The development of a safe and effective
drug product requires not only high
quality ingredients but also careful selection
of appropriate primary packaging
components as these come directly into
contact with the drug product. Interaction
between primary packaging components
and the drug product may result in failure
to meet the quality target product profile
(QTPP). This can be avoided by relying
on a Quality by Design (QbD) approach.
Component Selection Using QbD
QbD is a systematic approach to development
that begins with predefined objectives
and emphasizes product/process understanding
and process control. This approach
should be based around sound science and
quality risk management (QRM) (1). QbD
can help establish a correlation between the
material attributes of packaging components
and quality of the drug product
during the selection process for packaging
components. The impact of each type of
packaging component can be determined by
monitoring certain quality attributes of the
drug product. Table 1 presents the probable
relationships between material attributes
of packaging components and quality attributes
of the drug product.
Table 1 Effect of primary packaging components on drug product attributes (√=Likely potential
impact; X= Unlikely potential impact)
Figure 1 shows the QbD approach in
detail. The most important step, when
using the QbD approach, is identifying
the Critical Quality Attributes (CQAs) of
the drug product that can be affected by
the material attributes of the packaging.
In most cases, these CQAs consist of pH,
potency, impurities, particulate matter, dissolved
oxygen, leachables, and functional
performance.
Figure1 QbD Approach Chart
After defining the CQAs, the Critical Material
Attributes (CMAs) of the packaging
components must be defined. These attributes
include material of construction,
size of container to fill volume ratio, and
additional treatments, such as sterilization/depyrogenation,
that can impact the
CQA of the drug product.
Once the CMAs have been defined, the
high-risk CMAs of the packaging components
must be identified. These CMAs are
further assessed based on a risk management
approach. Risks can be classified
based on probability and severity.
As an example, a hypothetical packaging
component has the potential to interact
with a drug product in the presence of
light and heat. In this case, the severity is
high. During initial development, data
shows the component is incompatible
with the drug product in the presence of
light and heat. Thus, the probability of
interaction between the drug product and
the packaging component is also high.
Therefore, the risk of using this packaging
component is greater due to high severity
and high probability.
Thorough experimentation/data or
scientific justification should be provided
to lower identified risks. To understand
this step, consider again the hypothetical
packaging component. Since it has been dentified as high risk, the component
needs to be changed or additional controls
on light and heat exposure to the drug
product should be used.
Enter the Design Space
Based on data from
the experiments,
design space should
be established in
order to minimize
variability in drug
product attributes
due to the material
attributes of
packaging components.
As per ICH
Q8 Pharmaceutical
Development, design
space can describe
the relationship
between input variables
(e.g., material
of attributes) and
process parameters
demonstrated to provide assurance of
quality. Working within the design space
is not considered a change. For packaging
components, design space can be generated
by varying materials of construction,
dimensions, processing conditions, oxygen
permeability (in the case of semipermeable
components such as cyclic olefin copolymer
or plastic bags), etc. Design space is
proposed by the applicant and subject to
regulatory assessment and approval.
In the last stage of QbD, a control strategy
must be defined as the set parameters
of specifications for packaging components.
The limits for all critical material
attributes must be defined in the form of
specifications and must be controlled in
batch-to-batch manufacturing.
Conclusion
A QbD approach is a crucial consideration
when selecting primary packaging
components. Material attributes of packaging
components should be considered
to assess the impact on the quality of the
finished product. Hence, QbD is an approach
to mitigating risk associated with
primary packaging and can be emphasized
during the earlier stage of drug product
development.
References
- Guidance for Industry: Q8(R2) Pharmaceutical Development, US Food and Drug Administration,
November 2009
- Pillai, S., et al. “Pharmaceutical Glass Interactions:
A Review of Possibilities.” Journal of Pharmaceutical
Sciences and Research 8 (2016): 103–111.
- Markarian, J. “Plastic Shows Benefits in Parenteral Packaging.” Pharmaceutical Technology (December
19, 2012)
About the Authors
Nrupa Patel is a Product
Development Scientist
at Teligent Pharma Inc.
She has experience in
the development of
sterile injectable liquid and
lyophilized drug products.
Sandip Patel is a Formulation
Development Scientist at
Navinta LLC. He has been
involved in developing
difficult-to-formulate liquid and
lyophilized products for more
than four years.