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NOVEMBER 2015 Volume 27 Number 11
Exploring the Potential of
Continuous Coating
FORMULATION
Topical Bioequivalence
PEER-REVIEWED
Glass Delamination
SUPPLY CHAIN
Track and Trace
West seeks partners for its SmartDose electronic wearable injector technology platform. This platform
is intended to be used as an integrated system with drug filling and final assembly completed by
the pharmaceutical/biotechnology company. The SmartDose system, HealthPrize platform
integration is for conceptual purposes only.
West and the diamond logo and By your side for a healthier world™ are registered
trademarks or trademarks of West Pharmaceutical Services, Inc., in the United
States and other jurisdictions. SmartDose® is a registered trademark of Medimop
Medical Projects Ltd., a subsidiary of West Pharmaceutical Services, Inc.
For complete contact information please visit www.westpharma.com.
Copyright © 2015 West Pharmaceutical Services, Inc.
www.smartdose.com I (800) 345-9800
The SmartDose® electronic wearable injector
combined with the HealthPrize adherence program
makes for a powerful combination. The SmartDose
injector helps your patients leave the treatment
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Cover: Nicholas Eveleigh/Getty ImagesIllustration: Dan Ward
November 2015
Features
COVER STORY
18 Exploring the Potential of Continuous Coating
Industy experts share insights on the advances
in tablet coating technologies and the potential of
continuous coating in solid-dosage manufacturing.
PARENTERAL MANUFACTURING
22 Better Days for Parenterals?
Although shortages, quality, and regulatory
challenges remain, improved technologies and new
investments suggest that the worst may be over.
FORMULATION
26 Demonstrating Therapeutic Equivalence
for Generic Topical Products
The determination of topical bioequivalence
requires a multi-faceted approach, tailored
specifically to the generic-drug formulation.
SUPPLY CHAIN
35 Piloting Track-and-Trace Implementation
Virtual pilot programmes examine scenarios that may
occur while implementing serialization requirements.
PharmTech.com
Columns and Regulars
5 Editor’s Comment
Complexities of Compliance
6 European Regulatory Watch
EU’s New Telematics Strategy
for the Regulation of Medicines
10 Drug Development
Risk-Sharing Agreements in the EU
and Considerations for Moving Forward
14 Outsourcing Review
CMOs Continue to Improve
Overall Biomanufacturing Performance
33 API Synthesis & Manufacturing
Advances in Heterocyclic Chemistry for API Synthesis
37 Product/Service Profiles
41 Troubleshooting
Using Dynamic Thermal Imaging to Correct Sealing Problems
42 Ad Index
Peer-Reviewed28 Identifying Causes Of Delamination
A long-term study was conducted to determine
the causes of delamination. The findings enabled
the development of an improved manufacturing
process for glass vials and a new type of vial.
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28 3522 18
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EDITOR’S COMMENT
Complexities of Compliance
By July 2016, pharmaceutical companies in Europe will have to comply with the Identification of Medicinal
Products (IDMP) regulations, which were developed by the International Organization for Standardization (ISO)
as a means to globally harmonize the way medicinal products are referenced. IDMP standards provide the basis for
the unique identification of medicinal products—the aim is to simplify the exchange of data between pharmaceutical
manufacturers
across Europe and
facilitate regulatory
activities from
drug development,
registration, and product lifecycle
management to pharmacovigilance
and risk management. The reporting
requirements mandated under IDMP will
involve leveraging product information
from R&D, manufacturing, supply chain,
and commercial divisions. Successful
implementation could potentially
improve process and operational
efficiencies within an organization.
Nonetheless, the industry faces a
number of challenges in the run up to
the July 2016 deadline. Pharmaceutical
companies are well aware that
compliance is compulsory but timelines
are tight given the delay in the
finalization of the European Medicines
Agency’s implementation guidelines.
There are also cost implications that
must be factored in, for example, to
purchase the necessary software and
ensure that current data management
is under control. As IDMP should not
be considered an IT-only project to
standardize data across the company, it
is important that personnel from various
departments understand their roles and
responsibilities during the preparation
stage as well as for maintenance of IDMP
moving forward.
The regulation of medicinal products
has become increasingly complex over
the years, and IDMP implementation is
no exception. Non-compliance is not an
option for pharma because it comes with
financial penalties and in extreme cases,
marketing authorization licenses could
be revoked.
Adeline Siew, PhD
Editor of Pharmaceutical
Technology Europe
www.chemistry.umicore.com
Improvement is always on our mind. And in your mouth.
Of course we know that toothpaste is more useful in your
mouth than on a mirror, but sometimes we get carried away
with the brilliance of our formulas. Our Rhodium or Ruthenium
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chewing gum. Speaking of which, you should see the formulas
we pop out with gum.
Employee: Don Zeng/Sales and Business Development Manager
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6 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
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The European Union has embarked on an ambitious
programme to streamline the collection and use of data on
new and licensed medicines and their substances, including
excipients, throughout the EU. The scheme aims to ensure
that the European Medicines Agency (EMA), the EU central
organization for authorizing medicines throughout Europe,
and the licensing authorities of the EU’s 28 member states
will use the same IT system, based on a single data standard.
The objectives behind the programme are to improve the
efficiency of regulatory processes, raise cost effectiveness,
achieve interoperability for the sharing of knowledge, and
enhance collaboration through promoting open access to data
repositories.
The vision behind the scheme with details of its projects
and their benefits was outlined in a document (1) on an
EU telematics strategy and implementation roadmap for
2015–2017, published in August 2015 by the EMA and Heads of
Medicines Agencies (HMA) of the member states. The strategy,
however, is already running into problems, mainly stemming
from the complexity of the standards being applied to achieve
data uniformity and from variations in degrees of enthusiasm
among the members states for the scheme.
Most licensing agencies, called national competent
authorities (NCAs), are keenly supportive of the plan, but many
of them want to give precedence to pursuing their own IT
initiatives. A few are already refusing to participate in some
existing collaborative IT projects.
Industry views
In addition, the pharmaceutical industry is unhappy that it
has had minimal involvement in the creation of the strategy
while it is being offered, so far, limited participation in its
operation (1). The industry will not be engaged directly in the
EU telematics governance structure, which will be headed by a
management board representing EMA and HMA. Nonetheless,
the strategy document recognizes the “significant impact” of
the pharmaceutical industry, and is, therefore, allowing for its
participation in project working groups.
The main European pharmaceutical trade associations
are, nonetheless, expecting to be more of an active partner
in the achievement of improvements to and the operation
of the telematics strategy. “There has been one meeting (so
far this year) between the EU telematics management board
and industry representatives,” said Remco Munnik, chair of
the telematics working group of the European Generic and
Biosimilar Medicines Association (EGA), in an interview with
Pharmaceutical Technology Europe.
“However, the question of the frequency and the scope of the
industry’s strategic contribution still remains open and a meeting
once a year may not be sufficient to achieve real progress on
this,” he continued. “An efficient telematics structure, supporting
the EU regulatory network in its regulatory activities, is crucial
for the future. As an industry, we would like to be an active
partner, not only operationally but also strategically by being
involved in setting objectives that can be achieved.”
The industry is already participating in an EU task force
on the implementation of the International Organization for
Standardization’s (ISO) Identification of Medicinal Products
(IDMP), which is a key working group in realization of the
telematics strategy. The five standards of the ISO, which
comprise the IDMP, are at the core of the EU strategy. IDMP
provides the basis for the scheme’s aim of consistency,
uniformity, and single repositories where data on products and
substances can be reused throughout a medicine’s lifecycle. It
also has the potential to be the cornerstone of an internationally
harmonious data system, particularly since the US Food and
Drug Administration (FDA) is also planning to implement IDMP.
In the longer term, EMA expects that IDMP will provide the
EU with a pathway to the operation of a Global Ingredient
Archival System (GiNAS), a common substance identifier that
uses a consistent definition of substances throughout the
world. The National Centre of Advancing Translational Sciences
(NCATS), part of the US National Institutes of Health (NIH), is
currently developing the GiNAS.
The introduction of IDMP is proving to be a massive
challenge not only for EMA and the rest of the EU’s regulatory
network of NCA, but also for the pharmaceutical industry.
The EU is taking on a pioneering role because it will be the
first globally to implement the IDMP standards. The job is
enormous, especially with substances, mainly because of
the amount of existing data that has to be collated and, if
necessary, changed to comply with IDMP. The aim is that the
IDMP standardization of definitions of product and substance
concepts will substantially improve the identification and
exchange of information on medicines, not just within the EU
but also internationally.
IDMP implementation deadline
In the telematics strategy document (1), July 2016 is given as
the deadline for the start of the implementation of IDMP because
it is the date set in the EU pharmacovigilance legislation for
compliance with the standards. However, even when the
document was being published, the European Commission,
the EU executive responsible for the EU telematics strategy,
EU’s New Telematics Strategy
for the Regulation of MedicinesThe scheme aims to ensure that EMA and licensing authorities of
EU member states will use the same IT system, based on a single data standard.
Sean Milmo
is a freelance writer based in Essex,
UK, [email protected].
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was being pressed to adjust the deadline so that regulators and
the industry would have more time to switch to IDMP.
Although there has been no official announcement,
the industry and software vendors understand that the
Commission has agreed that the IDMP will be introduced in
phases with the first step being the issuing in July 2016 of the
EU IDMP implementation guide. Also, the terms and controlled
vocabularies used with existing pharmacovigilance data will
by then be aligned with IDMP requirements. The submission of
pharmacovigilance data to IDMP standards will now start to be
mandatory in late 2017, according to the Commission.
“An important reason for the phased-wise approach is the
fact that the ISO standards are not yet final and will probably
only become final at the end of 2015 or early 2016,” says
Munnik. “[The] industry welcomes this approach. We should
rather take time and do this properly, instead of rushing and
resubmitting the data due to the short preparatory phase.”
“This IDMP data are available within industry, but might not
be in one place or structured,” he added. “In order to align
this data in a company, multiple departments and databases
will have to start sharing the same data. This is especially a
challenge for generic companies with large portfolios and
multiple manufacturing sites and partners.”
With substances, which include excipients as well as
active ingredients, the difficulty is that the data required by
IDMP, such as the characterization of chemical properties,
are not kept by the pharmaceutical manufacturers but
by external sources such as the contract manufacturers.
“There could be huge gaps in availability as well as quality
between the data held and controlled by the pharmaceutical
companies themselves and that held by external sources,”
Niels Henriksen, a consultant at the Danish IT service provider
NNIT A/S, told Pharmaceutical Technology Europe. “The data
required by IDMP, sometimes derived from work in the early
development phase of a drug, will be lying around somewhere
in a document. The difficulty will be finding it.”
The main vehicles for the introduction of the IDMP—at least
at the EU level—will be single data repositories, the biggest of
which will be that of the Periodic Safety Update Reports (PSUR)
set up under the EU’s current pharmacovigilance legislation. This
legislation requires marketing authorization holders (MAHs) to
provide updates on the safety profiles of the more than 500,000
medicines on the EU market. Another repository is EudraGMDP
on Good Manufacturing and Distribution Practice, giving details
on all GMP certificates and statements of GMP non-compliance.
Data integration and uniformity
An important stage in the implementation of the EU telematics
strategy will be when all application dossiers will have to be
IDMP-compliant and submitted in an electronic Common
Technical Document (eCTD). This requirement has been sched-
uled to be mandatory by 2018 for all application dossiers within
the EU’s centralized and decentralized licensing procedures.
This deadline, however, may have to be rescheduled following
the postponement of the start of the IDMP implementation.
A lot of the barriers facing the realization of the EU telematics
strategy at the member state level are derived from differ-
ences in priorities between EMA and the NCAs. EMA is required
mainly to implement EU legislation on medicines regulation
while the NCAs have a range of obligations including meeting
EU requirements and also carrying out national policies.
“In many cases,” the EU telematics strategy document (1)
acknowledges, “the NCAs have a variety of obligations outside
the pharmaceutical regulatory domain.” These obligations will
be dictated by public health needs, legislative mandates, and
economic conditions. As a result, a lot of NCAs will be giving
greater importance to their own IT projects and objectives.
The Netherlands Medicines Evaluation Board (MEB), for
example, is considering the option of working with groups of
other NCAs on data projects. “We are currently reconsidering
our own IT strategy and infrastructure, and keeping an open
eye on EU developments,” says Stan van Belkum, MEB deputy
director. “Wherever and whenever, the MEB will work with
colleague member states of similar size and adapt EU solutions
if proven functionally advantageous.”
The agency also wants to concentrate on improving its own
IT services, particularly those aimed at helping the industry
and some of which provide different services to those at the
EU level. “Since 2007, the MEB has a fully operational workflow
and document management system dedicated to all MEB
business processes in both national and EU procedures,”
says van Belkum. “On top of that, we provide marketing
authorization holders online access to information about the
status of their application procedures. For the coming years,
the MEB’s IT strategy aims to extend this portal with additional
functionality and to make part of the information in that portal
publicly available—for example, assessment reports, product
information and relevant patient information.”
Within the EU’s medicines regulatory network, full data
integration and uniformity may not be accomplished for many
years, but for the industry, the priority will be to advance the
introduction of IDMP as far as possible not just for the sake of
reducing regulatory aacosts but also for its business opportunities.
Reference
1. HMA and EMA, EU Telematics Strategy and Implementation Roadmap
2015–2017, EMA/532765/2015 (London, August 2015). PTE
IDMP provides the basis for the scheme’s aim of consistency, uniformity, and single repositories
where data on products and substances can be reused throughout a medicine’s lifecycle.
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DRUG DEVELOPMENT
Risk-Sharing Agreementsin the EU and Considerationsfor Moving ForwardThe authors look at key factors driving the risk-sharing agreements
that have been implemented to reduce drug expenditures across Europe.
Payers across the globe are becoming increasingly
assertive regarding products whose costs aren’t in
line with perceived performance—a trend that shows
no signs of slowing down. In fact, Express Scripts, one
on the largest pharmacy benefit managers (PBMs)
in the United States, recently announced a plan that
would link the price of some cancer drugs to their
real-world performance (1). Express Scripts’ action is
significant, considering that the US has been slower
than many European markets to implement new
pharmaceutical reimbursement schemes.
Managed entry or risk-sharing agreements (RSAs)
represent another mechanism that payers use to
mitigate the cost of new drugs based on real-world
performance. Financial and performance-based RSAs
(PBRSAs) have been widely employed throughout
Europe to reduce drug expenditures. While these
agreements may not be universally applicable or
without challenge, they are gaining momentum in
certain markets where they will likely play a role in
enhancing economic efficiency.
This article explores some of the driving forces
behind RSA implementation, provides an update
on the status of RSAs in the European Union,
and discusses some of the inherent challenges
manufacturers will need to overcome to achieve
success under these types of arrangements.
Linking drug reimbursement to valueIn most realms of commerce, if a product fails
to deliver what’s been promised, consumers are
financially covered through refunds and warranties.
Consumers of pharmaceutical products and other
stakeholders, however, have no such protections.
Rather, the pharmaceutical industry has had a
longstanding model of selling products and getting
paid regardless of product performance. Perhaps
that explains estimates that 90% of conventional
medicines are not efficacious in 50–70% of cases (2).
In therapeutic areas such as oncology, which is often
characterized by high-priced drugs, the efficacy rate
with standard treatment has been reported to be as
low as 25% across all cancer types (3, 4).
Against this backdrop, global spending on
medicines is expected to grow to nearly US$1.3
trillion by 2018 (5). Government and commercial
payers in most developed markets face aging patient
populations and shrinking budgets. Not surprisingly,
they are increasingly calling for manufacturers to
“put more skin in the game” in return for broader
coverage. Contractual arrangements directly linking
reimbursement to a product’s effectiveness or
budget impact clearly represent one mechanism
through which risk can be shared between payers
and manufacturers.
In efforts to contain spending, public and private
payers are also shifting risk to healthcare providers
through alternative payment models such as
bundled payments and capitation. As these changes
progress, manufacturers must realize that they face
a future in which they will increasingly be required to
assume greater risks related to the performance of
their products.
Risk-sharing agreements have been largely confined to Europe, where payers have been more restrictive in their coverage, particularly of cancer drugs, and have used value calculations based on comparators and quality adjusted life years.
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The benefits of RSAs for payers are
quite apparent—cost containment,
efficiency (i.e., improved value for
money), and/or improved outcomes
for the covered population. There
are, however, potential benefits
for drug manufacturers as well,
including earlier market access,
differentiation, and the opportunity
for a premium price. Taken together,
it’s not surprising that RSAs continue
to gain attention from payers and
manufacturers and are becoming
a more integral part of leadership
objectives for both parties.
Trends in the growth of RSAs in the EU For years now, national health
authorities in European markets
have “hedged” their reimbursement
decisions with pricing controls and
negotiated price cuts and RSAs
to control costs. To date, RSAs
have been largely confined to
Europe, where payers have been
more restrictive in their coverage,
particularly of cancer drugs, and
have used value calculations based
on comparators and quality adjusted
life years. For instance, in addition to
successfully negotiating the lowest
price in Europe for Gilead’s Sovaldi,
the French government secured a
volume-based discount as well as a
money-back guarantee if treatment
doesn’t work (6).
Financially based schemes (e.g.,
price-volume agreements, price-
capping, volume capping, and
rebates) have been more widely
employed throughout Europe
compared to PBRSAs because
they are easier to implement and
track (7). In contrast, the design
and implementation of PBRSAs has
historically been more complex
due to the need for patient
follow up, lack of reliable data
generation/registration (e.g., lack
of infrastructure to track drugs or
non-responders), and increased
administrative burden for payers
and manufacturers alike. These
were just some of the clinical and
operational complexities that largely
characterized the United Kingdom’s
multiple sclerosis scheme in the
early 2000s, which proved to be both
costly and rather ineffective.
Nevertheless, RSAs, including
performance-based arrangements,
continue to be explored and
implemented in select EU markets
(see Table I). A recent review of
RSAs established between 1993 and
2013 identified 148 arrangements,
the majority of which were initiated
within in the past six years (8). Italy,
the UK, the Netherlands, and Sweden
accounted for approximately 71% of
these arrangements. In contrast, the
prevalence of RSAs in other major EU
markets such as Germany, France,
and Spain is markedly lower (2–3%).
Of the 148 arrangements,
approximately 36% included a
component that linked product
reimbursement to clinical outcomes
observed in the real world. Not
surprisingly, oncology was the most
active area for RSAs, likely due to the
number of new cancer drugs, the
high disease-related costs, and the
Table I: Examples of performance-based risk-sharing agreements (PBRSAs) from Italy and the United Kingdom.
Country Drug Indication Company Year Details
Italy
Vidaza
Myelodysplastic syndromes/
chronic myelomonocytic
leukaemia/acute myeloid leukaemia
Celegene 2010
Manufacturer provides 11% rebate
for patients not responding to three
cycles of the treatment.
Votrient Advanced renal cell carcinoma GSK 2011
Manufacturer pays for patients
not responding after 24 weeks of
treatment.
United Kingdom
Revlimid Multiple myeloma Celgene 2009
Manufacturer pays for patients
not responding after 26 cycles of
treatment.
Votrient Advanced renal cell carcinoma GSK 2011
Manufacturer provides an initial 12.5%
rebate with the possibility of future
rebates based upon the results of a
head-to-head trial against Sutent*.
Velcade Multiple myeloma Janssen 2007
Manufacturer refunds the full cost of the
drug for patients who experience less
than a partial response after four cycles.
*Note: The National Institute for Health and Clinical Excellence (NICE) revised this agreement in 2013, removing the head-to-head
trial component.
Source: Ernst & Young Biotechnology Industry Report 2013 and “List of Technologies with Approved Patient Access Schemes”
from the official site of NICE (9, 10).
Drug Development
www.anton-paar.com
Small, smart, powerful
MCP 150 polarimeters
The compact MCP 150 polarimeters
combine a small footprint with full
21 CFR Part 11 compliance,
including electronic signature, and
an accuracy of ± 0.005 °OR.
premium price tags typically associated
with these products.
A closer look at some of these
markets reveals certain nuances that are
important to call out. In the UK, there has
been a trend away from more complex
arrangements toward increasing adoption
of financial-based arrangements. In fact,
the majority of recent arrangements
were implemented as simple confidential
discounts (9). In Italy, RSAs have often
consisted of both financial-based and
performance-based components;
however, more recent arrangements have
included one or the other, not both.
In France, the aforementioned
Sovaldi example is just one sign that the
government is willing to expand the use
of performance-based arrangements. In
fact, Celgene committed to the French
government on the effectiveness of
their multiple myeloma drug Imnovid
in exchange for a higher price (11). The
agreement required Celgene to build a
registry for collecting real-world efficacy
and safety data.
Considerations for manufacturersPayers’ concerns with pharmaceuticals
in the current healthcare environment
include rising budget impact, differential
value, large patient populations with
difficulty in identifying responders,
and the uncertainty regarding duration
of treatment. At the same time,
manufacturers are concerned with
delayed market access due to prolonged
price and reimbursement negotiations,
demonstrating differentiated value in
crowded therapeutic areas, and earning a
premium price that is in-line with the value
their products create.
RSAs represent an appealing option for
both parties if designed appropriately and
implemented in a collaborative manner.
It’s true that these arrangements are
likely to increase administrative burden
for both payers and providers, particularly
PBRSAs that require patient-level data
tracking. It should also be noted that
PBRSAs bring inherent risks outside the
manufacturer’s direct control, including
inefficient healthcare delivery and poor
patient compliance. For these reasons,
RSAs do not represent a “one-size-fits-all”
solution.
Before entering into an RSA,
pharmaceutical companies should always
ensure that the potential benefits are
significant enough to justify the effort
and risks associated with these types of
agreements. In addition, manufacturers
must understand how their products
deliver value to ensure that the particular
measures agreed upon align with that
value story. Implementing RSAs requires
not only lengthy negotiations and
potentially costly administration, but also
the ability to efficiently capture real-world
evidence. As a result, pharmaceutical
companies must develop the appropriate
IT and data analytics capabilities to
successfully implement these types of
agreements.
References1. P. Loftus, “New Push Ties Cost of Drugs
to How Well They Work,” The Wall Street
Journal, 26 May 2015, www.wsj.com/
articles/new-push-ties-cost-of-drugs-to-
how-well-they-work-1432684755, accessed
28 Sept. 2015.
2. Cowen & Co: Therapeutic Categories
Outlook, 2008–2012 estimate, Cowen Group,
NY, USA (2008).
3. C. Womack, The Pathologist in Drug
Development, presentation at the Edinburgh
Pathology 2013 conference (Edinburgh,
June 2013).
4. I. Miller et al., Pers. Med. 8 (2) 137–148 (2011).
5. IMS Institute for Healthcare Informatics,
Global Outlook for Medicines Through 2018
(November 2014).
6. T. Staton, “France Strikes Big Hep C
Treatment Deal for Gilead’s Sovaldi,”
FiercePharma, 20 Nov. 2014, www.fiercep-
harma.com/story/france-strikes-big-hep-c-
treatment-deal-gileads-sovaldi/2014-11-20,
accessed 28 Sept. 2015.
7. J. Espín, J. Rovira, L. García, Experiences and
Impact of European Risk-Sharing Schemes
Focusing on Oncology Medicines. Granada,
Spain: European Medicines Information
Network (EMINET), Andalusian School of
Public Health, 2011.
8. J. Carlson et al., Appl Health Econ Health
Policy, 12 (3) 231–238 (2014).
9. Ernst & Young, Biotechnology Industry
Report 2013.
10. NICE, List of Technologies with Approved
Patient Access Schemes, retrieved
December 2014 from NICE, www.nice.
org.uk/about/what-we-do/patient-access-
schemes-liaison-unit/list-of-technologies-
with-approved-patient-access-schemes,
accessed 28 Sept. 2015.
11. C. Ducruet, “Médicaments: quand les la bora-
toires sont rémunérés à la performance,” Les
Echos, 3 March 2015. PTE
OUTSOURCING REVIEW
(Sp
otl
igh
t im
ag
e)
Sto
ckb
yte
/Ge
ttyIm
ag
es
Biomanufacturing efficiency is on everyone’s
minds, being the single most important area
of focus for global bioprocessing. And contract
manufacturing organizations (CMOs) are on the
leading edge as they implement performance
improvements. CMOs must remain efficient if they are
to be competitive—so this is no surprise. Results from
BioPlan Associates’ 12th Annual Report and Survey
of Biopharmaceutical Manufacturing Capacity and
Production (1), offer some clues as to what CMOs are
doing to remain competitive.
CMOs’ love affair with single-use devices has been
well documented. Indeed, single-use implementation
and integration is a much larger focus for CMOs than
it is for biotherapeutic developers. And as the results
in Figure 1 indicate, it’s easy to see why: nine out of
10 CMOs agree that biomanufacturing improvements
over the past year are coming from the use of
disposable and single-use devices.
Given that CMOs have long been at the forefront of
single-use adoption, it’s perhaps more interesting to
look at factors that are rising in importance for CMOs.
One such factor is better process development, cited
by 81.8% of CMO respondents as contributing to
improved biomanufacturing performance, up from
two-thirds of respondents in 2014.
This is a notable result, as process development
outsourcing has been on the rise in recent years.
Separately, 43% of industry respondents reported
outsourcing at least some upstream process
development activities to some degree, up from just
17.1% back in 2010. Additionally, 41% reported at least
some outsourcing downstream process development
activities to some degree. Improvements in process
development, therefore, are an encouraging sign
for CMOs as this becomes a growing business
opportunity.
A similar pattern plays out in validation services.
This is also a growing area of opportunity for CMOs,
with validation services a more popular outsourcing
activity than process development. In the 2015
survey, for example, almost three-quarters (73%) of
industry respondents reported outsourcing at least
some validation services, up from less than two-thirds
in 2010.
Another area to which more CMOs attribute
internal performance improvements is upstream
production operations. In the 2015 survey, 64%
of respondents said that these improvements
contributed to better overall performance, up from
56% in 2014. In fact, CMOs were almost as likely
to credit upstream improvements as downstream
improvements with better biomanufacturing
performance. That may partly be due to the current
bottlenecks being experienced in purification and
separation operations. And CMOs’ experience with
multiple products and campaigns provide them
expertise that in-house manufacturers may not have.
Upstream biomanufacturing operations outsourcing
has been growing more rapidly than downstream
operations, according to BioPlan’s data. In the space
of five years, the percentage of industry respondents
outsourcing upstream operations has doubled, from
21% in 2010 to 42% in 2015. While outsourcing of
downstream operations has been on the rise, it hasn’t
had quite the same growth trajectory, up from 28% in
2010 to 39% of respondents in 2015.
Upstream operational improvements are less
of an industry focus for both CMOs and in-house
manufacturers. Indeed, when BioPlan surveyed
the industry on the single most important area or
operational focus in 2015, not a single CMO pointed
to upstream processing advances as the top area;
because downstream production (DSP) operations
issues remain strong. A worrisome 64% of CMOs said
that downstream processing is impacting capacity
and overall production by causing at least some
bottleneck problems (noted by 64%). In fact, only a
CMOs Continue to Improve Overall Biomanufacturing PerformanceBetter process development is creating industry benchmarks for bioprocessing.
OUTSOURCING REVIEW
Eric Langer is president
of BioPlan Associates,
tel. +1.301.921.5979, elanger
@bioplanassociates.com,
and a periodic contributor
to Outsourcing Review.
Upstream biomanufacturing operations outsourcing has been growing more rapidly than downstream operations.
14 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
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rommelag USA, Inc.27905 Meadow Drive, Suite 9Evergreen CO 80439, USAPhone: +1.303. 674.8333Fax: +1.303.670.2666E-Mail: [email protected]
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Fig
ure
1 i
s c
ou
rte
sty
of
the
au
tho
r.
quarter of respondents are currently
enjoying no bottlenecks in their
downstream processing.
CMOs spending to offset potential capacity crunchNot surprisingly, CMOs are seeing
more problems than biotherapeutic
companies due to downstream
processing, and are experiencing
more significant production capacity
constraints too. The BioPlan study
indicated they will likely continue to
invest in better DSP technologies as a
way out of these problems, for example.
Facility constraints are the most
common factor CMOs cite as creating
capacity crunches at their facilities
over the next five years (cited by
more than two-thirds). Probably by no
coincidence, seven in 10 CMOs plan
to increase their spending on new
facility construction this year, by an
average amount of 11.3%.
The next biggest culprit in projected
capacity constraints is downstream
purification capacity. Spending plans
for CMOs are positive: almost three-
quarters would be increasing their
capital equipment budgets, with an
average increase of 11.7%.
Expected budget hikes—for
capital equipment (11.7%) and new
facility construction (11.3%)—were
the largest of all areas tracked. To
grow their businesses, CMOs are
dedicating funds to offset potential
capacity constraints in the future.
Not surprisingly, better
downstream purification technologies
are also on the agenda. CMOs
note that downstream innovation
is the leading way to avoid future
capacity constraints. Spending
projections aren’t quite as buoyant
for downstream innovation, though
they are solid. In 2015, six in 10
will increase spending on new
technologies to improve efficiencies
and costs for downstream
production, for an average budget
increase of 6.1%. This is likely due
to new technologies providing more
incremental increases in efficiencies
as opposed to new equipment that
can quickly provide access to more
capacity and avoid crunches.
ConclusionSingle-use equipment is helping CMOs
achieve performance improvements,
both for downstream purification and
for manufacturing productivity overall.
But CMOs are taking numerous other
factors into account as they improve
efficiencies and lower costs. These
range from better analytical testing
and product release services to better
operations staff training, optimized
media and improved existing quality
management systems. Better process
development is also a growing area
of interest for CMOs as they take on
more process development work—both
upstream and downstream—for clients.
Nevertheless, one of the main
routes to overall productivity
improvements for CMOs will be
better downstream operations.
Besides the use of disposable
equipment, a majority of CMOs are
developing downstream processes
with fewer process steps. Many are
also using or evaluating a number of
technologies, including:
t� Membrane-based filtration
technologies
t� Ion-exchange membrane
technologies
t� Ion-exchange technologies with
higher capacity.
Biotherapeutic developers might
keep a close eye on these activities.
CMOs, with their broad experience,
multiple product lines, and need for
rapid changeovers, are often at the
forefront of innovation. Though their
requirements clearly differ from
those of biotherapeutic developers,
the process improvements sparked
by innovations and adopted by
CMOs can provide a recipe for the
industry as a whole. As such, it
will be interesting to monitor the
activities and technologies that
CMOs adopt to improve downstream
production operations and overall
biomanufacturing productivity.
Reference1. BioPlan Associates, 12th Annual Report
and Survey of Biopharmaceutical
Manufacturing Capacity and
Production (Rockville, MD, April 2015),
www.bioplanassociates.com/12th,
accessed 12 Oct. 2015. PTE
Use of disposable/single-use devices
Better process development
Overall better control of process
Improved downstream production operations
Better analytical testing & product release services
Improved upstream production operations
86.4%
83.3%
81.8%
66.7%
68.2%
77.8%
68.2%
72.2%
63.6%
66.7%
63.6%
55.6%
2015 2014
Source: 12th Annual Report and Survey of Biopharmaceutical Manufacturing, April 2015, www.bioplanassociates.com/12th
Figure 1: Improving biomanufacturing performance for CMOs, 2015 v. 2014 (Select Responses).
To grow their businesses, CMOs are dedicating funds to offset potential capacity constraints in the future.
16 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
Nic
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Da
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Tablets are coated for several reasons, such as to improve
appearance; for taste- and odour-masking purposes; to protect
the API from moisture, oxygen, or the gastric environment of the
stomach (e.g., using acid-resistant enteric coating); to separate
incompatible substances; and to control drug release, among others.
As the industry continues to explore the advantages of switching
from batch manufacturing to continuous processes, Pharmaceutical
Technology Europe spoke to Ali Rajabi-Siahboomi, chief scientific
officer at Colorcon; Charlie Cunningham, senior manager, Product
Development, Colorcon; Martin Hack, vice-president and general
manager, L.B. Bohle; and Hubertus Rehbaum, manager, Scientific
Operations, L.B. Bohle, to gain insight on the advances in coating
technologies and the potential of continuous coating in the production
of solid-dosage forms.
Tablet coating processPTE: What are the steps involved in a typical tablet coating
process? How do you control the different variables
affecting the quality attributes of the coated tablets, such
as uniformity and functionality of the coating?
Hack (L.B. Bohle): The coating processes currently used in the
pharmaceutical industry vary from simple taste- or colour-masking
up to highly complex multilayer functional coatings. But as tablets
become more sophisticated therapeutic systems (e.g., with controlled
release mechanisms or combined APIs), manufacturers must pay
Exploring the Potential of Continuous CoatingIndusty experts share insights on the advances in tablet coating technologies
and the potential of continuous coating in solid-dosage manufacturing.
A Q&A by
Adeline Siew, PhD
closer attention to the quality of
the coating. To achieve the required
high-quality standards, process
parameters such as air flow, spray
rate, spray gun position, and tablet
bed movement must be taken into
account. By using equipment with
reliable hardware components and
fine-tuned control loops, those
critical process parameters can be
kept in the design space, ensuring the
targeted product quality. In addition
to using laboratory analysis to
monitor the process, Raman or near
infrared (NIR) spectroscopy will also
play an important part in ensuring the
final product and process quality.
Rajabi-Siahboomi (Colorcon): In
my view, all tablets should be coated,
whether for trade-dress purposes
or for the functional properties
mentioned above. The tablet must
have a robust formulation with good
mechanical strength to withstand
the handling, transport, and film-
coating processes. Therefore, robust
formulation and physical design of
tablets are crucial for film-coating
success. Tablets with good hardness,
low friability, appropriate shape, and
low propensity for moisture uptake
are desirable.
The film-coating process is fairly
complex but can be broken down into
three primary control areas:
t� Coating application. The coating
dispersion is delivered to the
spray guns and atomized using
compressed air into fine droplets
for deposition to the tablet
surfaces. The viscosity of the
coating formulation, number of
spray guns (depending on scale of
coating pan), atomization, and air-
pattern conditions all play a role in
how smoothly and uniformly the
coating will be applied to the tablet
surface. The solids concentration
of the dispersion influences coating
process time, coating uniformity,
and ultimately, the quality of the
finished tablet surface.
t� Thermodynamics. The drying
air parameters of temperature,
humidity, and volume (air flow)
must be carefully balanced with
the spray rates for the liquid-
dispersion coating application.
As the coating dispersion is
applied continuously, maintaining
appropriate temperature and air
18 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
Tablet Coating
volume versus the coating spray rate is important.
The right balance will prevent coating defects related
to over-wetting (tablet-to-tablet sticking), or over-dry
conditions (spray-drying).
t� Mechanical movement. Tablets are typically coated in
rotating, perforated drums, ranging in diameter from
10” at laboratory scale to more than 60” at production
scale, with batch sizes from a few hundred grams up to
several hundred kilograms. The speed of pan rotation
governs how many passes an individual tablet will pass
through the spray zone in a given coating cycle and has
a great influence on coating uniformity. Appropriate
design of baffles within the pan also facilitate tablet
movement and mixing to influence coating uniformity.
Scaling upPTE: What about scaling up the coating
process?
Hack (L.B. Bohle): When scaling up a
coating process, the three unit operations
of a film-coating process—which are mixing, spraying/
film building, and drying, operated simultaneously within
a coating pan during a film-coating process—must be
understood. Important parameters are the drum rotation
speed, the ratio of the air and liquid flows (as process air
flow and coating solution spray rate), and the tablet bed
temperature.
When scaling up, normally, the tablet bed temperature
or exhaust air temperature is kept constant. The reason is
to have the same film building temperature of the polymer
of the coating solution. The spray droplets spread on
the tablet surface, and film building is generated with a
certain temperature. Also, the ratio between mass flow
of process air and mass flow of coating solution (spray
rate) should be equal to have the same thermodynamic
condition for the drying. The drum rotation speed should
be scaled in a way that the tablet velocity—while tablets
move through the spray zone—is almost the same in
laboratory scale, pilot scale, and production scale. Other
parameters such as atomizing air flow and pattern air
flow and the distance of the spray nozzle tips to the tablet
bed surface need to be adjusted properly for even spray
performance in each scale.
Geometrical similarity of the selected coating drum
from laboratory to production size is useful too. Special
spray nozzles (laboratory, pilot, or production coater)
designed for different coater sizes (spray rates and droplet
sizes) are recommended for successful scale up.
Coating technologiesPTE: Can you tell us more about the recent
advances in coating technologies and their
impact on continuous coating?
Rajabi-Siahboomi (Colorcon): In the
past, continuous coaters were most often employed
for high-volume products with tablet throughput rates
in the range of 500 kg to over 1000 kg per hour. The
scale of equipment is now being modified to meet
lower production capacity demands, ranging from 50
kg to 500 kg per hour. New mechanisms have also been
developed to eliminate the start-up and shut-down
product losses associated with earlier continuous coater
equipment. Studies evaluating these improvements
conducted in an O’Hara Fastcoat continuous coating
system showed consistent colour uniformity for all
tablets from start-up through shut-down. Some machine
manufacturers have developed novel approaches to
coating in semi-continuous modes. In one example, the
GEA ConsiGma coater is able to coat small, 3-kg sub-
batches rapidly, with a high degree of accuracy. Using
this method, each sub-batch is able to be tracked from
the upstream continuous tableting process, and critical
coating attributes can be monitored in real-time. Use of
in-line, process analytical technology (PAT)-based Raman
analytics during coating ensures product quality of each
sub-batch.
Film-coating formulation technology is also advancing
with the use of lower-viscosity polymers that provide
significantly improved process efficiency compared with
more traditional hypromellose-based coating systems. A
benefit of low-viscosity coating formulations is the ability
for application of the coating dispersion at significantly
higher solids concentration compared to traditional
coatings, resulting in considerably shorter process times.
Rehbaum (L.B. Bohle): For the coating process,
two different approaches are currently being applied.
Some vendors have presented truly continuous coaters,
for which a continuous product flow into the long
coating drum and a continuous product flow out of the
Pharmaceutical Technology Europe NOVEMBER 2015 19
Tablet Coating
drum is characteristic. R&D at L.B.
Bohle, however, has shown that
at this point, a truly continuous
coating process does not meet
the requirements for functional
coatings. For tablet coating, the time
that each tablet is exposed to the
process directly affects the quality
of the coating. Therefore, a narrow
residence time distribution, ideally
a spike, is the key to achieving an
outstanding coating uniformity. As
the travel time of all tablet cores
through a truly continuous coater
cannot be controlled sufficiently
using inserts or other guiding
elements inside the drum, L.B. Bohle
has decided to follow the concept
of a fast-batch coating design with
our KOCO machine family. In this
approach, by optimizing the charging
and discharging as well as the coating
process in terms of spray rate, air
flow, and tablet-bed formation, we
are able to achieve a high throughput
at constant, spike-shaped residence
time distributions.
There is another reason to
decouple the coating process
from the upstream continuous
manufacturing of the tablet core,
which is the tablet core relaxation
time. For the majority of products, the
core needs to be given a sufficient
time to expand after the compression
process. Feeding the tablet cores
from the de-duster directly into a
truly continuous coater does not
allow the cores to expand before
applying the film coat. This implies
that the expansion of the tablet core
will continue with the film coat in
place, leading to cracks in the coating
layer. For functional coating, such
defects are unacceptable. As a result,
the tablet core expansion step, which
interrupts the continuous product
stream of a continuous production
line between the tablet press and
the coater, makes the advantage of
a truly continuous coater to keep the
product stream continuous obsolete.
Continous versus batch coating
PTE: How does continuous
coating compare with the
traditional batch coating?
Cunningham
(Colorcon): Compared to batch
coaters, the commercially available
continuous coating machines have
pan diameters that are half, or less,
than the diameter of manufacturing-
scale batch coaters; but the length
of the pan can be as long as 15 feet.
However, the resultant tablet-bed
depth, which is low, is more consistent
with laboratory or pilot-scale batch
coating pans; this shallower bed depth
ensures greater frequency of tablet
presentation to the spray zone.
In recent work, Colorcon studied
the effect of tablet residence time
and uniformity of tablet progression
and coating variability in a Thomas
Engineering Flex CTC continuous
coater. We were able to conclude
that individual tablets progressed
uniformly through the continuous
process at production rates of up
to 850 kg per hour with relatively
small variability in transit times and
superior coating weight and colour
uniformity compared to the traditional
batch coater process.
In another study conducted in a
Driam Driaconti-T continuous cycled
coater, we evaluated the performance
of a novel film-coating formulation
developed by Colorcon capable of
application at solids concentrations
up to 35% w/w solids. Although this
coater employs elongated rotating
drum technology, the drum is divided
into individual coating segments,
giving it the advantages of small-scale
batch production. In this coater, with
production rates of 110–180 kg/hour,
we also found that coating uniformity
was significantly improved over batch
coaters.
The common theme around all
currently available continuous and
semi-continuous coater technology is
a significantly reduced coating cycle
time and reduced exposure of the
tablets to the coating environment.
Rehbaum (L.B. Bohle): At this
point, we do not see advantages in
truly continuous coating, as indicated
previously. However, based on
experience with our KOCO machine
family, we can achieve shorter cycle
times and higher throughput, while
maintaining the coating uniformity.
PTE: What aspects of
continuous coating still
need to be addressed by
the industry?
Cunningham (Colorcon):
With continued innovation in
equipment design, some of the
past limitations in throughput rate
are being addressed. Equipment
is now available to meet a wide
range of production capacity
demands. Although current film-
coating formulation technology
provides satisfactory results in these
machines, new, low-viscosity coating
formulations are being developed to
maximize coating efficiency. Linking
continuous coating processes to
newly evolving continuous tablet
manufacturing lines is underway, and
continued technology development is
needed for ‘real-time’ PAT monitoring
of coated tablet quality attributes
to ensure seamless quality from
start to finish in continuous tablet
manufacture. Although there may
not be an issue with the regulators,
another aspect to be considered
is the definition of a batch while
manufacturing using continuous
processing. A batch can be defined
on a time or material lot basis,
depending on specific product
manufacturing flows. These may
be related to a mindset change for
manufacturers as well as the need for
clarification from the regulators.
Hack (L.B. Bohle): Currently,
truly continuous coating from our
perspective is limited to simple taste
masking or colour coatings, as long
as the tablet core is not required
to expand or the film coating has
highly elastic properties. One of the
limitations is because of the wide
residence time distribution, which
results in poor coating uniformity. To
be able to overcome this limitation,
new ways to control the flow of all
(100%) tablet cores are needed. Some
vendors have suggested solutions
with compartments and mechanical
barriers or inserts to guide the tablet
bed flow. Unfortunately, from our
experience, none of these measures
can ensure a spike-shaped residence
time distribution. The efforts to
overcome this limitation only provide
benefits if the coating process can
be an integral part of the continuous
material flow. If the expansion
behaviour of the tablet cores
forestalls the seamless transfer of
the core from tablet press/de-duster
to the coating process, there is no
benefit in using truly continuous
coaters. PTE
20 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
Register for free at www.pharmtech.com/pt/thermal
EVENT OVERVIEW:
Proper drug release of high-dose hydrophilic drugs is a challenge
for formulators since both the initial drug burst release, as well as
the consequent sustained release, need to be controlled.
Excipients can provide an answer to drug release challenges when
their hydrophobic nature is coupled with thermal sintering. This
approach intensifies the retardation of drug release by forming
plastic matrices of high mechanical strength, which can withstand
dose dumping and achieve controlled release. In this webcast, a
formulation expert will:
■ Discuss BASF’s Kolliwax grades and their suitability for thermal
sintering
■ Describe how high-dose hydrophilic actives were selected to
demonstrate the efficacy of thermal sintering (60-65% w/w)
using Kolliwax grades.
■ Present processing parameters to enable customers to
reproduce controlled drug release of hydrophilic drugs using
thermal sintering.
For questions contact Sara Barschdorf at
Sponsored by
Presented by
ON-DEMAND WEBCAST Originally aired October 22, 2015
Thermal Sintering for Controlled Drug Release of Hydrophilic Drugs
PRESENTERS
Rajkiran Narkhede
Assistant Manager
Technical Services at BASF
Moderator
Rita Peters
Editorial Director
Pharmaceutical Technology
Key Learning Objectives
■ Learn how to control drug release of
hydrophilic drug using plastic matrices.
■ Review the sintering mechanism and
technology with provided examples.
■ Understand how to choose suitable
ingredients for sintering technology.
Who Should Attend
■ This webcast targets formulation
scientists, research scholars in the field
of pharmaceutical technology, polymer
industry professionals, as well as
graduate and postgraduate students in
pharmaceutical technology.
Ph
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The past five years have been extremely challenging for parenteral
pharmaceutical manufacturers. For commodity workhorse products,
the aftershocks of manufacturing and quality issues and pricing pressures
continue to be felt in operating rooms, neonatal facilities, ambulances,
hospitals, and healthcare facilities, particularly in the United States.
On the large-volume (i.e., 100 mL or higher volume) side, intravenous
fluids and compounds used for dialysis, nutritional supplementation, and
irrigation have been in short supply due to contamination, manufacturing
problems, or product discontinuation. On the small-volume side, supplies
of chemotherapy agents and anaesthetics may have emerged from the
crisis they faced in 2013, but continue to be tight.
In 2015, Baxter had to recall some basic large-volume parenterals
such as intravenous saline and dextrose, which were found to
contain particulates. The same problem had prompted the company
and other suppliers, including Hospira and B. Braun, to recall large-
volume parenterals in 2013 and 2014 (1). For large-volume products,
most of which are heat-sterilized, the major problem continues to be
particulates. Small-volume products are vulnerable to both microbial
and particulate contamination, which has been traced to glass and
packaging materials, and problems such as leaching and sorption.
As experts from the Parenteral Drug Association (PDA) have pointed
out (2), particulates are either extrinsic or intrinsic, based on whether
they originate from outside or within the project. Recalls called out
both types of particulate contamination. Between January 2013 and
June 2014, the Medicines and Healthcare Products Regulatory Agency
(MHRA) in the United Kingdom found that 11 out of 42 drugs listed on its
Drug Alert website were listed because of particulate contamination.
Between 2008 and 2012, particulate contamination issues led to 22% of
all injectable drug recalls (3).
Microbial contamination can have several sources. In an interview
with Pharmaceutical Technology Europe, consultant Barry Friedman
traces many recent cases to inadequate sampling plans and media fill
studies. Ideally, media fill studies should be designed to account for
worst-case conditions (4), and they should be repeated periodically
and adjusted for batch size.
Agnes Shanley
“With both small-and large-volume
parenterals, people often come up with
sampling plans based on small lots.
They do media fills and get acceptable
results, but then lot sizes increase,”
Friedman says, “and some of them
don’t increase the size of media fills to
a comparable degree.”
Another problem is failing to follow
United States Pharmacopeia (USP)
<71> guidance in the number of
samples taken as the drug moves from
Phases I to commercial production,
says Friedman. The number of
samples required is based on the size,
volume, and number of containers
to be filled (5). In addition, Friedman
notes the need to reduce the potential
impact of operators on the process
and product. Investing in isolators
can often be the best way to go, he
notes, as long as the equipment is
properly maintained and operators
are adequately trained to recognize
potential sources of problems. “It’s
important to check seals and to
examine sample ports and gloves for
cracks,” Friedman says.
Solutions to parenteral
manufacturing challenges focus
on technology, new materials, and
components. A number of companies
are using automated systems to
reduce the potential for operators
to contaminate product. Vetter AG,
a contract development and
manufacturing organization (CDMO)
in Germany, has invested EUR 300
million to more than double its sterile
fill and finish and other capacity (6).
The expanded sites are expected
to become fully operational in 2017.
Central to Vetter’s efforts is its
“Improved RABS Concept,” developed
inhouse, that combines the features of
an isolator with those of a restricted
access barrier system (RABS). The
company’s Improved RABS Concept
creates a two-barrier design with
a walk-in isolator to reduce risk.
Cleanroom staff work in a Class 10,000
area that can be entered only after
proper gowning and passage through
air locks. The RABS contains the
filling line in an ISO-5 area, providing
redundancy so that problems can be
detected, contained, and fixed before
they affect product (7).
Vetter’s equipment includes
an automated hydrogen peroxide
decontamination module, and can
22 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
Better Days for Parenterals?Although shortages, quality, and regulatory challenges remain,
improved technologies and new investments suggest that the worst may be over.
Parenteral Manufacturing
Pharmaceutical Technology Europe spoke with Miriam Beyer,
European marketing manager, West Pharmaceutical Services,
Germany about the company’s parenteral business.
PTE: The past few years have seen manufacturing issues and
severe shortages of both small- and large-volume parenterals.
What are the reasons behind these problems?
Beyer: The US Food and Drug Administration has recognized
that drug shortages are a critical issue for the healthcare industry.
Approximately 37% of shortages are due to manufacturing issues.
Other major factors causing drug shortages are issues associated
with raw materials (27%) as well as delays and capacity difficulties
(27%). Drug shortages can result in problems ranging from the wrong
expiration date on the package to particulates in the drug product or
sterility issues with injectable drugs (see Table I).
PTE: What are some best practices for maintaining sterility and
avoiding non-compliance for each type of parenteral?
Beyer: Maintaining sterility is vital to avoiding the main causes of
drug shortages. Primary packaging plays a pivotal role in ensuring
sterility, since it is in direct contact with the drug and poses risk of
interaction if the packaging is not compatible with the drug product.
Manufacturing quality can be affected by several issues, including
bacterial endotoxin, particulate matter and bioburden. One example
of the impact is well reflected in an FDA guidance recommending
‘the time between washing, drying (where appropriate), and
sterilizing should be minimized because residual moisture on the
stoppers can support microbial growth and the generation of
endotoxins’ (1). This can cause a challenge if primary packaging
components are not available already sterilized.
Achieving lowest visible and subvisible particulate levels is
currently a hot topic. While associated with cleanliness, it is a key
factor today to meet product target profiles and ensure compliance.
Close collaboration between a pharmaceutical manufacturer
and its drug packaging partner is key to ensuring that high quality
standards are maintained throughout the manufacturing process.
In terms of packaging, it is important that both parties agree upon
the validation processes that will be used during manufacturing
in order to establish—and adhere to—quality specifications for
primary packaging components. Validation processes can have
significant benefits for drug manufacturing. For instance, a state-
of-the-art validated washing process must reduce endotoxin
content by at least 99.9% (a 3-log reduction).
Sterilization processes are generally also validated to meet
sterility assurance levels. Furthermore, a sterilization process
validation is maintained through appropriate change control and
revalidation/periodic review programmes, all of which comply with
applicable cGMP requirements.
There are, however, additional variables that play a role in meeting
best practices. Product configuration and formulation, for instance,
may have an impact on quality, as do bioburden resistance and
weight, along with bag material. It is also important to note that
the packaging of the actual components in question should also be
evaluated to determine whether a component/packaging format
meets the necessary regulatory specifications.
PTE: What role can packaging play in preventing these problems?
Beyer: Packaging plays a significant role in maintaining the
quality of a drug product and preventing impurities. To minimize
interaction with the drug, it is essential that the packaging
components’ design and formulation meet the containment
requirements mandated by the physical and chemical attributes of
the drug. Different drug products have different packaging needs,
and what works for one product might not necessarily be the best
choice for another. Selecting the right closure for a particular drug
product is crucial to ensuring that the drug reaches the patient
safely and with the intended therapeutic effect.
To ensure the perfect match between a drug and its packaging,
it is important for pharmaceutical manufacturers to work closely
with experienced packaging partners from the early stages of drug
development through production. Having a reliable packaging
partner allows pharmaceutical companies to focus on their core
competencies: bringing valuable drug products to the marketplace.
PTE: Can you please describe your company’s technology, its
history, how it was developed, and how it is being applied?
Beyer: West was founded in 1923. Its early efforts pioneered the
safe distribution of penicillin, insulin, and other life-saving drugs.
Today, approximately 110 million West components and devices are
used around the world every day.
West has a long-standing partnership with Japan’s Daikyo Seiko,
a manufacturer of high quality pharmaceutical delivery system
components. Daikyo has built a strong reputation for materials and
manufacturing innovation. Our partnership with Daikyo has enabled
us to develop products that help customers mitigate drug product
development risks and enhance patient safety. These products
include: FluroTec coated serum and lyophilization stoppers, syringe
plungers, and tip caps, Daikyo Crystal Zenith vials and syringe barrels,
and ready-to-sterilize (RSV) components.
We recently launched Daikyo ready-to-use/validated (RUV)
components. We believe these components meet the highest
sterilization and quality standards, helping pharmaceutical
manufacturers comply with rigorous aseptic processing
requirements while reducing operational and capital resources.
PTE: Can you please elaborate on any innovative science/
methods used and results achieved so far?
Beyer: Daikyo RSV and RUV components are manufactured
using clean, high-quality elastomer formulations, and then washed
and sterilized as needed to help reduce the manufacturing foot-
print, streamline processes, outsource risks around component
preparation, and eliminate bioburden. Both Daikyo RSV and RUV
components are prepared to a tight particulate specification and
fully visually-inspected. The new Daikyo RUV offering, which takes
RSV components and steam-sterilizes them in a validated process,
offers pharmaceutical manufacturers the opportunity to focus on
the fill-finish with a high-quality, ready-to-use component.
Reference1. FDA, Guidance for Industry, Sterile Drug Products Produced
by Aseptic Processing: Current Good Manufacturing
Practice (Rockville, MD, September 2004).
Addressing parenteral manufacturing challenges
Table I: Trends in injectables shortages.
Year 2011 2012 2013 2014
All Forms 251 117 44 44
Injectables 183 84 35 30
Source: FDA, Drug Shortages Infographic,
www.fda.gov/Drugs/DrugSafety/DrugShortages/ucm441579.htm
Pharmaceutical Technology Europe NOVEMBER 2015 23
Parenteral Manufacturing
reportedly complete a sterilization
cycle in three hours. After successful
pilots, the company plans to
implement this module in all its
cleanrooms within the next few years.
In September 2015, Italian
equipment manufacturer Fedegari
opened a Technology Innovation
Centre in Philadelphia that features
advanced equipment and aims
to facilitate collaboration on
development of new processes (8). It
also launched a new website, www.
Sterilize.it, where specialists can
share data and collaborate.
Other companies are developing
prefilled technologies as a way to
improve ease of use and protect
product safety. On 3 and 4 November,
PDA will focus exclusively on this
topic with a specialized event, The
Universe of Prefilled Syringes and
Injection Devices.
Driving innovations include high
heat-resistant and non-leaching
plastics, new processes such
as blow-fill-seal (BFS), and new
configurations for bottles, closures
and caps. The CDMO, Catalent, used
quality-by-design (QbD) principles to
develop its glass-free Advasept vial
design to improve BFS systems. The
process aims to reduce particulates,
the number of process steps, and
the need for operator intervention,
thereby, reducing contamination risk.
By using medical-grade polypropylene,
the risk of glass delamination and
breakage is eliminated (9).
West Pharmaceutical Services, Inc.
has developed closure and capping
technologies to reduce risk (see
sidebar). The company established
a centre of excellence in Ireland in
2014, devoted to improving new
generations of this technology.
Companies are also investing in
new capacity and buying CDMOs that
have special expertise in working
with parenterals (see Table I). Pfizer,
for instance, bought Hospira in
September 2015 (10), while a number
of Indian pharmaceutical companies
have acquired contract manufacturing
organizations (CMOs) in the US.
Piramal Enterprises’ Pharma Solutions
bought Kentucky-based Coldstream
Labs earlier in 2015 (11). Coldstream
has special expertise in advanced
aseptic manufacturing equipment and
highly potent API (HPAPI) handling
and processing.
The large-volume parenterals
market is fairly staid, with competitive
pressures and low profitability. In
2014, some manufacturers withdrew
long-established products for financial
reasons. Small parenterals, however,
are seeing healthy innovation and
growth, according to Vivek Sharma,
CEO of Piramal Enterprises’ Pharma
Solutions, who summarized market
developments in CPhI’s 2015 Annual
Industry Report (12).
Over the past 15 years, Sharma
says, 900 new injectable drugs have
been approved, and another 2400 are
currently in the pipeline. Innovation is
being seen in oncology, particularly in
the use of targeted delivery systems
using liposomes, PEGylation, and
depot injections. Prefilled syringes,
which reduce safety risks, will
experience major growth, Sharma
predicts, with biologics accounting for
half of the injectables R&D budgets
for the top 15 pharmaceutical and
biopharma companies.
Generic injectables, which were a
US$37-billion market in 2013, should
grow to US$70 billion in 2020, he
says, while the need to reduce risk
will drive more pharma companies to
outsource parenterals development
and manufacturing to CDMOs
and CMOs. Currently, injectables
outsourcing is a $6-billion business,
and Sharma expects it to show 10%
annual growth for the next five years.
References 1. FDA, FDA Updates on Saline
Drug shortage, www.fda.gov/
Drugs/DrugSafety/UCM382255.
htm, accessed 20 Oct. 2015.
2. PDA, Industry Perspective on the
Medical Risk of Visible Particulates
in Injectable Drug Products, www.
pda.org/docs/default-source/
website-document-library/
publications/industry-perspec-
tive-on-medical-risk-of-visible-
particles-in-injectable-products.
pdf?sfvrsn=2, accessed 20 Oct. 2015.
3. S. Tawde, J Pharmacovigilance online,
http://dx.doi.org/10.4172/2329-
6887.1000e128, 5 Jan. 2015.
4. M. Akers, “Parenteral Preparation,”
Chapter 26 in Remington Essentials
of Pharmaceuticals, Ed. Felton, L,
Pharmaceutical Press, 2013.
5. E. Kastango, Understanding USP
71 Sterlity Tests and Extending
Beyond Use Data, http://asp.
pharmacyonesource.com/images/
simplifi797/USP71ExtendingBUD.
pdf, accessed 20 Oct. 2015.
6. Vetter, “Vetter Embarks on a 300 Million
Euro Investment Strategy for Further
Development To its Manufacturing
Sites,” Press Release, 30 Sept. 2015.
7. Vetter, “Improved RABS concept
combines two proven aseptic
processes,” www.vetter-pharma.
com/en/services-solutions-en/
vetter-answers/improved-rabs-
concept-combines-proven-aseptic-
processes, accessed 22 Oct. 2015.
8. Fedegari, “Official Opening of Fedegari
$2.9M State-of-the-Art Technology
Centre,” Press Release, 15 Sept. 2015.
9. Catalent, Advanced Aseptic
Processing, www.catalent.com/
index.php/offerings/A-Z-Offerings/
advanced-aseptic-processing/
10. Pfizer, “Pfizer Completes Acquisition of
Hospira,” Press Release, 3 Sept. 2015.
11. “Piramal Invests $30.6 Million
in Coldstream Acquisition,”
PharmTech.com, www.pharmtech.
com/piramal-invests-306-million-
coldstream-acquisition.
12. “Injectables to Show Double-Digit
Growth Through 2020,” PharmTech.com,
www.pharmtech.com/injectables-show-
double-digit-growth-through-2020. PTE
Table I: Outsourcing injectables: M&A activity in CMOs (in US dollars).Buyer Acquisition Approximate sale value
Pfizer Hospira $17 billion
Pfizer Innopharma $360 million
Hikma Bedford Labs $225 million
Sun Pharma Pharmalucence N/A
Mylan Strides Arcolab $1.6 billion
Piramal Coldstream Labs $30.65
Source: CPhI 2015 Annual Industry Report, Part 3, and PharmTech.com,
www.cphi.com/documents/129623/1844059/CPhI+Annual+Report+2015+-
+Part+I/57d8295a-a73a-444e-b593-c6fccdf00dae.
24 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
Presenters
George Svokos
Chief Operating Officer
AMRI
James Grabowski, PhD
Associate Director of
Mergers & Acquisitions
AMRI
Moderator:
Agnes Shanley
Editor
Pharmaceutical Technology
EVENT OVERVIEW:
Merger and acquisition (M&A) trends in the contract
services and biopharma space are set to continue in the
coming years. Although M&A at contract manufacturing
organizations (CMOs) can be a stressful time for clients,
customers should know that M&As offer various
opportunities for continuous improvement and the
service providers that go through M&A integration most
frequently are likely to be among the best proponents of
the process.
Key Learning Objectives
■ Best practices in approaching integration planning
■ Find out why change management is vital during
acquisitions
■ Learn what you should be communicating during
integrations and when you should be talking to the
CMO
Sponsored by Presented by
Optimizing M&A Integration for Customer Success: The CMO Perspective
For questions contact Sara Barschdorf
On-Demand WebcastOriginally aired October 29, 2015
Register for free at www.pharmtech.com/pt/maintegration
Who Should Attend:
■ Branded Pharma/Biotech
Companies
■ Generic Pharmaceutical
Companies
Ad
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Ga
ult
/Ca
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ag
es
For a new generic-drug product to be approved by a regulatory
agency, it is necessary to prove that it is bioequivalent
with a reference product. For orally administered dosage
forms, bioequivalence is demonstrated by determination of
the pharmacokinetic profile of the generic-drug product and
demonstration of similar drug absorption and drug elimination
characteristics compared with the reference product.
Demonstration of therapeutic bioequivalence for topical
dermatological products, however, is not as straightforward. Most
topical dermatological products are designed to deliver the drug to
the skin and not into the systemic circulation. Therefore, evaluation
of blood pharmacokinetics does not provide information on
drug delivery into the skin. A survey of international regulatory
bioequivalence recommendations for generic topical dermatological
products provides useful insights into currently accepted practices (1).
In summary, the approaches that can be used to demonstrate
bioequivalence are:
t� bioequivalence study with clinical endpoint
t� bioequivalence study with pharmacodynamics endpoint
t� in-vivo dermatopharmacokinetic study
t� bioequivalence study with in-vitro endpoint
t� waiver from bioequivalence study.
Demonstrating Therapeutic Equivalence for Generic Topical Products The determination of topical bioequivalence requires a multi-faceted
approach, tailored specifically to the generic-drug formulation.
Robert Harris, PhD,
is chief technical officer at
Juniper Pharma Services.
Almost all regulatory
authorities will require data from
a bioequivalence study with a
clinical endpoint (i.e., proving
that clinical performance of the
generic-drug product matches
that of the reference product) for
most topically applied generic-
drug products. These studies often
involve a large patient population (n
> 500) to provide sufficient data for
statistical evaluation. Cost and time
for conducting these studies can be
significant. Ironically, these studies
are often considered to be the least
accurate, least sensitive, and least
reproducible means of demonstrating
bioequivalence for topically-applied
products. Sometimes regulatory
authorities will also request blood
pharmacokinetics, if there are
safety concerns relating to possible
permeation of the drug into the
systemic circulation.
An alternative approach to clinical
endpoint studies, which is generally
accepted for topical corticosteroid
products, is the application of
the vasoconstrictor assay (VCA),
otherwise known as the human
skin blanching assay. This assay is
effectively a bioequivalence study
with a pharmacodynamic endpoint.
Corticosteroids absorbed into the
skin cause a whitening of the skin
due to a vasoconstrictive effect.
Measurement of skin whitening
(by use of a scoring scale or
chromameter readings) provides an
indication of the extent of absorption
and action of the corticosteroid.
Although there has been much
debate relating to the reliability of
data generated by this approach, it is
still widely accepted and less costly
compared with clinical endpoint
studies—however, it only applies to
topical corticosteroid products.
*O�WJWP�dermatopharmacokinetic
studies can be used to support
demonstration of bioequivalence
through measurement of absorption
of drug into the top layer of the
skin, the stratum corneum (SC), as
a function of time. Tape stripping
is used to determine the depth of
penetration of the drug at a given
time. This method of determining
drug penetration into the skin is
applicable to all therapeutic classes
of drugs. Nonetheless, acceptability
26 Pharmaceutical Technology Europe NOVEMBER�������PharmTech.com
of this approach to bioequivalence
testing has been hindered because of the
variability in methods and study designs
between testing laboratories. Recent
advances to the dermatopharmacokinetic
principle have been the use of open flow
perfusion (OFP) or dermal microdialysis
(DMD). These methods involve positioning
an ultrathin, semipermeable vessel into the
dermis and then perfusing the vessel with a
buffer solution. A drug applied to the skin,
which permeates the SC, will diffuse into
the tiny artificial vessel, and continuous
measurement of drug transport into the
dermis can, therefore, be measured.
This approach, however, is not relevant
for products that are designed to deliver
drug into the SC only. To support JO�WJWP�
studies, it is usual to conduct additional
in-vitro studies to compare in-vitro
performance of the generic-drug product
versus the reference product (e.g.,
rheology, pH, droplet size) and also possibly
in-vitro release testing (IVRT) using Franz
diffusion cells to determine drug diffusion
through artificial membranes or into/
through skin.
In some cases, it may be appropriate
to apply for a waiver from conducting
bioequivalence studies—although
generally, this situation only applies to
topical solution products. To qualify
for a waiver, the drug substance and
the excipients in the generic-drug
product should be qualitatively (Q1)
and quantitatively (Q2) the same as in
the reference product. Often, it is also
necessary to demonstrate that functional
attributes (Q3) of the generic drug match
the reference product (e.g., pH, particle
size, viscosity, etc).
It is apparent that selecting the most
appropriate approach for demonstrating
bioequivalence for a topical generic-
drug product is not a straightforward
process. However, there are continuing
initiatives within the pharmaceutical
industry for harmonization in regulating
generic-drug products, particularly topical
dermatological products.
In 2012, the International Generic Drug
Regulators Pilot (IGDRP) project was
launched to support global harmonization
for the regulation of generic-drug products.
In 2013, a workshop was organized by
the Product Quality Research Institute
(PQRI) with the objective of addressing
the harmonization of regulatory practices
relating to topical drug products (2). One
of the conclusions from the workshop
was that determination of topical
bioequivalence requires a multi-faceted
approach, tailored specifically to the
generic drug/formulation. Subsequently,
a decision tree “strawman” was proposed
as a guide for deciding what is required
for determination of bioequivalence for a
given topical product. The “strawman” is
summarized as follows:
t� 1st option: Evaluate feasibility of
biowaiver based on formulation similarity.
t� 2nd option: Is the product amenable to
VCA? If so, evaluate feasibility of using
the VCA method.
t� 3rd option: Is the product amenable
to pharmacokinetic determination
(i.e., transdermal drug delivery)? If so,
conduct a pharmacokinetic study (alone
or with other supporting studies).
t� 4th option: If the site of action is
the SC/epidermis, evaluate clinical
endpoint/dermatopharmacokinetics/skin
permeability.
t� 5th option: If the site of action is the
epidermis/dermis, evaluate clinical
endpoint/dermal microdialysis/skin
permeability.
t� 6th option: If the site of action is below
the dermis, evaluate clinical endpoint/
dermal microdialysis/pharmacokinetics-
based bioequivalence study.
Furthermore, the European Medicines
Agency published a concept paper (3) on
the development of a guideline on quality
and equivalence of topical products,
which to a large extent, reflects the
recommendations from the PQRI (2013)
workshop.
In summary, the three bioequivalence
approaches that are currently consistently
accepted by regulatory authorities are
bioequivalence studies with clinical
endpoints, in-vivo pharmacodynamic
studies (in particular VCA for topical
corticosteroid products), and waivers
for topical solutions. Also, most require
pharmacokinetic studies if there are safety
concerns relating to systemic exposure.
However, it is refreshing to see that the
regulatory authorities are giving credence
to alternative science-based methods for
demonstration of bioequivalence, rather
than insistence on clinical endpoint studies.
References1. A.C. Braddy et al., ""14�+ 17 (1) 121-133
(2015).
2. A. Yacobi et al., 1IBSN�3FT �31 (4) 837-846
(2014).
3. EMA, $PODFQU�1BQFS�PO�UIF�%FWFMPQNFOU�
PG�B�(VJEFMJOF�PO�2VBMJUZ�BOE�&RVJWBMFODF�PG�
5PQJDBM�1SPEVDUT�(London, Dec. 2014). PTE
28 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
PEER-REVIEWED
Identifying Causes Of Delamination Carol Rea Flynn, Dan McNerney, and Palak Shah
Even the exceptionally inert Type I borosilicate
glass is susceptible to attack by aggressive
chemicals, causing it to spall. This phenomenon in
primary packaging for parenteral products, which
is referred to as delamination, has increased since
the introduction of innovative biopharmaceuticals.
A long-term study was conducted to determine
the causes of delamination. Of the factors in
the manufacturing process that can affect the
propensity for vial delamination, this study identified
the forming temperature of the vial bottom as
the greatest correlation to the phenomenon. This
knowledge enabled the development of an improved
manufacturing process for glass vials and a new
type of vial.
Glass is recognized as the gold standard for primary
packaging of parenteral drugs. Glass is durable, inert,
clean, and transparent—properties that are important in the
manufacture of containers for sophisticated applications.
The composition of the glass used has been continuously
improved over time. With its high hydrolytic resistance,
borosilicate glass (Type I glass) has long replaced the simple
soda-lime glass for the packaging of parenteral products.
Nonetheless, even a material as resistant as Type I glass
can be tested to the limit by aggressive chemicals. When
packaging liquids have a particularly high or low pH value,
for example, an interaction with the glass can take place
in which the entire surface of the glass corrodes due to
the migration of alkali ions from the glass into the solution.
Another known phenomenon is when layers of glass
flake off in specific zones of the packaging product and
contaminate the solution. This process, which is called
delamination, is observed during the long-term storage
of high-pH solutions and solutions containing chelating
agents or buffer systems as well as during the storage of
biologics such as monoclonal antibodies. Figure 1 shows
an extreme case of delamination created in the laboratory,
not under realistic pharmaceutical storage conditions. A
series of product recalls in the United States has affected
all the major manufacturers of primary pharmaceutical
packaging made of glass. Delamination has become a
serious problem from both a medical and an economic
viewpoint. The detached glass flakes could potentially lead
to health problems in conjunction with intravenous or intra-
muscular injection, although no cases of this kind are known
yet. In addition, each product recall generates significant
losses for the pharmaceutical industry, especially in the
high-cost biologics sector.
Delamination testing
In view of the increasing number of product recalls, in early
2011, the US Food and Drug Administration instructed the
pharmaceutical industry, in collaboration with primary pack-
aging manufacturers, to come up with solutions for the dela-
mination problem. Joint meetings involving representatives of
the industry and the regulatory bodies were held to assess
the current state of knowledge and discuss the future course
of action. One year later, on this basis, the US Pharmacopeial
Convention (USP) presented a new draft of General Chapter
<1660> proposing test procedures going beyond those previ-
ously laid down (1). The use of these more aggressive test
Carol Rea Flynn is director of technical services, Dan McNerney is
director of engineering, and Palak Shah is engineering specifications
manager, all at Gerresheimer, Vineland, NJ. All correspondence should be
addressed to Marion Stolzenwald, [email protected].
Submitted: 31 March 2015; Accepted: 20 April 2015.
CITATION: When referring to this article, please cite it as C.R. Flynn,
D. McNerney, and P. Shah, “Identifying Causes Of Delamination,”
Pharmaceutical Technology 39 (11) 2015.
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Pharmaceutical Technology Europe NOVEMBER 2015 29
Delamination
conditions is intended to facilitate more reliable predictions of
the tendency of primary packaging to delaminate.
In spite of these efforts, a host of questions remained
unanswered on the subject of delamination. Little was
known about the causes of the phenomenon at the time,
and there was no established industry standard for
methods of systematic investigation. A comprehen-
sive long-term study on the subject of delamination
was conducted in association with Alfred University
(New York, US). The first task was to develop a reliable
method for the qualitative and quantitative analysis of
delamination. The study then forced delamination under
laboratory conditions to identify the causes of this phe-
nomenon.
Methods
Detecting delamination. Five different solutions
(highly purified water; sodium chloride [NaCl] solution
with citrate buffer pH 7; and solutions with pH values
of 5.5, 8, and 9.5) were used in the study. The solu-
tions were tested for the presence of visible and subvis-
ible particles, extractables (i.e., chemical compounds
and inorganic elements), and pH changes. The iden-
tification of particle formation in the solution using
dynamic light scattering (DLS) proved to be inconclu-
sive. So, in addition to pH determination by μ-electrode,
the study focused in particular on the filtration of the
solution with subsequent energy-dispersive X-ray spec-
troscopy (EDX) of the filter. Extractables were ana-
lyzed using an inductively coupled plasma (ICP) and
micronebulizer. A hydrolytic resistance test in accord-
ance with European Pharmacopoeia (3.2.1A) and
US Pharmacopoeia (USP) <660> was also conducted
(2, 3). This test determines the resistance of the interior
surfaces to migration of ions out of a filled vial.
Data were also collected on the vials. Surface morphology
data collected by scanning electron microscope (SEM) was the
main method used over and above visual inspection. Stress in
the section of the vial particularly at risk to delamination was
also visualized using a polariscope. A methylene blue surface-
Figure 1: In delamination, detached
glass flakes contaminate the stored
medicinal product. The vial shows
an extreme case created in the
laboratory, not a typical case.
Glass forming time
and temperature
Glass forming
technology
Surface treatment
Type of
glass composition
Thermal sterilization
or autoclaving
Time and storage
conditions
pH drug product
Chemical composition drug/
drug formulation
(e.g. buffer)
Other factors
Annealing temperature
Figure 2: Vial production (left) and pharmaceutical processes (right) are both
potential triggers of delamination.
All
fig
ure
s a
re c
ou
rte
sy o
f th
e a
uth
or.
30 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
Delamination
staining test was conducted, but was
only of secondary significance.
Root-cause analysis. Once a reli-
able analytical procedure had been
developed as described in the previous
section, a design-of-experiment (DOE)
study was created to identify the root
cause(s) of delamination. To ensure
that all the potential influence varia-
bles were taken into account, a broad
approach was chosen encompassing
the relevant factors during vial produc-
tion and also during the subsequent
pharmaceutical processes, which are
illustrated in Figure 2. First, in the
area of material formulation, the two
borosilicate glass types (Type I class A
Gx33 and class B Gx51-V) were tested.
For control purposes, a batch of vials
made of molded glass was included
in the study. In each case, 3-mL and
10-mL vials were investigated. During
the production process, the effects of
different burner settings and the asso-
ciated forming temperatures were
determined. As both temperatures and
temperature gradients are high during
formation, these parameters were the
prime focus of the study. The effects
of three temperature steps during the
formation of the vial bottom were com-
pared, and the potential influence of
continuous and indexing forming proc-
esses was investigated. A further focus
of the study was the effect of treating
the vials with ammonium sulfate to
remove alkali ions from the surface
(pre-leaching) and, in this way, render
them more hydrolytically resistant.
On the processing side, the effects of
washing, sterilization, and depyrogena-
tion were also investigated.
Forty-eight batches with an approxi-
mate total of 100,000 vials were pro-
duced and delivered to Alfred University
for the study, where they were filled
with test solutions and stored at 5, 25,
and 40 °C. The degree of delamination
was investigated at the beginning of the
test and again after three months, six
months, and one year. Further examina-
tions will take place after three years.
On conclusion of the evaluations
made at the end of the one-year
storage period, an additional series of
tests using USP <1660> was conducted
with correspondingly higher solution
concentrations and temperatures as
follows (1):
t� 0.9% potassium chloride (KCl), pH 8.0,
2 h at 121 °C
t� 3% citric acid, pH 8.0, 24 h at 80 °C
t� 20 mM glycine, pH 10.0, 24 h at 50 °C.
For these additional vials, an eval-
uation was made after 2 or 24 hours
(as required by USP <1660>) and again
after 4–6 months.
Results and conclusions
Effect of time. After one year, detailed
results on the triggers and course of
delamination were seen. The destruc-
tion of the glass surface to the point
where particles become detached is
clearly a time-dependent phenomenon.
Delamination was more evident the
longer the glass came into contact with
aggressive solutions. Corroded surfaces
and detached glass flakes occurred
with increasing frequency during later
tests (four to six months and longer).
The changes observed during the
study under realistic storage conditions
were confirmed during the test series
in accordance with USP <1660>, which
involves more stringent test conditions.
Despite high solution concentrations and
extreme temperatures, no corrosion or
detached glass flakes were observed
during the test phase (2–24 hours), with
glass flakes only becoming detached
after several months, as shown in an
SEM in Figure 3, for example.
Effect of solution and glass type.
There were also differences in the spe-
cific effects of different solutions. In
conjunction with Gx51-V glass, KCl solu-
tion had the most pronounced dela-
mination effect, followed by solutions
with citrate buffer and glycine. With
Gx33 glass, however, the solution with
citrate buffer had the most pronounced
delamination effect, followed by solu-
tions with glycine and KCl.
Effect of treated glass. Treating the
vials with pre-leaching makes the sur-
face of the glass susceptible to dela-
mination. The most severe forms of
delamination were found in conjunction
with treated glass. Taking all sample
types together, filled with aggressive
solutions, treated vials showed statisti-
Figure 3: Delamination occurs during longer-term storage of aggressive
medicinal products: unimpaired glass surface (left), initial signs of pitting
(middle), then detachment of glass flakes (right).
Bottoming Burner
Stress Ring
Original Glass Tube
Prime ROI forVisible Flakes
Figure 4: When the vial bottom is formed, glass components evaporate and
condense at the stress ring; ROI is region of interest.
Delamination
cally significant higher occurrence
of delamination than untreated vials.
Treated glass should therefore be
avoided when packaging delamina-
tion-inducing medicinal products, no
matter how successful it has proven
to be in other areas of application.
Effect of forming temperature.
An interesting finding in this study is
that in the manufacturing process,
the factor that has the greatest cor-
relation to the propensity for delami-
nation is the bottom forming temper-
ature. It was observed that only the
heel area of the sample vials dela-
minated, and this area is subject to
particularly high thermal loads.
As shown in Figure 4, vial dela-
mination typically occurs in a clearly
defined region of interest (ROI)
between the heel stress ring and
the base of the vial due to the base
forming process. In this process, the
vial is turned upside down and the
upper part is heated to such a high
temperature that sodium, potas-
sium, and boron evaporate from the
glass matrix. The vapours released
condense on cooler parts of the vial.
At the same time, the temperature
conditions directly underneath the
base permit the formation of a sec-
ondary thin layer of glass with an
average thickness of 0.5 µm. This
process is abetted by the supply
of sodium and potassium in the
vapour, which lowers the melting
point. In contrast, the body of the
vial is so cool that no new layer of
glass can form. The surface layer of
glass at the stress ring is less inert
than the tubular glass and has a dif-
ferent thermal expansion coefficient,
which makes it more susceptible to
attack and degradation by stored
solutions. The central role of the
forming temperature in delamina-
tion also explains the initially sur-
prisingly result that the 10-mL vials
were more prone to delamination
than the 3-mL vials. Larger vials gen-
erally have greater wall thicknesses,
necessitating a correspondingly
greater supply of heat during for-
mation, which resulted in a greater
tendency to delaminate.
Cumulative % samples that delaminated
Bu
rner
tem
pera
ture
gu
ard
ban
din
gfo
r TH
OR
– 1
0 m
L V
ials
0 0,05 0,1 0,15 0,2 0,25 0,3
Figure 5: Correlation between burner temperature and delamination.
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Delamination
cally significant higher occurrence
of delamination than untreated vials.
Treated glass should therefore be
avoided when packaging delamina-
tion-inducing medicinal products, no
matter how successful it has proven
to be in other areas of application.
Effect of forming temperature.
An interesting finding in this study is
that in the manufacturing process,
the factor that has the greatest cor-
relation to the propensity for delami-
nation is the bottom forming temper-
ature. It was observed that only the
heel area of the sample vials dela-
minated, and this area is subject to
particularly high thermal loads.
As shown in Figure 4, vial dela-
mination typically occurs in a clearly
defined region of interest (ROI)
between the heel stress ring and
the base of the vial due to the base
forming process. In this process, the
vial is turned upside down and the
upper part is heated to such a high
temperature that sodium, potas-
sium, and boron evaporate from the
glass matrix. The vapours released
condense on cooler parts of the vial.
At the same time, the temperature
conditions directly underneath the
base permit the formation of a sec-
ondary thin layer of glass with an
average thickness of 0.5 µm. This
process is abetted by the supply
of sodium and potassium in the
vapour, which lowers the melting
point. In contrast, the body of the
vial is so cool that no new layer of
glass can form. The surface layer of
glass at the stress ring is less inert
than the tubular glass and has a dif-
ferent thermal expansion coefficient,
which makes it more susceptible to
attack and degradation by stored
solutions. The central role of the
forming temperature in delamina-
tion also explains the initially sur-
prisingly result that the 10-mL vials
were more prone to delamination
than the 3-mL vials. Larger vials gen-
erally have greater wall thicknesses,
necessitating a correspondingly
greater supply of heat during for-
mation, which resulted in a greater
tendency to delaminate.
Cumulative % samples that delaminated
Bu
rner
tem
pera
ture
gu
ard
ban
din
gfo
r TH
OR
– 1
0 m
L V
ials
0 0,05 0,1 0,15 0,2 0,25 0,3
Figure 5: Correlation between burner temperature and delamination.
galenIQª Filler-BinderGreat choice. Great taste.
• Iso alt (Ph. Eur., USP-NF, BP, JPE)
• The filler-binder with sweet sugar-like taste.
• Your best choice excipient to be used for a broad variety of dosage for s.
Our team of experts is available for your product develop ent with galenIQ™.
Contact us for an appointment and a sa ple package.
[email protected] · www.galenIQ.com
ES691109_PTE1115_031.pgs 10.23.2015 02:54 ADV blackyellowmagentacyan
Delamination
cally significant higher occurrence
of delamination than untreated vials.
Treated glass should therefore be
avoided when packaging delamina-
tion-inducing medicinal products, no
matter how successful it has proven
to be in other areas of application.
Effect of forming temperature.
An interesting finding in this study is
that in the manufacturing process,
the factor that has the greatest cor-
relation to the propensity for delami-
nation is the bottom forming temper-
ature. It was observed that only the
heel area of the sample vials dela-
minated, and this area is subject to
particularly high thermal loads.
As shown in Figure 4, vial dela-
mination typically occurs in a clearly
defined region of interest (ROI)
between the heel stress ring and
the base of the vial due to the base
forming process. In this process, the
vial is turned upside down and the
upper part is heated to such a high
temperature that sodium, potas-
sium, and boron evaporate from the
glass matrix. The vapours released
condense on cooler parts of the vial.
At the same time, the temperature
conditions directly underneath the
base permit the formation of a sec-
ondary thin layer of glass with an
average thickness of 0.5 µm. This
process is abetted by the supply
of sodium and potassium in the
vapour, which lowers the melting
point. In contrast, the body of the
vial is so cool that no new layer of
glass can form. The surface layer of
glass at the stress ring is less inert
than the tubular glass and has a dif-
ferent thermal expansion coefficient,
which makes it more susceptible to
attack and degradation by stored
solutions. The central role of the
forming temperature in delamina-
tion also explains the initially sur-
prisingly result that the 10-mL vials
were more prone to delamination
than the 3-mL vials. Larger vials gen-
erally have greater wall thicknesses,
necessitating a correspondingly
greater supply of heat during for-
mation, which resulted in a greater
tendency to delaminate.
Cumulative % samples that delaminated
Bu
rner
tem
pera
ture
gu
ard
ban
din
gfo
r TH
OR
– 1
0 m
L V
ials
0 0,05 0,1 0,15 0,2 0,25 0,3
Figure 5: Correlation between burner temperature and delamination.
galenIQª Filler-BinderGreat choice. Great taste.
• Iso alt (Ph. Eur., USP-NF, BP, JPE)
• The filler-binder with sweet sugar-like taste.
• Your best choice excipient to be used for a broad variety of dosage for s.
Our team of experts is available for your product develop ent with galenIQ™.
Contact us for an appointment and a sa ple package.
[email protected] · www.galenIQ.com
ES691109_PTE1115_031.pgs 10.23.2015 02:54 ADV blackyellowmagentacyan
32 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
Delamination
Improving vial production
This finding that vial delamination is
primarily triggered by the tempera-
ture conditions during vial formation,
in addition to the interaction of the
glass with the pharmaceutical product,
makes it possible to systematically
improve the production process. To
produce vials intended for the storage
of innovative or particularly aggressive
pharmaceutical drugs, formation below
a defined temperature limit takes pri-
ority over other factors, such as optical
perfection of the vial bottom. By imple-
menting quality-by-design principles in
the production operations, the input
parameters—in this case, the tempera-
ture of the bottom forming burners—
are continuously adjusted according to
the output on the basis of statistical
process control (SPC).
If the evaporation and recondensa-
tion of sodium, potassium, and boron
from the glass matrix is the most sig-
nificant cause of delamination, any
optimization of the production process
must start at precisely this point. The
most effective way to achieve this is
to optimize the forming temperature,
especially when smoothing the base
of the vial. During the study, vials were
produced across the entire forming
temperature spectrum. The cumula-
tive results across all other DOE vari-
ables show a clear correlation between
the burner temperature and the
number of delaminated vials, as shown
in Figure 5. Here, different process-
related temperature ranges were
taken into account for continuous and
indexing machines. However, the cor-
relation applies equally to both produc-
tion methods. It is, therefore, possible
to determine temperature limits for
each machine type below which dela-
mination in the ROI is greatly reduced.
This being said, there are still aggres-
sive solutions that are not recom-
mended to be used in Type 1 glass con-
tainers.
T h e T H O R p r o c e s s ( T h e r m a l
Hydrolytic Optimization and Reduction)
was developed by Gerresheimer to limit
the process temperatures and use an
improved bottom heat profile. A deci-
sive factor for the success of the opti-
mization is that THOR is designed as a
feedback SPC-controlled cycle.
In the process cycle, the forming
temperature (entire bottom matrix and
not a point sensor) of every single vial
is measured inline by camera systems
using proprietary software for the cam-
eras and subsequent data processing.
The results are forwarded to the
Infinity SPC system on the production
lines, which rejects all vials where the
forming temperature was exceeded.
In addition, the method of displaying
process statistics at the hot end was
modified so that an on-screen warning
signal is generated on occurrence of
excessive forming temperatures. The
forming parameters can be adjusted
in this case to keep the process within
the preset limits and reduce the reject
rates. Another positive side effect of
THOR cycle production is the improved
hydrolytic resistance of the vials. The
long-term study shows that vials pro-
duced within the defined formation
temperature limits fail the hydrolytic
resistance test far less often.
Quality-control test procedure
A p r o p r i e t a r y t e s t p r o c e d u r e
(Gerresheimer’s FLASH test) takes
into account the specific occurrence
of delamination in the stress ring near
the bottom of the vial. In this Ph. Eur.
3.2.1.A-compliant test, a vial is filled
with test liquid up to the nominal
volume and, after autoclaving, the
solution is titrated to determine the
hydrolytic resistance of the vial. If,
however, the tendency for delamina-
tion of the vial is the focus of the test,
it makes sense to fill the vial only to
a level just above the ROI in order to
obtain precise, delamination-specific
test results. Figure 6 shows a high cor-
relation between the test results with
a reduced filling volume and the rate
of delamination of vials in the frame-
work of the study for two types of glass
(Gx33 and Gx51). This method can be
used as a quality-control test.
Next steps
As there is no reliable way to replace
long-term testing, the study will be
continued for another year to deliver
further results on the interaction of
stored pharmaceuticals and vials pro-
duced under different conditions.
References
1. USP General Chapter <1660>, “Evaluation
of the Inner Surface Durability of Glass
Containers” (US Pharmacopeial Convention,
Rockville, MD, 2012).
2. Eur. Ph. 3.2.1A, “Glass containers for pharma-
ceutical use” (EDQM, Strasbourg, France, 2013).
3. USP General Chapter <660>, “Container–Glass”
(US Pharmacopeial Convention, Rockville, MD,
2013). PTE
Cumulative % samples that delaminated
1,20
1,00
0,80
0,60
0,40
0,20
0,00
0,00 0,10 0,20 0,30
Gx51
Linear (Gx33)
Linear (Gx51)FLA
SH
valu
e f
or 1
0 m
L v
ials
Figure 6: Correlation of Gerresheimer FLASH test with reduced filling volume
and delamination for two types of borosilicate glass (Gx33 and Gx51).
API SYNTHESIS & MANUFACTURINGM
ich
ae
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an
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Ge
ttyIm
ag
es
The structural complexity of newer small-molecule
drug candidates is increasing, with many
containing several different heterocyclic
substructures and numerous stereogenic centers.
Preparing single isomers of these compounds can be
quite challenging and requires the use of atom-
efficient, low-waste, regio- and stereoselective
reactions, according to Dave Green, vice-president of
R&D with ANGUS Chemical Company. “A considerable
amount of effort is being consumed to expand the
utility of classic synthetic methods, often focusing on
enantioselective catalysis or combining steps into
what are now being called multi-component reactions
(MCRs),” he observes.
In particular, multi-component coupling reactions
for the generation of heterocycles in fewer steps
with high regioselectivity and reduced processing
times, cost, and waste are attracting significant
interest. A new cross-dehydrogenative,
heteroaromatic carbon–hydrogen (C–H) silylation
reaction catalyzed by the simple base potassium
tert-butoxide (KOtBu) is also a potentially useful
reaction for API synthesis.
Cascade reactionsOlder methods for the synthesis of heterocycles
typically relied on the stepwise construction of linear
frameworks followed by final cyclizations. “Today,”
says Green, “reaction conditions and catalytic
methods are being developed such that three or even
four reactive components can be simultaneously
combined, resulting in a cascade that leads to a highly
functionalized product.” Nitroalkanes are often one of
the building blocks used for the synthesis of nitrogen-
containing heterocycles.
Nitroalkane MCRsIn one example published by Maiti et al. in 2010 (1),
fully substituted pyrroles were prepared with five
independently selected substituents (four-component
reaction) in a completely regioselective manner. “It is
also notable that all of the starting materials used in
the reaction are readily accessible monofunctional
reagents,” Green notes. For reactions using
nitromethane, isolated yields were often in the
70 to 80% range, and typically higher than those
using nitroethane (1). The 3-ketopyrroles obtained
from the reaction are highly versatile intermediates
and can be used for a variety of synthetic
applications, according to Green.
Dehaen and co-workers reported a three-
component coupling reaction between nitroalkanes,
alkyl azides, and aldehydes that affords tri-substituted
triazoles, again in a regioselective manner (2). This
reaction proceeds via 1,3-dipolar cycloaddition of the
azide with a nitroalkene formed in-situ. Tazobactam is
one example of a current API that contains a
1,2,3-triazole moiety.
Heterocycles as in-situ intermediatesANGUS utilized MCR technology to synthesize
3-(N-methyl)-1-phenyl-1-propanol via a heterocyclic
intermediate. The three-component reaction of
formaldehyde and styrene with N-methyl
hydroxylamine, which was readily prepared by
selectively reducing nitromethane, proceeded through
an isoxazolidine intermediate that was ring-opened to
give only the desired regioisomer in nearly
quantitative yield. This direct route to 3-(N-methyl)-1-
phenyl-1-propanol is an important development,
because this compound is the key intermediate in the
manufacture of fluoxetine, according to Green. “By
using the MCR technique, isolation of the methyl
nitrone intermediate was avoided, preventing the
issues associated with its propensity to oligomerize,”
he explains.
Handling energetic materials One of the challenges when preparing nitrogen-
containing heterocycles via multi-component
reactions that require the use of nitromethane or
compounds like N-methylhydroxylamine (MHA) is the
reactivity of these substances. Nitromethane,
Efficient syntheses are possible using multi-component and
cross-dehydrogenative, heteroaromatic C–H silylation reactions.
Advances in Heterocyclic Chemistry for API Synthesis
Cynthia A. Challener
is a contributing editor to
Pharmaceutical Technology
Europe.
Pharmaceutical Technology Europe NOVEMBER 2015 33
API Synthesis & Manufacturing
azides, and to a lesser extent MHA
are energetic materials, and special
handling requirements must be
considered. “Minimization of the
quantities of in-process and/or
isolated materials is an excellent way
to also minimize the potential energy
release at any given point in the
process,” Green says. He points to
the recent development of
commercially available micro-flow
reactors as providing both
laboratory- and production-scale
options. “At the lab scale, a variety of
process conditions and
stoichiometries can be evaluated in
order to define the safe operating
limits for reagent concentrations/
temperature/pressure with
essentially no potential energy
release risk. In turn, scaling the best
operating conditions in an analogous
configuration greatly minimizes the
risk associated with handling the
larger volumes needed for
commercial production,” he
observes.
Interest in heteroarylsilanesThe substitution of carbon for fluorine
is recognized as an attractive method
for preparing drug candidates with
improved lipophilicity and other
attractive properties. More recently,
compounds containing silicon-carbon
bonds have attracted interest,
because such derivatives are also
often more stable and have improved
solubilities and pharmacokinetic
properties.
To date, heteroaromatic
organosilanes have been prepared
using two rather limited methods:
stoichiometric reaction of a
heteroaromatic organometallic
intermediate generated via a Grignard
reaction with a silicon electrophile
and catalytic C–H silylation mediated
by a rhodium or iridium catalyst in the
presence of an excess of a hydrogen
acceptor. The functional group
tolerance of these methods is
minimal. In addition, they require the
use of large quantities of reactive
and/or expensive reagents. As a
consequence, there is a desire for
more general routes to organosilanes
that are not only more cost-effective
and practical on an industrial scale,
but also provide access to novel
compounds.
Fortuitous discoveryStudents in the Grubbs and Stoltz
groups at the California Institute of
Technology recently stumbled on an
interesting reaction catalyzed by
KOtBu. They were investigating the
conversion of biomass to chemicals
via the breakage of carbon-oxygen
bonds using an iron catalyst,
potassium tert-butoxide, and a
hydrosilane as a hydride equivalent
and observed that a control reaction
with just KOtBu and the hydrosilane
gave silylated heteroaromatics as
byproducts (3).
Using 1-methylindole as a model
substrate, the reaction conditions were
optimized for the selective production
of a single organosilane in high yield. A
catalytic amount (1-20 mol%) of KOtBu
was found to be most effective, and
cross dehydrogenative heteroaromatic
C–H silylation occurs without the need
for an acceptor, resulting in the
generation of hydrogen gas as the only
byproduct. Extensive studies were also
performed to confirm that the KOtBu
was indeed the catalyst (3).
The reaction is noteworthy not only
because it is novel, but also because of
its scope, scalability, and the fact that
it is catalyzed by an inexpensive,
commercially available substance based
on potassium, which is an abundant
alkali metal and not a rare and expensive
precious metal. Furthermore, the
reaction proceeds under mild conditions,
has no complicated byproducts, the
product is readily isolated, and in many
cases, no solvent is required.
With respect to the scope of the
reaction, indoles with a variety of
substituents on the nitrogen (N)
molecule and at various positions on
the arene ring, and many different
electron-neutral and electron-rich N-,
oxygen- and sulfur-containing
heterocyclic compounds are
tolerated, although carbonyl groups
generally are not unless protected as
acetals. In addition, bromide, iodide,
cyano, and nitro substituents inhibit
the reaction, while fluoride, chloride,
trifluoromethyl, epoxide, N-alkyl
aziridine, pyridine, and tertiary amine
and phosphine groups do not (3).
Simple arenes also undergo the
dehydrogenative heteroaromatic C–H
silylation reaction, but the reactivity
depends on the substituents. Anisole
affords the ortho-substituted silylated
product, while toluene and similar
compounds undergo directing-group-
free C(sp3)–H silylation to generate
silylated benzyl derivatives. The
electronic nature of any oxygen
substituents also determines the
regioselectivity (on the ring or the
substituent) of the silylation (3).
Importantly for pharmaceutical
applications, the reaction appears to
be readily scalable; the neat reaction
of N-methyl indole with 1.5
equivalents of triethylsilane at 45 °C
was performed on a 100-gram scale
followed by simple filtration and
distillation, affording the desired C2
silylated product in 76% yield with
high regioselectivity (> 20:1) (3).
In addition, the facile silylation of
APIs was achieved to demonstrate
the potential for application of the
reaction for late-stage modification of
pharmaceutically relevant
compounds. The antihistamine
thenalidine and the antiplatelet drug
ticlopidine were successfully
subjected to the regioselective C–H
silylation reaction (58–68% yield with
high chemo- and regioselectivity) (3).
Therefore, this method should be
useful for the rapid synthesis of
compound libraries. Different
heteroarylsilanes obtained using the
KOtBu chemistry were also converted
to more complex molecules via
silicon-directed Suzuki–Miyaura
cross-coupling and Hiyama–Denmark
cross-coupling reactions to
demonstrate their synthetic utility (3).
References1. S. Maiti et. al., J. Org. Chem. 75 (5)
1674–1683 (2010).
2. W. Dehaen et al., Angew. Chem. Int. Ed.
53 (38) 10155–10159 (2014).
3. A. A. Toutov et al., Nature 518 (7537)
80–84 (2015). PTE
Multi-component coupling reactions for the generation of heterocycles in fewer steps with high regioselectivity and reduced processing times, cost, and waste are attracting significant interest.
34 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
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The pharmaceutical industry faces complex issues in its effort
to meet the requirements of the United States Drug Supply
Chain Security Act (DSCSA) (1). Pilot programmes are needed to
determine the feasibility of solutions, but the number of pilots
required will be costly, in terms of money, time, and human
resources. Virtual pilots, which use computer software to project
or simulate physical pilots, can reduce this burden by providing
some measure of learning or proof that a particular set of solutions
would be scalable and workable.
Traditionally, databases, spreadsheets, dashboards, and test
systems are used to understand systems, processes, and information
and to predict the expected outcome of a physical pilot. Simulation
software, however, is a more efficient technique that can be used
to create and execute a virtual pilot for any process, including
implementing the DSCSA in the pharmaceutical supply chain.
Simulation software has traditionally been used in manufacturing
environments to replicate complex processes and provide a way
to compare variations on specific scenarios to gain insights beyond
algorithmic calculations found in spreadsheets. Due to the increase
in computing power, simulation software has become easier to
use and is increasingly seen in many industries, where it is used
to study processes within and between systems, departments,
companies, and industries, including flow of products, people, cash,
and information. Simulations can also address human behaviour, time
considerations, and the physical environment.
The software has matured to the point that it can be used during
the information collection phase of a process study; it can provide
meaningful results, both at a summary level and in the details and
Piloting Track-and-Trace ImplementationVirtual pilot programmes examine scenarios that may occur while implementing
serialization requirements of the United States Drug Supply Chain Security Act.
Robert Celeste
is a founding partner of
RC Partners healthcare
consultancy, rceleste@
rcpartners.biz, tel:
1.215.584.7374.
nuances of a process. Simulations
can be used to create multiple
scenarios to examine alternatives
before large amounts of resources
are expended to plan, develop, and
execute a physical pilot. In fact, the
virtual pilot can become the blueprint
for the physical pilot.
Considering space and time constraintsCertain trading partners have
physical space or time constraints
that must be considered while
implementing DSCSA requirements.
Production lines, for example, vary
in terms of space available to include
serialization equipment. Simulation
can provide insight into how best to
use existing space, such as whether
to serialize on the production line
or serialize label-stock prior to the
production run. Because case and
pallet packing may be accomplished
elsewhere in the facility, a simulation
of the environment could help
address product and staff flow.
Likewise, wholesalers may have
time constraints in their window of
operations for picking and packing
orders to be delivered the next day.
Timing and positioning of product
and staff can be simulated to give
projections of what to expect upon
scale-up.
In addition to product and staff
flow, information flow is crucial
to meeting DSCSA requirements.
Creating, supplying, and archiving
DSCSA data can be simulated in
order to gain experience with the
latency, scalability, and feasibility
of making data available from other
systems within the organization.
All of these flows can be studied
in one simulation, to gain better
insight on how they interact with
each other and depend on each
other. For example, the DSCSA law
sets requirements for the timing of
transaction information. A virtual
pilot may be created to examine the
process flow of information, product,
and staff, should the product arrives
prior to the required Transaction
In addition to product and staff flow, information flow is crucial to meeting DSCSA requirements.
Pharmaceutical Technology Europe NOVEMBER 2015 35
Supply Chain
Information, Transaction History, and
Transaction Statement.
Another potential problem is
that during the transition to 100%
serialized products, companies
in the supply chain may receive
some serialized product and some
non-serialized product. To better
understand the transition, simulation
techniques could examine varying
numbers of products received, the
mix or percentage of serialized vs.
non-serialized products on hand, and
daily variability of serialized product
and associated traceability data.
Simulations can also examine the
latency of delivery and number of
suppliers.
Assessing human factors For complex systems or processes,
it’s often difficult to assess the
impact of individual tasks or even
understand these tasks and their
variation throughout the workweek
with enough clarity to confidently
declare that a pilot and ensuing
implementation will be successful.
Operations under the various stages
of DSCSA will require supplier,
customer, and internal process
changes as new steps are added to
existing processes, such as receiving,
picking, packing, and shipping. A
virtual pilot could demonstrate how
these new processes will affect daily
tasks as well as identify what changes
to support systems must be made.
Simulations could also provide insight
as to the activity balance needed to
keep up with throughput of product
and information.
A study of process and information
will include interviewing or speaking
to the people that perform the
process. It is imperative that they are
actively engaged in the information
collection and analysis process. There
are often nuances of why particular
step occurs and opportunities to
explore with the process expert
how newly accessible information,
equipment, or adjacent processes
might improve their process. Some
of this information may be difficult to
analyze. Using a virtual pilot, however,
allows inclusion of behaviours,
preferences, and other information
points that can directly affect the
outcome of the study or pilot. Also,
the process expert often is drawn into
the simulation process because it is
interactive and easily understood. The
end result is a more robust picture of
the process under study that can be
viewed at many levels and replicated
with different scenarios (e.g., five
people performing a task instead
of four). Lastly, simulations can
take into consideration the physical
environment itself, such as the layout
of equipment and materials, size
of rooms, and distance between
process points.
Incorporating business changesBusinesses are incorporating DSCSA-
triggered changes into established
operations that are constantly
changing due to changes in business
practices and economic conditions
(e.g., new customers, the loss of
existing customers, acquisitions, and
divestitures). Virtual pilots based on
simulations are an economic way of
re-running DSCSA scenarios, given an
ever-changing business environment.
Adding a newly acquired warehouse
or system to the simulation, for
example, offers an opportunity to
take advantage of existing work and
test it against the new reality.
ConclusionUnlike a static diagram, a simulated
environment actually runs; processes
require certain input, and if that input
is not there, the process simulation
stops until that problem is fixed. Each
glitch that is fixed in the simulated
environment is a glitch that won’t
have to be fixed in the final physical
pilot, during implementation, or in
production.
Not every pilot requires an
enormous investment in time, staff, or
funds. A pilot may merely demonstrate
proof-of-concept or experiment with
connecting systems to those of trading
partners in a test environment. A
company may be interested in piloting
what to do with all the new traceability
data made possible due to the DSCSA
law. A simulation or virtual pilot is
capable of generating a lot of data and
regenerating it based on changes in
input parameters.
Implementing the DSCSA, with
its serialized traceability system
that is interoperable with thousands
of trading partners, is a complex
challenge. There are many issues yet
to be understood and many details
that need to be incorporated into a
company’s plans and investment.
There are also many benefits and
opportunities to be gained by early
adopters who realize the value that
a more connected and visible supply
chain brings. Virtual pilots, with
simulation at their core, allow for
better contingency planning, “what
if” analysis, and even training of staff
in developing an awareness of new
departmental dependencies and
contributions toward the new reality
that serialization brings.
Reference1. R. Celeste, “Global Serialization: Could
Virtual Pilots Be in Our Future?” www.
pharmtech.com/global-serialization-
could-virtual-pilots-be-our-future,
accessed 12 Oct. 2015. PTE
Virtual pilots based on simulations are an economic way of re-running DSCSA scenarios, given an ever-changing business environment.
The Drug Supply Chain Security Act (DSCSA) became
law in the United States in November 2013, but the
requirements of the law are to be phased in over a
10-year period.
The first phase, implemented in 2015, included the
requirement for trading partners to share transaction
information. Individual item serialization takes effect
in 2017, and traceability is scheduled to be in place by
2023. Visit www.PharmTech.com for more articles on
serialization in the US and globally, such as:
t� Serialization: Are you prepared?
Why this time is different
t� Serialization Shake Out
t� Considering Full Serialization
More on serialization
36 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
PRODUCT/SERVICE PROFILESPRODUCT/SERVICE PROFILES
Anton Paar’s Pharma
Qualification Package
To identify, analyze, control, characterize or
check your raw materials, intermediates,
APIs and final formulations, benefit from
Anton Paar’s portfolio of instruments
covering polarimeters, refractometers,
density meters, viscometers, rheometers,
synthesis instruments, sample preparation
instruments, X-ray analysis systems and
zeta potential instruments.
Anton Paar understands your need for
completely traceable results and supports you
to meet the strict pharmaceutical regulations.
Make life easier in your lab with
t� traceability via a complete user
management system
t� audit trail functionality
t� GMP-compliant printouts and reports
t� electronic signature
t� fulfillment of the requirements of 21
CFR Part 11
t� Pharma Qualification Package for defined
instruments which complies with
pharmaceutical regulations (GMP, GAMP
5, 21 CFR Part 11, USP <1058> including
risk analysis and traceability matrix).
Anton Paar develops and provides
laboratory instruments and process
measuring technology for industry and
research that fulfills the requirements of the
pharmaceutical industry.
Anton Paar GmbH
www.anton-paar.com
Fast Dissolve Oral Dosing
of Macromolecules
Catalent’s Zydis® ODT fast-dissolve
formulation is a unique, freeze-dried oral
dosage form that disperses instantly in the
mouth, requiring no water. This may
enhance the molecule’s performance and
could contribute towards better patient
compliance.
With more than 20 products launched
in 50 countries, Zydis is the world’s
best in class, orally disintegrating tablet
(ODT) technology. Whether to advance
pharmacokinetics through pre-gastric
absorption, potentially improve patient
compliance, or add marketing advantage
to a valued brand, Catalent’s customers
draw on Zydis fast dissolve technology
to potentially enhance investment value
and accelerate a product’s potential.
Catalent has now expanded the
Zydis technology platform to overcome
traditional oral delivery challenges of large
molecules such as proteins, peptides,
viral vaccines and allergans. Zydis Bio
has the potential to deliver fast-dissolve
formulations of such therapies in a
patient preferred oral fast dissolve dose
form, in as little as three seconds.
Catalent Pharma Solutions
www.catalent.com
galenIQ™—The filler-binder
excipient with exceptional
taste properties
BENEO’s excipient galenIQ™ (Isomalt Ph Eur,
BP, USP–NF, JPE and approved in China with
an Import Drug License) is a range of water-
soluble filler-binders. Derived from beet
sugar it has a sweet taste and promotes a
pleasant, well-balanced gustatory profile
in pharmaceutical formulations. Due to
these unique sensorial properties, it is
an optimal choice for the formulation
of solid and liquid oral applications, and
especially those in combination with
active ingredients or plant extracts which
have a bitter and/or unpleasant flavour.
The galenIQ™ range includes specific
grades for direct compression, for wet
granulation and also for specialized
processing technologies such as hot
melt extrusion, roller compaction, pan
coating, and as a sugar-free starter core for
multiple unit systems. The grades for direct
compression are free-flowing and highly
compressible. Furthermore the unique
surface morphology of these grades prevent
segregation within a powder mixture,
thereby ensuring high content uniformity,
in both low- and high-dosage formulations.
Moreover the physical and chemical stability
of galenIQ™ safeguards the constancy of the
corresponding finished formulations, making
it an ideal choice for the manufacture
of tablets, effervescent, sachets,
lozenges, and syrups that taste good.
BENEO, part of the Südzucker
Group, is a member of the International
Pharmaceutical Excipients Council (IPEC)
and produces galenIQ™ under GMP
conditions for pharmaceutical excipients.
BENEO GmbH
www.galenIQ.com
Pharmaceutical Technology Europe NOVEMBER 2015 37
PRODUCT/SERVICE PROFILES
MicroSphere Refiner™
from the PSL Sterile
Production range
PSL have developed the MicroSphere
Refiner™ for microsphere formulation,
designed for process scale-up technologies
from lab scale to commercial production.
Polymeric microspheres obtained from
various micro encapsulation processes
require unique handling that differs from a
typical filtration and drying operation. With
side and bottom filtration, classification,
steam-in-place, drainability, tiltable
sterile discharge, vacuum drying and a
high yield, the MicroSphere Refiner™
technology has been designed to meet
such criteria for aseptic processes.
PSL is proud to participate in this great
technological advancement that will
improve the wellbeing of millions of
suffering patients.
PSL is an award winning international
manufacturer providing quality innovative
technology with process development
expertise to the pharmaceutical,
biopharmaceutical, chemical and laboratory
industries since 1989.
PSL will showcase the GFD® (Labora-
tory Filter Dryer) and the tiltable Micro-
Sphere Refiner™ for small scale pro-
duction from the PSL Sterile Production
range at P-MEC India, Hall 6, stand F50.
PSL (Powder Systems Limited)
www.powdersystems.com
PRODUCT/SERVICE PROFILES
38 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
Nexera UC unified
chromatography system
Shimadzu’s Nexera UC unified
chromatography system is the world’s first-
ever unified and fully automated instrument
combining supercritical fluid extraction (SFE)
with supercritical fluid chromatography
(SFC). The SFE/SFC/MS platform merges
quick and easy online sample preparation
with advanced chromatographic analysis
and high sensitivity detection.
The Nexera UC serves a wide range of
applications, e.g. food control, research
in biopharmaceuticals and environmental
analysis. It enables highly reproducible
extraction and stable analysis even of
unstable samples prone to oxidation or
dissociation if exposed to light or air.
Shimadzu Europa GmbH
www.shimadzu.eu
bottelpack® 430—compact
blow-fill-seal technology
What is expected from a compact and
flexible laboratory BFS machine? A minimal
mould size to keep the costs for trials and
stability tests, etc. with various mould tools
low and also the advantages provided by
the rotation machine technology (con-
tinuous parison, little plastic waste) of
the popular bottelpack® 460/461 models.
The result of this mix is the bottelpack®
430—a combined shuttle and rotation
machine. The basic principle of the rotation
machine technology with a continuous,
extruded, uncut parison forms the basis
for this machine. The mould follows the
continuously extruded parison during the
blow-fill-seal process. Once the mould
has been opened, it cycles back and is
positioned directly above the recently
produced ampoule bar to shape the next
block. This creates a continuous ampoule
strip that is fed into an external punch. The
bottelpack® 430 is ideal as a laboratory
machine and also for small batch sizes.
rommelag ag
www.rommelag.com
PRODUCT/SERVICE PROFILESPRODUCT/SERVICE PROFILES
SmartDose® Electronic
Wearable Injector
Designed to deliver high volumes of
injectable drugs over an extended period of
time, the SmartDose® electronic wearable
injector is designed to make it easier for
patients to self-administer medication
and can help encourage compliance
with prescribed treatments. Thousands
of SmartDose injectors have been used
in clinical studies, where patients have
self-administered the established dose.
The single-use, electronic wearable
injector is adhered to the patient’s body,
usually on the abdomen, and is provided
pre-programmed to provide the required
dose. The SmartDose injector includes a
silicone-free Daikyo Crystal Zenith® drug
container that is commercially available in
the ready-to-use format. West developed
the SmartDose injector with extensive
human factors analysis to understand and
design for preferences and behaviors at
various stages of the patient journey
West Pharmaceutical Services, Inc.
www.westpharma.com
Pharmaceutical Technology Europe NOVEMBER 2015 39
Advanced Homogeneous
Catalysts
Umicore is a materials technology
group focused on applications where its
expertise can make the difference.
We understand the rapidly changing needs
of our clients worldwide and provide innovative
metal based chemistry, homogeneous
catalysts and APIs, commercial-scale
manufacturing and supply chain expertise
to enable current and future technologies.
We offer an integrated long-term
collaborative partnership approach to
research, development and commercial
manufacturing that makes innovation
possible and offers customers continued
support throughout the product’s life cycle.
Key to our success is understanding
customer-specific applications —
enabling us to translate ideas into
chemistry solutions that work for our
customers’ process technologies.
Our Advanced Homogeneous
Catalysts allow you to design and run
t� a stereoselective hydrogenation,
t� cross-coupling and amination reactions,
t� metathesis reactions
with high efficiency and selectivity.
Combined to Umicore’s precious
metal recycling technologies, they
enable maximum cost efficiency in your
processes. Contact us to see for yourself.
Umicore
www.chemistry.umicore.com
Cleanroom Documentation
Systems
VAI is proud to introduce a new line of
Cleanroom Documentation Systems.
We have addressed and solved the
challenges surrounding particulate and
fiber contamination in controlled areas
from GMP required documentation
by developing, CleanPrint 10, the
Core2Print, and Core2Write.
CleanPrint 10, is the synthetic, cellulose
free, low particulate, writing substrate.
It is extremely durable, yet pliable, while
being resistant to abrasion, chemicals,
and ink smearing. The Core2Print, is a
316L Stainless Steel HEPA filtered printing
system. The Core2Print prints wirelessly
onto VAI’s pre-sterilized CleanPrint 10
paper into the controlled area. Core2Write
is a line of custom documentation
featuring: logbooks, ID tags, forms,
and labels. All Core2Write products are
printed on CleanPrint 10 synthetic writing
substrate. Core2Write products available
are sterile, and quadruple bag packaged
in VAI ABCD Cleanroom Introduction
System. Each product is completely
customizable, based on customer specific
requirements, and offer traceability via
barcode or patented RFID technology.
Veltek Associates, Inc.
www.sterile.com
PharmTech.com
NOVEMBER 2014 Volume 26 Number 11
MARKET REPORT
Germany Post AMNOG
TECHNICAL Q&A
Continuous Manufacturing
PEER-REVIEWED
Sublingual Formulations
QbD in
Parenterals
Addressing
Particulate
Contamination
Advancing Development & Manufacturing
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TROUBLESHOOTINGD
an
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ett
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TROUBLESHOOTING
Fabian Schapiro
is VP Marketing and Sales
of DIR Technologies,
www.dir-technologies.com.
Problems in an induction-sealing process can be identified and corrected in real time.
Primary packaging sealing integrity is crucial in
ensuring product viability and shelf life. The days
of sampling as the primary means of inspection and
analysis for the quality control of pharmaceutical
packaging may be nearing an end. One method
for non-destructive, 100% inspection of packages
is using dynamic thermal imaging to inspect the
integrity of induction-sealed bottles. Inspection
is performed through closed bottle caps without
damaging or degrading the product and without
reducing line speeds. Precise data can also be
collected to increase understanding of the process,
improve quality, and allow operators to detect and
amend issues in real-time.
This solution goes beyond the level of accept/reject
analysis to also indicate the source in the process that
may have caused the faulty seals, including problems
related to the raw material, the capper, or the sealer.
Incorrect settings can be quickly detected, allowing
the immediate removal of defective bottles from the
production line and adjustment of the source of the
problem. Problems can be corrected in real time,
before an entire batch is completed. This process
analytical technology (PAT) for the induction-sealing
process allows the input and output to be tracked,
enabling continuous process verification.
How dynamic thermal imaging worksAll objects have a certain temperature and emit
waves of energy, called infrared radiation (IR), invisible
to the naked eye. In general, hot objects emit more
energy than cold objects. A thermal imager creates a
viewable image from the IR waves, showing a “heat
picture” of a scene.
Thermal imaging was originally developed for the
defense industry and is regularly used for military
and security applications, as well as non-intrusive
inspection of plumbing, electrical systems, and
insulation. Combined with high-speed image analysis,
this technology provides unique monitoring and
detection capabilities that can be used to inspect
pharmaceutical primary packaging, specifically,
induction sealing.
Induction sealing process problemsIn the induction sealing process, as shown in
Figure 1, a bottle is filled, and a closure with
a composite liner inside is screwed onto the
filled container. The container then travels by
conveyor under an induction sealer, which uses an
electromagnetic field to heat the aluminum foil layer
of the liner. The heated foil, in turn, causes the heat-
seal layer to melt. When cooled, the polymer creates
a bond with the container, resulting in a hermetically
sealed product. When the cap is removed, the foil
remains, providing an airtight seal and preventing any
tampering or contamination of the bottle’s contents
until the customer pierces the foil. A good induction
seal prevents product leakage, is tamper-evident,
maintains product quality, and fosters consumer
confidence.
Maximizing the efficacy and efficiency of an
induction sealer requires a holistic, carefully
coordinated approach that incorporates machine,
materials, quality control, and operator education.
The container, closure seal liner, and induction sealer
must be compatible, and an operating window that
allows the sealer to be successful within a range
of predetermined operating tolerances must be
established. Defects can originate at various steps
along a packaging line, including the capper, induction
machine, conveyor and, of course, the raw material
itself. Potential problem areas are described as
follows:
t� Material-related problems include bent or
damaged foil; missing foil; damaged edge or edges;
or an upside-down liner (Figure 2a).
t� Problems related to the capping equipment include
untorqued or crooked caps (Figure 2b).
t� Problems tied directly to the sealer itself usually
involve overheating or under-heating (Figure 2c).
Underheating the foil can result in the familiar
Using Dynamic Thermal Imaging to Correct Sealing Problems
Pharmaceutical Technology Europe NOVEMBER 2015 41
All
fig
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s a
re c
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e a
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or
Troubleshooting
‘potato-chip’ effect, as shown in Figure 2c. Overheating
the foil can cause damage to the seal layer and to any
protective barriers, which could result in faulty seals,
even weeks after the initial sealing process. Other
sealing problems do not typically originate with the
induction sealer but rather, are associated with a fault
earlier in the process that made it impossible for the
sealer to perform properly.
Torquer problem case studyIn a classic torquer problem, an incorrectly calibrated
torquer does not correctly close the cap, and as a
result, the induction sealer cannot create a proper seal.
Figure 3 shows thermal imaging results used to track the
process. In the first batch of 2000 bottles, a significant
number of rejections (shown as red dots) is seen. This
deviation from the defined process window indicates
that there is a faulty process that should be stopped and
the source of the problem checked before more bottles
are incorrectly sealed. The rejections in this case were
discovered to be associated with the tightness of the
cap. Based on this information, the line operator stopped
the line and adjusted the torquer. The batch was then
continued and rejections return to an acceptable number,
as shown in Figure 3.
ConclusionGiven the myriad potential problem areas, the need for a
troubleshooting process that assures the highest possible
level of quality control is clear. In each of these cases,
use of dynamic thermal imaging allows the operator to
identify the problem early, stop the line, immediately
remove any defective bottles, and make necessary
corrections to the production line process. Preventing
issues before they become significant problems minimizes
the cost of wasted time, work-backs, materials, and
labour. This real-time, non-intrusive monitoring of package
integrity is currently in use on packaging lines at several
leading pharmaceutical packaging companies. PTE
42 Pharmaceutical Technology Europe NOVEMBER 2015 PharmTech.com
Airbridge Cargo Airlines ..........................................................................29
AMRI .........................................................................................................25
Anton Paar ................................................................................................13
BASF ..........................................................................................................21
Beneo ........................................................................................................31
Catalent .....................................................................................................44
CPhI India ..................................................................................................17
Hetero Inc ....................................................................................................9
Natoli Engineering ....................................................................................11
Powder Systems .....................................................................................19
Rommelag .................................................................................................15
Shimadzu.............................................................................................27, 43
Umicore .......................................................................................................5
Veltek ...........................................................................................................7
West Pharmaceuticals ...............................................................................2
Ad IndexCOMPANY PAGE COMPANY PAGE
Figure 1: Steps of the induction sealing process.
Figure 2: Problems can be related to materials (a), capping equipment (b), and sealing equipment (c).
Bent / damaged foil Missing foil Damaged edge Upside-down
liner
(a)
Under-heating Overheating
(c)
(b)
Untorqued cap Crooked cap
Figure 3: Thermal imaging tracks the induction-sealing process and inicates rejected bottles (red dots).
Batch continued with an acceptable number
of untorqued caps
Number of Bottles
Torquer
related
parameter
Torquer
problem
solved
Torquer
problem
identified
EMPTYBOTTLE
FILLERCAPS
TORQUER
INDUCTION SEALER
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