Drug product package systems, such as
vials and prefilled syringes, must provide
a barrier that protects drug product stability
and sterility throughout the entire
shelf life. Manufacturers are required to
demonstrate that systems are capable
of maintaining microbial barrier integrity.
When it comes to biologics, these
products may even require that package
systems maintain integrity in stringent
environmental conditions (such as frozen
or cryogenic environments).
The recent industry trend toward
combination product development and
patient-centered drug delivery has driven
increasingly innovative package design
using a wide selection of new packaging
materials—all this has implications for
testing the integrity of microbial barriers.
In addition, more package systems are
fully integrated with delivery devices. The
package systems not only have to meet
the traditional requirements of protecting
drug product but also need to enable
other system requirements such as proper
device functionality. These new requirements
lead to customized package design
with increased system complexity and, in
many cases, present a high level of technical
risk for maintaining container closure
integrity (CCI). Therefore, CCI testing
plays an increasingly important role in
informing material selection, derisking of
system design and verifying CCI performance.
Upon product filling and sealing, package
systems experience downstream processes,
ranging from device assembling, packaging,
storage, and distribution, all the
way to patient use. These processes may
introduce additional mechanical stresses
and expose the containers to unfavorable
environmental conditions that may affect
CCI. For example, additional mechanical
stress that occurs on a sealing component
during device assembly may affect its seal
quality. Frozen or cryogenic temperatures
during transportation and storage may critically affect sealing capability of
elastomer components. These processrelated
risks to CCI must be assessed and
the potential impact on product sterility
and stability considered. Appropriate CCI
testing should be integrated into process
development studies to detect and control
the risk of temporary or permanent loss of
integrity.
In response to increasing regulatory expectations
and industry needs, the pharmaceutical
industry has witnessed significant
technical advancements in CCI testing
technologies. Advanced technologies, such
as high voltage leak detection (HVLD)
and vacuum decay, have demonstrated
improved detection capabilities compared
to conventional dye and microbial ingress
methods. Many of the technologies have
been used for on-line inspection and/or
drug product stability testing. Even these
advanced technologies, however, have
limitations; there is no “one-size-fits-all”
solution that can be applied to all product–
package configurations and meet all
process development CCI testing needs.
The recently revised USP <1207> Package
Integrity Evaluation—Sterile Products
promotes a risk- and science- based approach
and uses the package integrity
profile database as a tool to ensure CCI
throughout the package design and development,
validation and routine manufacturing
phases. Under this framework,
pharmaceutical and packaging industries
are experimenting with best practices to
de-risk packaging design and verify continued
package integrity throughout the
product lifecycle.
The upcoming new PDA course, “Container
Closure Systems and Integrity
Testing,” scheduled to follow the 2017
PDA Annual Meeting, aims to better equip
the industry with information about
advanced CCI testing technologies as well
as practical business approaches to effectively
detect, mitigate and control package
integrity. First, the course features lectures by industry experts, on-site instrument
demonstrations, and hands-on exercises
for advanced CCI testing techniques. The
combination provides participants with
a unique opportunity to not only learn
the working principles but also personally
experiment with these relatively new technologies
and instruments, including tracer
gas detection (e.g., helium leak detection),
electrical conductivity and capacitance,
vacuum decay leak detection, laser-based
gas headspace analysis, mass extraction
leak testing.
Furthermore, the course introduces a
practical and meaningful risk-based methodology
to construct a package integrity
profile database using appropriate CCI
testing methods. Such an approach starts
with a thorough understanding of the
construction of package materials, system
design and manufacturing processes. The
CCI failure modes and effects associated
with each aspect are identified based on
which type of CCI study is needed. In
most cases, a series of CCI tests must be
applied in concert with product development,
including initial design confirmation,
machinability studies and product
stability testing, to ensure CCI is achieved
and well maintained. The comprehensive
results from these studies establish the
package integrity profile database and
inform CCI control strategy development.
Finally, the course uses case studies and
group discussions to promote active
participation among students, instructors
and industry experts. These open-ended
discussions should provide insight into the
fast-evolving regulatory landscape and novel
applications of CCI testing technologies.
Upon completing the course, participants
will be able to compare and contrast
various CCI testing technologies and
understand their applicability, advantages
and limitations. Through case studies, participants
will become familiar with establishing
a package integrity profile database
using appropriate test methods in support
of new product marketing approval and
commercial CCI control strategy development.
Furthermore, the best practices for
CCI method development and validation
will be discussed.
About the Author
Lei Li currently serves as an engineer
advisor at Delivery and Device R&D, Eli Lilly
and Company. He has nine years of
experience in the pharmaceutical
and medical device industry,
with a focus on developing API
and drug product packaging in
support of clinical development
and product commercialization,
and establishing cold chain
distribution for biologic products.
Learn more about this and other PDA Education courses following the 2017 PDA Annual Meeting.