> serving the global supply chain Drug Delivery
Pressures from consumers, investors, insurance compa-
Why Innovative
Drug Delivery
Packaging
Solutions are
needed for
Todays Patients
> BY Kevin Haehl General Manager, Unither Pharmaceuticals North America
Mr. Haehl is responsible for developing and growing Unither Pharmaceuticals contract
pharmaceutical manufacturing business for North America in niche fields such as
sterile unit dosage forms using Blow-Fill-Seal technologies and Unistick single dose
liquid stick packs, and the strategic leadership of the newly acquired manufacturing
site in Rochester, NY. He has over 25 years of broad experience across pharmaceutical
manufacturing, sales support, engineering, process development, financial, quality, and
supply chain. Prior to Unither, Mr. Haehl held management positions at Evonik, Eli Lilly
& Company, and worked in engineering at DuPont.
14 American pharmaceutical review Supplement April 2015
Abstract
nies, regulators, and governments to drive down costs
and improve product performance (efficacy, ease of
use, patient adherence, etc.) are driving pharmaceuti-
cal companies to consider all aspects of a formulated
drug, including the use of advanced drug delivery tech-
nologies (DDTs) and unique packaging solutions, much
earlier in the drug development cycle. In addition to
having a more patient-centric focus, the pharmaceuti-
cal industry is also shifting to greater outsourcing of
research and manufacturing activities. Drug manu-
facturers are therefore seeking custom manufactur-
ing organizations that can, in addition to fill finish
operations, offer unique DDTs and approaches to
product packaging combined with formulation
development and analytical support to ensure that pa-
tients get the medicine they need in the dosage form
they prefer.
Introduction
Numerous changes are occurring in the pharmaceuti-
cal industry today. Drug manufacturers face significant
pressure to reduce costs from governments, insurers,
and patients. The shift in growth from mature to emerg-
ing markets, where the demand for low-cost therapeu-
tics is predominant, is adding to the downward pricing
pressure. Poor patient adherence (taking medication
as prescribed) is a further problem that is contribut-
ing significantly to rising healthcare costs.1 Investors,
meanwhile, want to see much lower failure rates for
candidate drugs and a higher return on drugs that do
make it to the market.
In response, drug manufacturers are looking for ways
to determine the likelihood of success much earlier in
the drug development cycle. The industry has also ad-
opted a more patient-centric focus, paying closer atten-
tion to the development of drugs that are more likely to
not only be preferred by patients, but actually taken as
intended by their doctors.2, 3 Consequently, dosing regi-
mens (particularly single-unit dosing), delivery meth-
ods, and product packaging are now being considered
much earlier in the drug development cycle.4
This approach can be challenging, however, given
that the level of outsourcing of drug development and
manufacturing activities has increased dramatically.5
This trend is in part due to the fact that drug companies
see outsourcing as a mechanism for reducing costs. It
can also be attributed to the growing complexity of drug
candidates, the production of which often requires spe-
cialized capabilities that most pharmaceutical manu-
facturers do not have.
While growing numbers of contract manufactur-
ing organizations (CMOs) purport to offer integrated
services from discovery through commercial manu-
facturing, in general CMOs tend to focus either on the
synthesis and production of pharmaceutical intermedi-
ates and active pharmaceutical ingredients (APIs, drug
 substances) or the production of formulated drug prod-
ucts. This separation is even more pronounced for
products that require sterile manufacturing conditions
due to the need for more advanced equipment and
more extensive control procedures to ensure sterility
throughout the entire process. In addition, while some
secondary CMOs (formulated product producers) are
involved in the development of drug delivery technol-
ogy, many are not, and even fewer are involved in the
development of packaging solutions.
As a result, sponsor companies are looking for CMOs
that have the capability to develop novel drug delivery
and packaging technologies and an awareness of pa-
tient needs and expectations, and can work closely
with the drug development group throughout the devel-
opment cycle to ensure that the best possible solution
Level of patient is developed for the patient.4
non-adherence
The Problem of Poor Patient Adherence
50%
There have been numerous studies in the US highlight-
ing the level of patient non-adherence and its poten-
tial impact on the patients themselves as well as the
prescribed healthcare system in general. For example, it has been
medications found that over 50% of prescribed medications are
are taken taken incorrectly or not at all.6 One- to two-thirds of
incorrectly hospital emissions resulting from drug-related adverse
events are related to poor medication compliance,7 up
to 40% of nursing home admissions can be attributed
to non-adherence,8 and as many as 125,000 deaths per
$200B year in the US alone may be due to non-adherence.7 Giv-
en these statistics, it is not surprising that the financial
consequences are significantover $200 billion annu-
Financial ally, according to a 2013 report by the IMS Institute for
consequences Healthcare Informatics.1
Those numbers dont include non-prescription medi-
cines. They also dont reveal the fact that medication
errors of all kinds typically affect children and seniors
40%
more significantly than other age groups.4 In fact, a re-
cent study of data from the US National Poison Data-
base System revealed that during the period 2002 to
nursing home 2012, 696,937 children under 6 years old experienced
admissions out-of-hospital medication errors, which equates to 1
child every 8 minutes.9 The majority (80%) were liquid
doses, and the causes ranged from inadvertently tak-
ing or being given medication twice, incorrect dose,
125,000
confused unit of measure, to wrong medication taken
or given. Fortunately, most cases were resolved outside
of a healthcare facility (>93%), but 25 children died as a
death per result of the medication error.
year in uS
Taking Patient Preferences Into Account
The idea of patient-centricity is receiving growing at-
tention, and there are many interpretations of its mean-
ing.2 The main idea, however, is that patient preferenc-
es and needs should be considered early on in the drug
development process. One of the primary drivers of this
movement is the increasing access that people have to
medical information and the ability to learn from other
people about their experiences. As a result, patients ac-
tively seek a say in their treatment and are more vocal
about expressing their level of satisfaction.
Both the US Food and Drug Administration (FDA)
and insurance companies have also been pushing for
a more patient-centric approach to drug development.
For instance, the Patient Focused Drug Development
initiative from the FDA is a program that gets patients
involved in the design of clinical trials.10, 11 Insurance
companies, on the other hand, are looking for evi-
dence from patients that the drug products they use
provide value.12
Many factors contribute to that sense of value; ef-
ficacy, safety, minimal side effects, and cost are obvi-
ous issues. There are additional opportunities for drug
manufacturers, however, to address patient expecta-
tions around ease of use, portability, and even level of
comfort taking their medicine in a public location.2 Self-
administered drugs, for example, are often preferred
because trips to the doctors office or hospital can be
eliminated, which saves time and money. However, self-
administered drugs must be easy to use if they are to be
taken correctly, while improving the ease-of-use of such
therapies can help reduce patient non-adherence.
The Dose Matters
One of the problems with many types of medications is
that they are distributed in multi-dose packaging for-
mats. It is interesting to note that in hospitals, which
must distribute many different medications to a large
number of patients every day, medication errors are
reduced through the use of single-dose packaging.
Clear labeling of an accurately pre-measured dose are
the two most notable benefits of single-use doses, but
there are others as well: reduced risk of contamination,
reduced drug waste, and greater ease and convenience
for self-administration.
Packages designed to hold a single dose come in
many shapes and sizes for oral, topical, and injectable
drugs. Blister or pouch packages are widely used for
tablets, capsules, and other oral solid formulations.
Single-dose packaging units for oral liquids include
plastic syringes with rubber tips and squeeze tubes.
Single-dose stick packs are also now available for both
the oral and topical administration of liquids. Typical
unit-dose containers for injectable drugs include pre-
filled syringes and cartridges.
Drug Delivery and Packaging Technologies
Make a Difference
Advanced drug delivery and packaging solutions are,
in fact, receiving significant attention, and growth in
these sectors of the pharmaceutical market is expect-
ed to be quite strong. According to BCC Research, the
global market for advanced drug delivery systems was
$181.9 billion in 2013 and is expected to grow at a com-
pound annual growth rate (CAGR) of 3.2% to $212.8 bil-
lion in 2018.13 The advantages of advanced drug delivery
Americanpharmaceuticalreview.com 15
> Company Profile

Meet Unither Pharmaceuticals + Lifecycle management through the use of

Your one source for formulation support, innovative drug delivery novel single-dose drug delivery technologies
+ Comprehensive analytic development and
technologies, and single-dose, sterile fill-finish services validation services
+ ICH stability testing of clinical batches
Unither Pharmaceuticals is a global leader in the + Over 20 years of experience in drug
+ Multiple patented drug delivery solutions
manufacture of single-unit-dose pharmaceutical formulation, delivery, and filling
+ Facility dedicated to research and development
products using sterile Blow-Fill-Seal, stick pack, + Over 100 products on the market use
and effervescent tablet technologies. Our technology developed by Unither + BFS sterile unit dose presentations from 0.25
mission is to provide innovative, competitive, and to 20 mL with annual production volumes of
+ Flexibility and responsiveness needed for the
sustainable solutions to our customers. We do over 2 billion unit doses
manufacture of orphan drugs
that by combining our extensive expertise in drug + Liquid and suspension stick-pack unit dose
delivery technologies and fill finish operations with + GMP manufacture of batches for clinical trials
presentations from 2.5 to 15 mL with available
our growing understanding of patient needs and + Project support from early development pilot and commercial capacity in Europe
experience in product and process development. through commercial manufacture and the US

systems over traditional systems, according to the mar-
ket research firm, include more convenient routes of
administration, greater efficacy and duration of drug
activity, decreased dosing frequency, improved target-
ing, and reductions in toxic metabolites.14
Focusing on topical drug delivery systems, Micro-
market Monitor estimates that in 2013 the global topi-
cal drug delivery market was valued at $9.44 billion and
predicts it will grow at a CAGR of 3.50% to reach $11.21
billion by 2018.15 Growth in this sector is driven by pat-
ent cliffs, increased incidence of chronic diseases, in-
creasing competition, improving patient compliance,
and huge investments made by key pharmaceutical
companies, according to the market research firm.
Meanwhile, Markets and Markets estimates that the
global pharmaceutical packaging market will grow at a
CAGR of 6.7% from 2013 to 2018, reaching a value of
$78.8 billion.16 This value includes drug delivery sys-
tems that are also considered to be product packag-
ing. This sector of the packaging market is growing at
an even faster CAGR of 9.1% due to increasing demand
for delivery/packaging solutions as many drugs come
off-patent in the coming years, according to the mar-
ket research firm.
The Blow-Fill-Seal Solution
Blow-Fill-Seal (BFS) technology allows the creation and
filling of a variety of plastic containers on one piece
of automated equipment without human intervention.
It is recognized as an advanced aseptic process by
FDA and the European Medicines Agency (EMA) and
involves container molding followed by product filling,
and then hermetic sealing. The areas for both contain-
er molding and filling have minimal exposure to the
environment, and the container is sealed with a sterile
boundary and then sterilized in place.
In addition to increased safety of the aseptic pro-
duction process, BFS offers several other advantages
over conventional glass containers. The plastic res-
ins used in BFS processes are recyclable. In addi-
tion, because plastic is used for the packaging of BFS
drug products, there is no worry about glass shatter-
ing, and concerns about particulates, which have in-
creased in recent years,17 are much less of an issue.18
Furthermore, less energy is typically used in a BFS
process because the three steps are combined and
fully automated compared to conventional container
manufacture, filling, and sealing. Finally, because the
drug product is immediately and hermetically sealed
in the container, there is no need for the use of pre-
Blow-Fill-Seal (BFS)
servatives, which can cause allergic reactions in
some patients.
BFS technology can be used to produce a wide
range of products in various shapes and sizes, and
pre-molded, pre-sterilized inserts, such as sterile tip-
and-caps, rubber stoppers, or multi-entry inserts, can
be added once the container is filled, providing flex-
ibility and increasing the number of options for drug
delivery combined with enhanced sterility.
In fact, BFS is ideally suited for the production of
sterile, single-unit dose liquid products, including
ophthalmic treatments (eye drops), inhalation solu-
tions, topically applied gels, creams and ointments,
and oral liquids. Its use for the packaging and delivery
of biologic drugs, such as monoclonal antibodies, is
also being investigated.18
The Convenience of Stick Packs
Stick packs are a new delivery technology that offers Stick Packs
all of the benefits of single-dose packaging with the
added advantage of excellent barrier properties and
versatility with respect to volume and filling options.

16 American pharmaceutical review Supplement April 2015

 for the administration of drugs that would typically be
Consequently, dosing regimens, administered via intravenous injection. There is much
delivery methods, and product interest in developing technologies for transmucosal

packaging are now being drug delivery.19-21 In recent years, significant progress
has been made in the development of advanced tech-

global market
considered much earlier in the nologies for oral delivery through the buccal and sub-

for pharmaceutical drug development cycle. lingual transmucosal membranes. This path of admin-
istration is attractive because it is relatively painless
packaging and is easier for self-administration and in many clini-
In addition, they can be used for both powders and liq- cal settings.
uids (solutions and suspensions), and gels for oral and The buccal mucosa has a lipophilic epithelial mem-
CAGR
2013 to 2018 topical administration. They are also appropriate for brane that is highly vascular. As a result, lipophilic
molecules are very rapidly absorbed through the buc-

6.7%
drugs that require sterile processing.
Importantly for patients, no special device is re-
quired for delivery. Stick packs are also highly portable
and easy to carry, particularly when compared to con-
ventional bottles of liquids with separate cup dispens-
ers. They are also easy to open and inconspicuousall
features that can help improve patient adherence.
There are benefits for the sponsor company as well.
Security of the supply chain, another major topic of
discussion in the pharmaceutical industry today,
is ensured due to the toughness and durability of
2018
the material used to manufacture the stick-packs.
cal mucosa and then rapidly distributed throughout
the entire body via systemic circulation. This behavior
is very important for several reasons. Rapid absorption
and systemic delivery through the mouth avoids expo-
sure of the drug to harsh stomach acids and the unde-
sired metabolism of the drug in the liver, known as the
first pass effect. As a result, it is often possible to
achieve pharmacodynamic performance comparable
to that obtained with delivery via standard injection at
a much lower dose. In addition, increasing numbers of
drug candidates and new chemical entities (NCEs) are

78.8B As with BFS products, the single-use design of stick

packs can potentially eliminate the need for the use
of preservatives.
lipophilic and thus poorly water soluble, which means
that delivery by conventional means is not possible.
Buccal transmucosal delivery is a very promising new
drug delivery technology that can address this signifi-
Buccal Transmucosal Delivery Systems cant issue while helping to improve patient adherence
for Lipophilic APIs and increase the value that pharmaceutical manufac-
Buccal transmucosal delivery is a noninvasive route turers provide to their patients, payers, and investors. A

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Americanpharmaceuticalreview.com 17