Biomedical Engineering Reference
In-Depth Information
Prior knowledge,
scientific insight
Impact on
Stability
F/T behavior
processability
E&L
safety of
excipients
etc.
Excipient
space
Quality
attributes
Formulation
Safety and efficacy
Figure
10.1. Application of the QbD concept to formulation development.
of this heterogeneity. A well-designed formulation is, therefore, key to controlling
final product variability and ensuring an active product over the entire shelf life.
A rational process of developing a formulation is summarized in Fig. 10.1 and fits
the tenets of QbD as well as ICH Q8. The excipient space represents the choice of
excipients the formulator has available. This excipient space, combined with prior
knowledge as well scientific insight gained from preformulation (hot spot analysis,
pH-stability profile, etc.) and biophysical characterization studies (such as CD, DSC, and
fluorescence), allows the formulator to design appropriate formulation development
studies. These studies screen the test formulations through “filters” such as storage
stability, freeze/thaw behavior, processability, safety of excipients at dosed levels,
extractables, leachables, and so on. The objective is to select formulation(s) that are
“optimal” with respect to the quality attributes of the biologic.
Similarly, an illustration of the QbD process to an aseptic fill/finish has been
exemplified in Fig. 10.2. A successful and robust fill/finish operation will incorporate
process parameters as well as material quality attributes into the analysis. An assessment
of the impact of these on the process performance and product quality can be performed.
This will lead to the identification of those process parameters and material quality
attributes that may require further studies to develop the relationship to process
performance and product quality attributes.
Usually, when discussing QbD or design space, the discussion automatically
shifts to process variability. For a biologic, the drug product manufacturing operation
itself tends to be simple and is generally considered not to have an impact on product
quality. However, a systematic and comprehensive risk assessment of the product and
the process allows for the identification of areas where further experimentation will
lead to improved process and product knowledge. The quality of the product is a
consequence of the process as well as the formulation—a holistic approach is
required. This chapter provides an example of the risk assessment process and
presents some case studies on how this analysis can lead to the development of
design space for both formulation and process.
