Pharmaceutical Commerce - November/December 2016 - 24


Manufacturing & Packaging
Active packaging protects oral solid formulations
New technologies offer improved shelf life for moisture- and oxygen-sensitive oral solids
By Craig Voellmicke, CSP Technologies, Inc.

Fig. 2. The Activ-Blister technology addresses offgassing in
the headspace of a blister package. Credit: CSP

The age-old argument: bottles vs. blisters
Bottles and blisters are, of course, the OSD package
options of choice, with each facing its own headspace
management challenges. These challenges stem from the
headspace at the time of production, as well as ingress over
time and in various, often widely differing, environmental
conditions. While bottles have long dominated the US market
(not the case in the EU), there is growing demand for blisters,
from both existing and new drugs, driven by both consumer
preferences and regulatory requirements. However, this is
creating headspace management issues that have limited

HDPE Bottle

Cold Form Foil

% Impurities

Despite advancements in, and
the proliferation of, other drug delivery
platforms, oral solid dose (OSD) drug
delivery-a category that comprises
both capsules and tablets-remains the
most popular delivery method in use
today. In fact, six out of the 10 most
widely prescribed pharmaceuticals
are OSD. Reinforcing this continued dominance, the US
FDA Center for Drug Evaluation and Research's (CDER)
annual list of novel drugs, indicates that 24 of 45 such
innovative new products approved in 2015 are OSDs. This
market predominance is predicted to continue, even with
the emergence of new delivery options such as transdermal
applications.
The expansion is predicated, in part, by expanding
OSD technologies such as semi-solid and powder-blend,
which enable more challenging and potent APIs as well
as modified release specifications, such as sustained and
controlled release. Oral disintegrating tablets are yet
another technology that is driving OSD growth. However,
innovation often has complications: these new valuable,
highly specialized technologies can-perhaps even more
so than traditional capsules and tablets-result in products
that face significant stability challenges, especially from
moisture, oxygen, hydrocarbons and other gases, or a
combination of these. Among other unfortunate aspects,
this instability can also come from reactive impurities, such
as formaldehyde and formic acid, which
has been implicated in the degradation of drug products and
also cross-linking in gelatin capsules.
These advanced delivery technologies have created
the need for new and specialized active packaging
solutions that adequately address the formidable stability
challenges that have arisen simply through the march of
pharmacological progress. Market demand is growing for
solutions that not only protect products from unwanted
moisture and oxygen ingress, but also proactively remove
moisture and gases within the package headspace as well
as reactive impurities and off-gassing from increasingly
sophisticated-and, correspondingly, costly and valuable-
OSD products.

PCTFE Thermo Form with
ACTIV-BLISTER ™ Technology
(Molecular Sieve Desiccant)

Time in months
Fig. 1. Comparing impurity levels in (left) HDPE bottle; (center) cold-form foil; (right) CSP Activ-Blister with PCTFE
thermoform and molecular sieve desiccant. Data and graphic courtesy Tekni-Plex

solutions.
Since they offer individual unit-dose compartments,
blisters are preferable for situations where safety and patient
compliance are of paramount concern. Blisters offer patients
easy verification and indication that a dose has been taken,
and also offer ease of portability. In addition, blisters typically
feature tamper evidence superior to bottles and, by removing
the need for a bulk container, they eliminate the traceability
gap by providing improved track and tracing in pharmacy,
hospital and research (i.e., clinical trial) settings.
Reduced possibility of accidental misuse is another check
in the pro-blisters column, as is superior adaptability of the
unit dose for clinical trial needs, which often include the need
for expanded label content, high visibility, and built-in track
and trace features. Each of these factors and more showcases
why, when compared to bottles overall, blister packaging best
addresses regulatory concerns pertaining to supply chain
security, clinical trial reliability and hospital traceability.
Since each dose is housed in an individual package until
its use, there is an inherent advantage compared with bottles.
Still, challenges exist. Most relevant to the topic at hand is
a question that is seen as an obstacle to using blisters: How
can blisters offer effective and efficient product protection
from oxygen, moisture and off-gassing? This is particularly
important in extreme climates, such as Climate Zones III
(hot and dry) and IV (hot and humid).
Blister packaging's headspace challenge
Despite the larger amount of headspace, bottles have a
simpler solve than blisters for headspace management. Unlike
blisters, bottles can easily incorporate sachets and canisters
to provide desiccant and/or scavenger capabilities; adding
barrier technology to the actual bottle material can further
mitigate degradation. Advanced protection solutions for
blisters, outside of barrier technology, are less apparent, are
often non-standard, impact product and supply chain costs,
and can add steps to the customer experience.
Although the headspace within individual blisters may
be small, it is nonetheless more than enough to significantly
impact shelf life. In order to reduce ingress, aluminum foils
and high barrier thermoforms are used, but headspace
moisture, gases and impurities can persist.
Nitrogen purge is a popular headspace management
option but can be difficult to validate, requires additional
monitoring in production, and does not protect against offgassing. In addition, since it does not protect against ingress,
it must be paired with high barrier materials. Secondary
(so-called "tropical") packaging comprising sachets and

24 Visit our website at www.PharmaceuticalCommerce.com November | December 2016

fishbone designs with desiccant pucks are active solutions
that address the shortcomings of purging but add size and
complexity to the packaging, which in turn adds production
and shipping costs. Similar to purging, tropical packaging
does not protect against off-gassing.
And here lies blister packaging's desiccant and scavenge
challenge: How can blister applications address headspace
management efficiently and effectively to enable the growing
customer and regulatory demand for this application?
Get smart (packaging)
Smart packaging can be divided into two distinct areas:
active packaging, which provides proactive functions
such as moisture and oxygen absorption; and intelligent
packaging, which communicates product changes and other
information. The latter communicates something, while the
former actually does something.
For the purposes of this article, let's limit our discussion
to those situations requiring active packaging-specifically,
when pharma products need more than just protection and
instead require the proactive removal of moisture, oxygen,
hydrocarbons and reactive impurities such as formaldehyde,
etc.
This past year saw the introduction of a promising
packaging solution offering a novel approach to headspace
management for protecting sensitive OSD pharmaceuticals
from moisture, oxygen and other gases, as well as impurities
from the capsules and tablets, themselves. Branded as
Activ-Blister solutions, the innovation controls the internal
atmosphere of each blister cavity, allowing for better product
performance and shelf life, without the use of purging
or secondary packaging. The patented and proprietary
technology provides desiccant and scavenging capabilities to
traditional and existing blistering films and designs.
Specifically, an extruded polymer a mere 0.3 millimeters
thick, die-cut to fit within any blister shape and size, is
adhered to the blister's lidding via heat-staking just prior to
sealing, sitting beneath the capsule or tablet and completely
within the sealed space of the individual blister. The process
uses no adhesives, which themselves could generate the sort
of additives the technology seeks to remove; adhesive cost
also is avoided.
This type of active blistering can be made suitable for
any OSD packaged on thermoform-fill-seal and fill-seal
equipment; it is also compatible with child-resistant and
cold-form designs. Using silica gel or molecular sieve (two
substances widely used for their scavenging properties)
continued on page 26


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