5 Key Elements of Quality by Design in Pharma
Intentionally integrating quality directly into every manufacturing process
beginning with research and development is desirable and possible. The
outcomes are clearly superior to an after-the-fact testing and control process
that “only detects and removes substandard products,” but “doesn’t prevent
them from being created in the first place.”1
The benefits of embedding quality into every design and manufacturing phase
include:2
- Right-first-time batches.
- Safer, higher quality, optimized products.
-
Built-in
change controls
and
quality assurance. - Consistent compliance.
- Decreased oversight and increased flexibility within a proven design space.
- Shorter lead times and getting to market faster.
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A Regulatory Perspective and Preference for
Quality by Design
Quality flexibility opens the door to many ways of accomplishing this,
however, it’s not a slam dunk. It requires careful analysis and planning at
the beginning with the end in mind. The U.S. Food and Drug Administration
(FDA) and The International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH) emphasize
a more systematic approach known as
Quality by Design (QbD).3
Theoretical Foundations of QbD in Pharmaceuticals
QbD is a precise set of protocols that offers a preemptive and integrative
approach to quality manufacturing built on scientific and mathematical
foundations. QbD in pharmaceuticals stems from the
FDA’s recognition that increased testing does not increase product quality,
and that quality needs to be built into a product.4
Additional data from experiments and statistical analysis required by QbD
upstream is used to establish controlled parameters that can tolerate natural
variance downstream without disruption and slowdowns.
In terms of yielding a quality product, having deep knowledge about the
product and processes from the developmental phase results in better
performance than traditional end-of-the-line testing. It also reduces the need
for post-production interventions, which are riskier, more costly, and
labor-intensive. The underpinnings of this methodology are listed below:5
-
Thoroughly define product and process parameters, materials, and quality
attributes. -
Complete sufficient empirical testing and multivariate statistical analysis
upfront to understand material and process interdependencies. -
Optimize production to tolerate natural variance and mitigate anticipated
risks. - Engage in ongoing post-approval improvement of products and processes.
5 Practical Elements of
QbD in Pharmaceuticals
To qualify for QbD approvals and permissions from regulatory bodies, a
pharmaceutical manufacturer must clearly establish these key elements as part
of their QbD approach:6
-
Quality (QTPP + CQA).
The Quality Target Product
Profile (QTPP) is a summary of the desired quality of the end product,
taking into account safety and efficacy. It includes a list of critical
quality attributes (CQAs) of any output material, such as uniformity,
degradation, size, shape, and color, within an appropriate limit, range, or
distribution. -
Product (CMA).
Deep product understanding is
necessary to determine whether the product can meet patients’ needs and
maintain performance throughout its shelf life. Thorough product
understanding must include all critical material attributes (CMAs) of any
input material within an acceptable limit, range, or distribution to ensure
the desired QTPP. -
Process (CPP).
Deep process understanding must
include the identification of critical process parameters (CPPs), which by
definition have a significant influence on the final product; links between
CMAs, CPPs and CQAs; and a thorough understanding of scale-up principles.
CPPs should be monitored and controlled during production to ensure the
process yields the desired QTPP. -
Control Strategy.
In-process controls are
preferred over traditional end-product testing. A production environment
that operates within statistical control and within material and process
ranges governed by the design space (DS) reduces the need for regulatory
oversight. A
quality management solution
can be used to effectively implement the control strategy. -
Continuous Improvement.
Integrating quality
throughout design and production allows manufacturers to make adjustments to
processes and materials within the DS, even post-approval. Using an
effective quality control solution makes it easier for companies to refine
and redirect in real time and achieve the targeted results outlined in the
QTPP.
How a Quality Management System (QMS) Supports Quality by Design
The objective of QbD is robust production, which
implies predictable, consistent, and optimized outcomes that are risk
resilient even with a known degree of process and material variability. The
successful implementation of
QbD in pharmaceuticals ensures controlled
manufacturing operations and predictable product outcomes that pharmaceutical
manufacturers are seeking. Although this level of quality integration can
initially seem daunting, a purpose-built
pharmaceutical quality management system (QMS)
can help manufacturers overcome these hurdles.
According to Michael Lowenborg of DPT Laboratories, “QbD can be especially
difficult to implement across the board when operations are fragmented, either
geographically or functionally. Even when a
QbD system
is in place, technology and knowledge transfers can be problematic when new
personnel are being introduced without any prior guidance, for example, when a
product is making the transition from development to manufacturing.”7
This takes us full circle … back to the beginning with the end in mind. A
pharmaceutical QMS that offers electronic document management, ensures
training requirements are met, automates configurable workflows, and is
cloud-based can meet these challenges head-on, especially when it is linked to
automated
manufacturing software. Such an enterprise solution can connect processes with products and offer
deep data insights. An integrated solution provides the foundation necessary
for more rigorous empirical study and statistical analysis that
QbD demands, while also facilitating continuous
improvement.
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