Biomedical Engineering Reference
In-Depth Information
biomolecules. As all these activities are the building blocks of QbD, the concept of QbD
has in fact been practiced for the last few years and has in turn led to the development of
highly efficacious biopharmaceuticals and robust manufacturing processes. The issu-
ance of the ICHQ8 guideline was an attempt to formalize the QbD initiative and to allow
manufacturing flexibility based on the manufacturer's intricate knowledge of the
molecule and the manufacturing process. The concept of obtaining intricate knowledge
of the molecule along with the manufacturing process and the resulting flexibility in
manufacturing, the eventual goal of the QbD initiative, requires an understanding of the
various elements of QbD.
The two key components of QbD are [4]
1. The understanding of the critical quality attributes (CQAs) of a molecule. These
are the attributes of the molecule that could potentially affect its safety and
efficacy profile.
2. The design space of the process defined as the range of process inputs that help
ensure the output of desired product quality.
An overview of these components is discussed further in this chapter and elsewhere
in this topic.
1.2 CRITICAL QUALITY ATTRIBUTES
The starting point of QbD is developing a good understanding of the molecule itself.
Biomolecules are quite heterogeneous due to the various post-translational modifica-
tions that can occur and have been commonly observed. These modifications arise from
the glycosylation, oxidation, deamidation, cleavage of labile sites, aggregation, and
phosphorylation, to name a few. As many of these modifications could impact the safety
and efficacy of the molecule, defining the appropriate CQAs of the molecule is an
important starting point in the development cycle of a biopharmaceutical. Although the
understanding of the CQAs evolves during the life cycle of the product, understanding
the CQAs at an early stage of the development of the molecule is clearly desirable.
Studies conducted during the early research stages of development of a potential
biopharmaceutical may entail evaluating various forms of a particular biomolecule in
animal studies. The outcomes of such studies help “design” a biomolecule with the
desired quality attributes so as to be safe and highly efficacious.
Since the CQAs can impact the safety and clinical efficacy of a molecule, data
gathered in animal studies, toxicological studies, and early human clinical trails become
the starting point for defining the CQAs. On the basis of the safety and efficacy readout of
a clinical trial, one can start to define the product profile of a molecule. The assumption is
that if the CQAs of the molecule are similar to those used in preclinical and clinical trials,
the safety and efficacy will be comparable as well. Furthermore, historical data from
clinical trials of similar molecules can also provide valuable insight into the CQAs.
Evaluation of the in vitro biological activity via bioassays, reflecting the mechanism of
action, can provide a good assessment of how the various product attributes could
