Biomedical Engineering Reference
In-Depth Information
In purification, correlation between material attributes (e.g., buffers and resin proper-
ties), process parameters, and outputs can lead to the development of models that give a
better indication of packing integrity and process performance [26]. Care should be taken
with MVDA approaches to establish a causative relationship between observed trends
and a mechanistic understanding of the process; see also Section 13.5.1.
Finally, a number of software tools to support MVDA and to enable continuous
improvement and knowledge management are becoming available, but equally as impor-
tant, the regulatory mechanisms must be in place to support changes when changes bring
such improvements within established design space. As stated earlier, the regulators are
not planning to develop additional guidance documents but are instead looking to the
industry to develop and implement best practices through consensus processes. We must
continue to look to the groups and professional societies detailed earlier for best practices.
How the tools are deployed is discussed in a later section and in Chapter 12.
13.4 QUALITY BY DESIGN
The traditional approach to biopharmaceutical manufacturing processes has been that the
“process is the product.” This can result in regulatory filings that are descriptive of the
process, starting at the beginning and detailing specific activities at each point, rather like
a recipe or itinerary. Such submissions can be rich in descriptive detail in terms of what is
done at each step of the process, but lack an equally detailed explanation as to why
specific steps were chosen and what impact the chosen process parameters had on
process performance or product quality attributes and how they interact with each other.
The QbD approach however places greater emphasis on final product quality attributes
and is more concerned with the outcome than with the process by which it was arrived at.
A demonstration of product and process understanding is desired. The QbD approach, as
outlined in ICH Q8 (R1) [6], begins with product design (Fig. 13.2). The target product
profile (TPP) is first ascertained, with the primary focus being on safety and efficacy.
Additional attributes that may impact manufacturability, stability, and so on (such as
post-translational modifications, known “problematic” sequences) should also be con-
sidered, see Chapter 2. This is a particularly rich opportunity area for biotechnology
products, since by nature they are considerably more complex than small molecules.
A single modality such as a monoclonal antibody can provide sufficient diversity to
address a multitude of targets as either an agonist or an antagonist, yet still be sufficiently
similar such that common platforms of production and purification approaches can be
used [27]. This allows relevant process information frommultiple projects to be gathered
and compared to enhance process understanding.
Critical quality attributes (CQAs) are then derived from the TPP and are linked to
material attributes and process parameters based on their impact on safety and efficacy,
and a risk assessment is performed as a function of all unit operations andmaterial inputs.
The purpose of the risk assessment is to focus attention on those variables and parameters
which are most likely to have an impact on final product quality, such that an appropriate
level of understanding is developed and appropriate monitoring and control strategies
can be designed and implemented. Additional parameters may be further designated
