Peters
rpeters@advanstar.com
Senior Editor
Agnes Shanley
ashanley@advanstar.com
Managing Editor
Susan Haigney
shaigney@advanstar.com
Manufacturing Editor
Jennifer Markarian
jmarkarian@advanstar.com
Science Editor
Randi Hernandez
rhernandez@advanstar.com
Community Editor
Caroline Hroncich
chroncich@advanstar.com
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EVP & Managing Director, UBM
Medica
Georgiann DeCenzo
EVP, Strategy & Business
Development
Mike Alic
Contributing Editor
Cynthia A. Challener, PhD
Reinhard Baumfalk
Global Correspondent
Sean Milmo
(Europe, smilmo@btconnect.com)
Art Director
Dan Ward
Innovation
Sartorius AG
King’s College London
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Boehringer Ingelheim GmbH
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Information Services
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Director, Quality and EHS Audit
Senior Director
Boehringer-Ingelheim
Pharmaceutical Sciences
Christopher Burgess
Shire Pharmaceuticals
Managing Director
Clifford S. Mintz
Burgess Analytical Consultancy
President and Founder
Ryan F. Donnelly
BioInsights
Professor
Tim Peterson
VP & Managing Director, Pharm/
Science Group
Dave Esola
Queens University Belfast
Transdermal Product
Tim Freeman
Development Leader, Drug
VP & Managing Director, CBI/IVT
Johanna Morse
Managing Director
Delivery Systems Division, 3M
Freeman Technology
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Chair of Pharmaceutical
Instrumentation & Control
Director of Quality Systems
Publisher
Michael Tracey
mtracey@advanstar.com
Luigi G. Martini
Vice-President, R&D
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APRIL 2016
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Vice-President, R&D
Philips Respironics
Hovione
Thomas Rades
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Professor, Research Chair in
ReNeuron
Formulation Desgin and Drug De-
Anne Marie Healy
livery, University of Copenhagen
Professor in Pharmaceutics and
Rodolfo Romañach
Pharmaceutical Technology
Professor of Chemistry
Trinity College Dublin, Ireland
University of Puerto Rico,
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Puerto Rico
Senior Director, Plant
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PAREXEL
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Professor
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University of Ljubljana, Slovenia
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Product Owner-OSD, TTC-
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Tablets Technology Cell, GMS
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2016
The Parenteral Drug Association presents:
st
1 PDA Europe
Annual Meeting
T H E F U T U R E I N I N J EC TA B L E S
30 June - 1 July
Root Cause
Investigation
30 June - 1 July
Development of a
Pre-Filled Syringe
30 June
Test Methods for
Pre-Filled Syringes
30 June
Cleaning and
Disinfection
30 June
How to Find the Right
GMP for APIs
28-29 June 2016
Estrel Hotel Berlin
Berlin | Germany
europe.pda.org/AnnualMeeting2016
EDITOR’S COMMENT
The Repercussions of
Data Integrity Violations
P
harma has huge
responsibilities
resting on its shoulders
to deliver safe and
effective medicine.
As the push for
transparency heightens,
the industry finds itself
increasingly being
scrutinized in many
areas, from drug pricing and the reporting
of all clinical trial results to business ethics,
sales and marketing activities, and quality
control of manufacturing operations. But
how well is Pharma managing regulatory
compliance? A PwC report (1) in March
2016 noted a rise in the number of
pharmaceutical companies being issued
warning letters by the United States Food
and Drug Administration for GMP violations
related to data integrity deficiencies.
The three most common data integrity
issues cited by FDA for inspections from
2013 to 2015 were the lack of controls to
prevent alterations of data by staff, failure
to maintain records of accurate data, and
delayed reporting of data.
Data integrity is fundamental in
pharmaceutical manufacturing. It enables
traceability of a batch to its origin and,
more importantly, ensures that drugs are
6
Pharmaceutical Technology Europe
made and tested according to the required
quality standards. It is, therefore, crucial
that data records are accurate, complete,
legible, attributable, intact, and maintained
within their original context, including their
relationship to secondary data records.
Non-compliance does not only result in
revenue loss for the violator due to facility
shutdown, product recalls, import bans, and
delayed or denied drug approvals, but it also
tarnishes the company’s reputation and
provides competitors with an opportunity
to increase their market share. In addition,
warning letters divert the attention of
workers from their daily activities to
corrective and preventive actions, which
cost significant time and money.
According to Ernst & Young (2), one the
key root causes of data integrity issues is
staff shortage combined with excessive
workload that lead to inaccurate and
incomplete documentation; the emphasis
on quantity over quality forces workers to
compromise on quality so that production
targets and dispatch timelines can be met.
The lack of awareness among employees
and ineffective training are also known to
result in data integrity problems.
Regulators worldwide are increasingly
focusing on data integrity in their
enforcement efforts. Despite recent reports
APRIL 2016
PharmTech.com
of Indian and Chinese companies receiving
warning letters for data integrity violations,
the problem is, in reality, a global one. The
solution for the industry does not only
involve changing its approach from reactive
to proactive but embracing a culture of
quality so that regulatory compliance
becomes second nature in every company.
References
1. PwC, Health Research Institute Regulatory
Spotlight, Data Integrity Problems A Growing
Risk to Global Pharma Companies (March
2016), http://pwchealth.com/cgi-local/hregister.cgi/reg/pwc-data-integrity-spotlight.pdf,
accessed 1 Apr. 2016.
2. Ernst & Young, Analyzing the State of
Data Integrity Compliance in the Indian
Pharmaceutical Industry (June 2015),
www.ey.com/Publication/vwLUAssets/
ey-data-integrity-compliance-in-thepharma-industry/$FILE/ey-data-integritycompliance-in-the-pharma-industry.pdf,
accessed 1 Apr. 2016.
Adeline Siew, PhD
Editor of Pharmaceutical Technology Europe
asiew@advanstar.com
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OUTSOURCING REVIEW
CMC Development is Hot
Demand is driving expansion and consolidation
of formulation and clinical trial materials services.
Jim Miller is president of
PharmSource Information
Services, Inc., and publisher
of Bio/Pharmaceutical
Outsourcing Report,
tel. 703.383.4903,
Twitter@JimPharmSource,
info@pharmsource.com,
www.pharmsource.com.
arly development services are not the most
glamorous segment of the contract development
and manufacturing organization (CDMO) industry, but
these days they may be the hottest. Booming market
demand is driving record growth, expansion, and
acquisition activity.
Formulation development and manufacturing of
early-phase clinical trial materials (CTM) historically
have been some of the least attractive segments
of the contract services industry from a business
standpoint. Typically, price points were low relative to
larger-scale manufacturing services, and client churn
was high because projects were generally one-off
engagements for emerging bio/pharma companies
with short pipelines and limited funding. Further, the
business had low barriers to entry and there were few
economies of scale, so the industry remained highly
fragmented.
Market and technical trends in recent years
have drastically changed the significance and
attractiveness of early development services. The
serious formulation work is done in Phase II after
proof-of-concept is demonstrated, and at that
point, scale up and tech transfer to the commercial
manufacturer is a much greater consideration.
Commercial-scale contract manufacturing
organizations (CMOs) have a strong interest in
capturing the client at that point because they
have the opportunity to retain the business as the
product works through the development stages
to commercialization. Clients have an interest
in having the commercial CMO develop the
formulation because they expect it will facilitate
tech transfer with minimal need to change the
formulation as it is scaled up.
Formulation development services
Formulation development has also taken on greater
significance as delivery challenges have increased.
For instance, today’s highly potent APIs often present
major challenges for solubility and bioavailability
that require more sophisticated formulations such
as amorphous solid dispersions produced with
advanced technologies such as spray drying or
hot-melt extrusion. Advanced expertise is needed
to select the most appropriate formulation and
processing technology. Specialized knowhow may
8
Pharmaceutical Technology Europe
APRIL 2016
PharmTech.com
also be required as bio/pharma companies seek novel
presentations that can differentiate their products in
the market (e.g., taste-masked or controlled-release
formulations).
The demand for formulation and
other development services is
driving both capacity expansions
and new investor interest.
Development services have also been beneficiaries
of the boost in drug development activity fed by
record amounts of external fundraising. Total nondebt fundraising increased by approximately 50% to
US$31.5 billion (€27.68 billion), compared to US$21.5
billion (€18.9 billion) in 2014, according to data from
the PharmSource Lead Sheet. With ample funding,
clinical trial activity has been on the upswing.
According to data from clinicaltrials.gov, Phase I and
Phase II trial registrations declined from 2008 through
2013 when external funding was difficult to obtain,
but registrations have been trending upward in the
past two years.
Company investments
The increased demand for development services is
showing up in the financial results of the few CDMOs
that reveal them publicly. Catalent, Patheon, and the
Metrics Contract Services unit of Mayne Pharma have
all reported revenue growth of 20% or more for their
development services businesses in the past year.
Anecdotally, CDMOs report record levels of business
and tight capacity that in many cases is forcing clients
to wait six months for a project slot.
Not surprisingly the demand for formulation and
other development services is driving both capacity
expansions and new investor interest. For instance,
Patheon has established a new development services
unit at its Greenville, North Carolina, US, facility, while
Catalent invested in its Kansas City, Missouri, US, facility
as its centre for solid-dose development. Injectables
capacity is a particular focus, owing to the growth of
biologics: Alcami has announced expanded capacity at
its Charleston, South Carolina, US, injectables operation,
while Piramal Pharma Solutions has announced a US$10
million (€8.79 million) expansion of its Coldstream
Laboratories facility in Lexington, Kentucky, US.
(Spotlight image) Stockbyte/GettyImages
E
Lonza’s entry into the market is strong confirmation of
the opportunity for formulation and other development
services. The company will launch formulation and analytical
development in the fourth quarter of 2016; preclinical and
GMP-compliant clinical supplies manufacturing will begin
in 2017. The new drug product services offering will focus
on parenteral dosage forms and will include specialized
analytical services, such as particulate identification,
characterization, extractables and leachables, and container/
closure integrity testing.
Adding clinical-scale drug product development and
manufacture gives Lonza a more complete offering to help
customers get into the clinic and makes the company more
competitive with other biologics CDMOs. Its strategy for the
business is to lead with strong technical capabilities, which
will distinguish it from those fill/finish CDMOs that have no or
limited pre-formulation and formulation capabilities.
Acquisition activity has picked up in the development
services space in response to improved demand. At the end of
2015, Capsugel acquired Xcelience (Tampa, Florida, US) and its
Powdersize micronization unit (Quakertown, Pennsylvania, US).
They have become part of Capsugel’s Dosage Form Solutions
(DFS) business unit, which includes Bend Research (Bend,
Oregon, US) and Encap Drug Delivery (Livingston, UK).
The acquisition builds out the Capsugel DFS by adding
micronization to DFS’s portfolio of solubility- and bioavailabilityenhancing technologies, which already include spray drying,
hot-melt extrusion, liquid-filled hard capsules, and softgels.
Further, it bolsters Capsugel’s capabilities and capacity in
analytical testing, formulation, and CTM manufacture of soliddose products.
Other recent deals in the early development arena include
AMRI’s acquisition of Whitehouse Laboratories, a provider of
analytical testing services; and Amatsigroup’s (Fontenilles,
France) acquisition of Q Biologicals (Zwijnaarde, Belgium).
Amatsigroup is a private equity-backed French CDMO that has
rolled up some smaller operations in France and Belgium. It
is under the radar of most US-based companies but has now
reached revenues of more than US$33 million (€30 million),
which is decent for a standalone development services
company.
One situation worth watching is whether preclinical
contract research organization (CRO) Charles River
Laboratories decides to ramp up its presence in the
pharmaceutics arena. Charles River, which has revenues
of US$1.4 billion (€1.23 million), recently announced plans
to acquire WIL Research, whose QS Pharma unit provides
formulation, analytical, and CTM manufacturing with
revenues of more than US$50 million (€43.94 million) for
those businesses. Charles River already has a major position
in analytical testing for large-molecule analytical testing
and CEO James Foster indicated at January’s JP Morgan
Healthcare Conference that CMC services could be a new
growth avenue for Charles River.
So the formulation and CTM services space is very much in
play as its participants experience high double-digit growth.
There are only a few independent service providers left in this
segment of the industry so there aren’t many significant deals
left to be done, but it is a part of the industry that is rapidly
maturing. PTE
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Europe Moves Forward on
Anticounterfeiting Measures
The European Commission publishes regulations on mandatory packaging safety features to fight counterfeiting.
he European Commission (EC) has finally published a regulation on mandatory safety features for medicines packaging
to combat counterfeiting of pharmaceuticals. Publication of
the regulation means that a deadline of 9 Feb., 2019 has been
set for implementation of European Union (EU) rules on unique
identifier barcodes and anti-tamper devices for single-pack
medicines, many years after the rules were first suggested. The
three-year transition period, however, has already been questioned by information technology (IT) specialists as to whether
it will be long enough to allow time for the proper testing of
systems for authentication of the unique identification data.
The packaging safety features scheme will be an end-to-end
system under which the serialization and other data on each
pack will be fed by packaging units into a repositories network
so that it can be verified by a pharmacist with a scanner at the
dispensing point.
The EC, the Brussels-based EU executive, formally approved
the regulation in October 2015, after the European Parliament
and the European Council, representing the EU’s 28 member
states, delegated it with the task of drawing up detailed rules
on the single-pack serialization codes and their verification.
The packaging regulation is one part of the 2011 Falsified
Medicines Directive (FMD) of the EU, which was based on
legislative proposals first made by the EC in 2008. Sections
of the FMD, including those covering packaging, were drawn
up to strengthen rules first outlined in a 2001 directive on
medicines.
The regulation, which mostly applies to prescription
medicines, has taken so long to work out after many years of
consultation and bring to the stage of implementation because
of the complexity of serialization systems. Of the many pieces
of EU legislation on medicines, the packaging regulation
could turn out to be the one with the biggest impact on the
European pharmaceutical sector because of the broad range
of groups that it affects.
Medicine manufacturers and packaging contractors,
wholesalers and other distributors, and hospit al and
communit y pharmacists all have to be linked to a new
digitalized supply-chain system based on a network of data
repositories containing the serialization and other data on
each individual pack. In Germany alone, Europe’s largest
pharmaceuticals market, there are approximately 20,000
pharmacists to be connected to the system.
The difficulties of setting up the safety features scheme
within three years stem from the necessity to establish it
on two levels—one on the manufacturing side and the other
within a repositories network.
10
Pharmaceutical Technology Europe
APRIL 2016
PharmTech.com
Implications for manufacturers
The manufacturers or their packaging contractors are having
to reorganize and upgrade their packaging lines for the production of packs which, under the regulation, will be required
to have a 2D matrix serialization barcode containing a product
code, serial and batch numbers, and expiry date. The pack
will also have to have an anti-tamper device (ATD), the specifications for which are not laid down by the regulation, except
that it should not interfere with the verification process at
the dispensing point. In most cases, manufacturers and packaging companies will have to rely on the outside expertise of
software and equipment vendors, the most efficient of which
already have full order books.
A survey in 2015 by Domino Printing Sciences, Cambridge,
England, a specialist in packaging coding systems, found
that approximately 35% of companies investing in packaging
improvements to comply with the regulation were upgrading
100 or more packaging lines. Another 15% were converting
between 50 and 99 lines (1).
Around two-thirds of companies had allocated serialization
budgets of more than £2 million (US$3 million). However, 25%
had not fixed a budget, while around a quarter were also
expecting that preparation for serialization would taken them
longer than three years, according to the survey.
“A high number of smaller companies are still not even
aware of the regulation so it is likely a lot of them will not
make the deadline,” says Craig Stobie, head of Domino’s global
life-sciences team. “On the other hand many of the larger
and more proactive companies have been preparing for the
regulation for some time.”
Creating a repositories network
Parallel with the preparation work being carried out by the
manufacturers and their packaging partners is the creation of
a repositories network. This network will be run by National
Medicines Verification Organizations (NMVOs) in each of the
EU’s 28 member states and a central European Medicines
Verification Organization (EMVO) with a European Hub connecting all the national systems to ensure their interoperability.
The Hub will link the pharmacists authenticating the data on
packs with the national schemes.
Under the regulation, authentication is the responsibility
of manufacturers, distributors, and pharmacists so
the verification organizations are being formed by the
stakeholders, with much of the funding being provided by the
manufacturers. The NMVOs will be supervised by national
medicines authorities.
GLOBE: ZOONAR RF/GETTY IMAGES
T
The EMVO and the Hub has already
been set up. Of the EU member states,
only Germany has so far established an
NMVO, but its authentication system
is still in the pilot stage. Most of the
rest are well advanced in the process
of creating verification organizations
so that they should be ready to sign
contracts with authentication software
providers later this year.
“It will be challenging (set ting up
NMVOs on time), and for some countries
it will be more challenging than others,”
says Anci Kvarnstroem, a consultant at
PhQConsulting in Sweden. “But they will
all be able to meet the deadline. A lot of
countries had already started preparing
to implement the regulation even before
it was finally published.”
Testing the system
“The most challenging task will not be the
establishment of the NMVOs but putting
in place and testing the actual authentication systems in each country,” she continued. “[These will have to have] secure
connections to the European Hub and to
all stakeholders that are obliged to verify
and decommission the individual packs
by the deadline in February 2019.”
T h e r e i s a g row in g v i e w a m o n g
IT experts and groups involved in the
creation of the NMVOs that a key issue
is the time needed to test new systems.
T h u s b o t h t h e m a n u f a c t u re r s a n d
packaging companies and the NMVOs
will have to allow for a sufficiently long
testing period before the deadline of
February 2019.
“This is a huge change-management
project,” said Graham Smith, commercial
d i r e c t o r a t A e g a t e , a U K- b a s e d
a u t h e n t i c a t i o n s e r v i c e s p r o v i d e r.
“Before the re gulation comes into
effect in February 2019, we need to
make sure everything works properly.
Manufacturers need not only to serialize
medicines, but also to test that these
codes can be loaded into the database
and that the codes can be read by
wholesalers and pharmacists. It seems to
make sense that once an authentication
system is in place there should be
sufficient time allowed for testing.”
Some stakeholder groups are aiming
to leave as long as 18 months for testing
by set ting up NMVOs as quickly as
possible and appointing authentication
service providers to establish
verification systems by the end of 2016.
In the UK, for example, stakeholders are
expecting to have a verification system
at least at the pilot stage by mid-2017 so
that manufacturers will then be able to
start testing their serialization systems
on it.
“We believe that the testing period
needs to be a lengthy one,” says Rick
Greville, responsible for the implementation of FMD legislation at the Association
of the British Pharmaceutical Industry
(ABPI), representing UK manufacturers.
“We are advising manufacturers that they
should allow a minimum of six months
before the February 2019 deadline for
testing,” he says.
Experts have warned that manufacturers need to ensure that all their lines
upgraded for serialization are properly
tested. “The temptation is to concentrate on testing the better equipped lines
while it is the lines held in reserve which
will be causing problems,” says Stobie.
Opinion is nonetheless divided about
the amount and application of the data
provided by the new safety features
system. The Brussels-based Medicines
for Europe—formerly European Generic
and Biosimilar medicines Association
(EGA)—is, for example, urging medicines
agencies to allow the application of the
unique identifier data to be broadened
to applications like pharmacovigilance.
“The FMD legislation allows national
competent authorities to extend the
scope of the safet y features,” says
Maarten Van Baelen, the association’s
market access director.
However, others believe that the priority
should be ensuring that the serialization
system as laid down by the regulation is
operating by the February 2019 deadline.
“The potential for other data management
s c h e m e s i s v e r y a l l u r i n g ,” s a y s
Kvarnstroem. “We must remain focused
on the implementation of the serialization
system to comply with the regulation. If
we start to widen the scope of the project,
we won’t be able to get it ready on time.”
Reference
1. C. Stobie. “Compliance Waits for No
One!,” presentation at Pharmapack conference (Paris, February 2016). PTE
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Jill Wechsler is Pharmaceutical Technology
Europe’s Washington editor, tel. +1 301.656.4634,
jwechsler@advanstar.com.
Vaccine Development Faces
Urgency and Challenges
Global outbreaks energize vaccine R&D and drive production modernization.
he Ebola outbreak in 2015 and the current stampede to develop
a new vaccine to combat the Zika virus illustrate the increasingly important role of vaccines in advancing public health. Public
and private funding for vaccine development and production has
grown noticeably, from US$822 million (€722 million) in 2000 to
US$3.6 billion (€3.16 billion) in 2014, spurred by the “Decade of
Vaccines” (2011–2020) initiative launched by the Bill & Melinda
Gates Foundation and the global health community five years ago.
The campaign has helped move more vaccine candidates through
clinical testing to market approval, according to an analysis in
the February 2016 special issue on vaccines in the journal Health
Affairs (1). And it has prompted manufacturers to expand and modernize vaccine production facilities to be able to meet the global
demand for treatments and to avoid product shortages.
The urgent need for new treatments to combat Zika and
related birth defects also illustrates the inadequacies in the
current world health infrastructure to combat epidemic and
pandemic diseases. Experts seek to improve public health
infrastructure and to reach global agreement on clinical
trial design and regulator y decision making to support
rapid development of needed therapies. At a Ministerial
Conference on Immunization in Africa in February 2016,
officials emphasized the need for greater funding of national
immunization programmes, including expanded regional
capacity for vaccine development and production; they also
demanded increased price transparency to facilitate access to
affordable vaccines.
Scientific advances
To achieve these goals, scientists in academia, government, and
industry are moving to tap new genomics technology to reduce
the long R&D process and help modernize vaccine development
and production. The design of new antigens based on molecular
structure and advances in synthetic biology will help deliver
new vaccines to patients, noted GlaxoSmithKline (GSK) Chief
Scientist Rino Rappuoli at the PDA/FDA Vaccines conference in
December 2015.
Such strategies may accelerate development of a vaccine
for Zika, which is similar to that for dengue, East Nile virus, and
yellow fever. Sanofi hopes to build on its success in producing a
vaccine against dengue fever, which was approved in December
2015 in Mexico, Brazil, and the Philippines (2). GSK, Pfizer, Merck,
Johnson & Johnson, and Takeda, as well as several smaller
biotech firms, are examining vaccine research portfolios for
potential candidates to combat Zika.
Anthony Fauci, director of the National Institute of Allergy
and Infectious Diseases (NIAID), has explained at several
Congressional hearings that he hopes to begin Phase I studies
12
Pharmaceutical Technology Europe
APRIL 2016
PharmTech.com
on a Zika virus vaccine in a few months, building on a DNAbased vaccine for West Nile virus already under development.
Positive early results could lead to larger trials more quickly
than usual, but a fully tested and approved Zika vaccine still will
take several years.
Scientists are moving
to tap new genomics
technology to reduce the
long R&D process and
help modernize vaccine
development.
Meanwhile, testing continues on Ebola vaccine candidates
that have produced evidence of safety and efficacy from
“emergency use” and initial clinical studies. Merck announced
advanced clinical trials for its vaccine developed with NewLink
Genetics in January 2016, plus a deal with GAVI, the Vaccine
Alliance, for coverage and distribution by the end of 2017 (3).
Vaccines for other widespread infectious diseases also are
moving forward. Researchers recently reported progress in
combating Middle East Respiratory Syndrome (MERS), and
US investment in research to protect against bioterrorism
has led to a new vaccine to treat anthrax exposure. Efforts
to establish more reliable and efficient supplies of seasonal
influenza vaccine in the United States, moreover, have led
to development and US Food and Drug Administration (FDA)
approval of the first US adjuvant flu vaccine.
President Obama has asked Congress for US$1.9 billion
(€1.67 billion) in emergency funding to tackle Zika, much
of that designated for the Centers for Disease Control and
Prevention (CDC) to track the disease and prevent its spread,
and to the National Institutes of Health (NIH) to fund R&D on
vaccines and antiviral therapeutics. FDA would get US$10
million (€8.78 million) to support oversight of vaccines and
diagnostics, as well as assays to screen blood for the Zika virus.
Additional resources would help the US Department of Health
and Human Services’ (HHS) Biomedical Advanced Research
and Development Authority (BARDA) further the development
and manufacturing of new Zika vaccine candidates and other
innovative vaccine platform technologies. BARDA already is
GLOBE: ZOONAR RF/GETTY IMAGES
T
working with Brazilian agencies to
develop a Zika vaccine and to build
commercial-scale manufacturing.
Manufacturing challenges
In addition to support for innovation to
achieve a sustainable and profitable vaccine industry, manufacturers hope to gain
more streamlined vaccine development
requirements and clearer reimbursement
and coverage programmes. Despite the
proven effectiveness and value of vaccines, health agencies and insurers want
lower prices, while conflicting regulations
add to manufacturing costs.
For example, the transfer of
production of a long-used vaccine
adjuvant to a new facilit y at GSK’s
Marburg, Germany, production site took
five years and involved 15,000 pages
of nearly 300 documents, reported
GSK officials Hans-Joachim Mai and
Jutta Ochs at the 2015 PDA vaccines
conference. The extensive process was
needed to document unchanged quality
attributes of the adjuvant under a new
automated quality control system.
Similarly, Wilson Forsyth, director
of quality control at AstraZeneca (AZ)
Biologics Global Operations, described
a complex two-year process for shifting
a vaccine quality control operation
from California to the UK as part of a
consolidation of quality control and
vaccine R&D at AZ’s Liverpool facility. The
transfer process involved multiple work
streams and was complicated by different
time zones and the need to continue
production of seasonal influenza vaccine.
More modern vaccine production
aims to avoid supply shortages, which
regularly plague flu vaccine makers
due to tight production timelines. In
2015, AZ’s MedImmune experienced
production “challenges” that delayed
shipment of millions of doses to the
US of its FluMist nasal spray. Vaccine
shortages are difficult to resolve because
the cost of building and operating highquality vaccine production facilities limits
availability of alternate sources and the
ability to outsource production.
Costs and coverage
Vaccine shortages may be most common
with low-cost products because manu-
facturers are more likely to close a plant
that experiences vaccine quality production issues or to exit that market rather
than invest in improvements, according
to a recent analysis of the relationship
between vaccine prices and shortages by
David Ridley and colleagues at the Duke
University Fuqua School of Business (4).
The analysts found that most vaccine
shortages involved older, low-cost products, and fewer problems with newer
products, particularly innovative combination vaccines. Government health programmes and other payers want to avoid
over-paying for vaccines, Ridley noted, but
higher-priced products encourage R&D
in new vaccines and in high-quality and
high-capacity manufacturing facilities.
Co-pays and coverage limits by insurers
also can block access to vaccines, as
seen with Medicare beneficiaries who
have to pay more out-of-pocket for
vaccines, according to a recent study by
Avalere Health for GSK (5).
References
1. Health Affairs 35 (2) (February 2016), http://
content.healthaffairs.org/content/35/2.toc
2. Sanofi Pasteur, “Sanofi Pasteur’s Dengue
Vaccine Approved in the Philippines,”
Press Release, 22 Dec., 2015, http://hugin.
info/152918/R/1975412/722908.pdf
3. Gavi, “Ebola vaccine purchasing commitment from Gavi to prepare for future outbreaks,” Press Release, 20 Jan., 2016, www.
gavi.org/Library/News/Press-releases/2016/
Ebola-vaccine-purchasing-commitmentfrom-Gavi-to-prepare-for-future-outbreaks/
4. D. Ridley, X. Bei, E. Liebman, Health Affairs 35 (2) (February 2016), http://content.
healthaffairs.org/content/35/2/235.abstract
5. Avalere, “Medicare Has the Potential to
Avoid Preventable Illnesses by Encouraging Broader Coverage for Adult Vaccines,”
Press Release, 18 Feb., 2016, http://avalerehealth-production.s3.amazonaws.com/uploads/pdfs/1455800241_20160217_Part_D_
vaccine_coverage_release.pdf PTE
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Pharmaceutical Technology Europe
APRIL 2016
13
Advances for
Bio/Pharma
Analytical
Laboratories
Agnes Shanley
14
ime travelers from the 1980s would not recognize
the typical pharmaceutical laboratory of
2016. Large spaces filled with dedicated tabletop
instruments have disappeared, as pharmaceutical
companies have shut down facilities, downsized, and
are outsourcing more analytical laboratory work to
contract analytical service providers.
As pharmaceutical facilities become modular and
more flexible, instruments are shrinking. Portable
devices bring more data to the warehouse, plant
floor, and the lab, while wireless operation and use
of radiofrequency identification (RFID) tags are being
used to reduce operator error.
Data manipulation has been simplified in
more user-friendly chemometrics and statistical
analysis software. In addition, procedures such as
chromatography have become easier and more
powerful, while workhorse methods are gaining
ground as “first-pass” alternatives to expensive and
complex analytical methods.
To wrest value from every procedure and
instrument, laboratories are embracing some of the
basic concepts of lean manufacturing and optimizing
workflow to reduce waste and improve efficiency.
“With a move toward outsourcing and greater
focus on biotherapeutics, customers are asking for
more and better workflow solutions,” says John
Rontree, senior director, chromatography and mass
spectrometry at Thermo Fisher Scientific. “These
solutions simplify tasks for outsourcing vendors, and
reduce the complexity that comes with analyzing
biologics,” he says.
Pharmaceutical Technology Europe
APRIL 2016
PharmTech.com
A growing number of pharmaceutical companies are
outsourcing most, if not all of their analytical work.
Today, stability testing, dissolution, and method
development are typically outsourced, says Keith
Moore, vice-president of analytical services at Metrics
Contract Services.
Standard processes include high-performance
liquid chromatography (HPLC) assays, dissolution
testing by either HPLC or ultra violet (UV), and
Karl Fischer testing procedures, says Moore.
Pharmaceutical manufacturers are also outsourcing
operations that require specialized equipment and
highly trained users, such as mass spectrometry,
X-ray powder diffraction (XRPD), and nuclear magnetic
resonance (NMR) spectroscopy, he says.
Pharmaceutical manufacturers either outsource
directly to contract laboratory companies or
to larger contract manufacturing organizations
(CMOs) that have acquired analytical capabilities.
Metrics, for example, is a contract development and
manufacturing organization (CDMO) with analytical
testing capabilities.
According to Industry Standard Research’s
reports on the state of pharma outsourcing, lab
services are the seventh most widely outsourced
function for small molecules and the sixth largest for
biopharmaceuticals. It’s also an area that is seeing
more mergers and acquisitions. Eurofins, for instance,
which bought Lancaster Labs in 2011, acquired
Sinensis Life Sciences, an analytical services company
in the Netherlands, in 2016. At the end of December
Resolution Productions/Getty Images
Today’s analytical laboratory equipment reflects the
realities of downsizing,
outsourcing, and the need for speed.
Lab Procedures
2015, AMRI bought Whitehouse
Analytical, a major analytical services
company.
Both pharmaceutical sponsors and
their contract partners benefit from
more powerful analytical methods.
The workhorse method, HPLC,
still dominates pharma labs, but
alternatives such as UHPLC (ultra-high
pressure liquid chromatography),
offered by leading chromatography
vendors, including Waters, Varian,
Perkin Elmer, and Thermo Scientific,
are gaining users.
UHPLC, which uses smallerdiameter resin particles to improve
resolution, speed, and sensitivity,
allows more samples to be
analyzed faster than with other
methods. In addition, it reduces
solvent requirements and waste for
disposal, and requires less space,
hood space, and storage.
UHPLC for analytics has been likened
to continuous processing in the
manufacturing world. “If continuous
processing reduces the cost of
goods sold, UHPLC lowers the cost
of analysis,” notes Emil Ciurczak, NIR
spectroscopist who published the
industry’s first papers on the use of
process analytical technology (PAT) in
pharmaceutical manufacturing when
he worked at Sandoz in the 1980s.
“With UHPLC, less material is
required, and less time is needed
for preparation,” Ciurczak says. “So,
if, for example, you move sampling
from 40 mLs to 1–2 mLs per run,
you also save the cost of buying,
storing, and disposing of materials,”
he says. “The throughput increases
are especially remarkable, with one
instrument capable, in some cases,
of doing the work of six conventional
HPLCs,” he adds.
For bioseparations, notoriously
difficult to achieve efficiently, vendors
such as BIA Separations, Diosynth,
Biorad, Agilent, and Merck Millipore
have developed monolithic columns
that improve mass transfer and
reduce purification times.
Continuous and simulated moving
bed (SMB) chromatography, which
allows several columns to be run in
parallel, has also been developed
by companies that include Novasep,
GE Healthcare, Tarpon Biosystems,
Knauer, ChromaCon, and Semba
Biosciences. Vendors claim that this
approach can improve productivity by
a factor of up to six, and reduce the
use of resin and buffer by 75% (1).
For dissolution testing, Moore
says, UV spectroscopy is often the
first choice, even before HPLC,
because it provides immediate data
for trending and saves solvent,
disposal, and other costs. It also
uses one value, absorbance, to
analyze data, so there is no need to
transfer samples to vials.
In some situations, FourierTransform infrared (FTIR) and Raman
spectroscopy are being used to
evaluate polymorphism, instead of
the more challenging x-ray powder
diffraction.
In general, chemical imaging is
becoming more important, says
Ciurczak, and vendors such as
Innopharma, which developed
a real-time particle size imaging
platform with Glatt in 2015, as well
as Chemimage, Malvern, Bruker, and
Perkin-Elmer, are improving their
offerings in this segment.
Use of ion mobility spectroscopy is
also increasing for some applications.
“It’s becoming the poor man’s mass
spectrometer,” he says. Originally
used in airport security applications,
the technique, offered by vendors
that include Smith’s Detection, Water,
SelexION, and SCIEX, found its first
pharma applications in cleaning
validation back in the late 1990s.
Today, it is finding increased use in
some lower-end mass spectromet