Biomedical Engineering Reference
In-Depth Information
described multivariate tools for design, data acquisition and analysis, process analyzers
and controllers, continuous improvement, and knowledge management tools.
Systematic approaches to pharmaceutical manufacturing may be of benefit even if
they do not use each of these specific tools. Although PAT may allow for greater
flexibility, manufacturing may still be improved in the absence of real-time analysis of
material attributes and without real-time linkage to process control. The term Quality
by Design (QbD) [5, 6] is used to describe a more general approach to systematic
pharmaceutical manufacturing. As described by Dr. Janet Woodcock, the desired state
that drives all these manufacturing initiatives is a maximally efficient, agile, flexible
pharmaceutical manufacturing sector that reliably produces high-quality drug products
without extensive regulatory oversight [7].
Over the last few years, there has been significant progress in moving forward with
these initiatives for small molecules, including a pilot program for QbD submissions [8].
However, biotechnology products are a growing part of the drug development pipeline
[9]. It is important to consider how to approach the “desired state” for more complex
products, such as biotechnology products. The principles of Quality by Design should be
applicable to all pharmaceuticals including biotechnology products [10].
2.2 QUALITY BY DESIGN
Quality by Design is defined as a systematic approach to development that begins with
predefined objectives and emphasizes product and process understanding and process
control based on sound science and quality risk management [11]. Dr. Moheb Nasr has
summarized QbD in a diagram [12] (Fig. 2.1). A systematic approach to pharmaceutical
development should start with the desired clinical performance and then move to product
design.Thedesiredproduct attributes should thendrive theprocessdesign, and theprocess
design should drive the strategies to ensure process performance. This systematic
approach may be iterative and thus the circular design as shown in Fig. 2.1. The inner
circle interactswithmanyother specificmeasures of pharmaceuticalmanufacturing, such
as specifications, critical process parameters, and so on. This QbD circle can be divided
into twomajor semicircles, product knowledge and process understanding. Acritical tool
for enabling QbD manufacturing is a defined way of linking these two semicircles.
The International Conference on Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) has bridged this gap using the
concept of a design space. A design space is the multidimensional combination and
interaction of input variables (e.g., material attributes) and process parameters that have
been demonstrated to provide assurance of quality [3]. This is the scientific definition of a
design space. Design space also has a regulatory definition. Movement within a design
space is not considered as a change that requires regulatory approval. However, change
within a design space does need oversight by the sponsor's quality system. Design space
is proposed by the applicant and is subject to regulatory assessment and approval.
A design space could potentially link process performance to variables such as scale and
equipment. The design space is thus a very flexible tool that links process characteristics
and in-process material attributes to product quality. A recent definition of product
