Biomedical Engineering Reference
In-Depth Information
formulation development results are representative. Drug product prepared from future
API lots would be expected to perform similarly.
9.6 PREFORMULATION CHARACTERIZATION
The aim of preformulation studies is to characterize the effect of the various formulation
variables on different types of degradation andmodification. The effect of pH on solution
stability is probably the most important factor. In particular, effects of pH should be
evaluated for (i) physical and chemical stability, (ii) thermal stability, and (iii) solubility.
Preformulation studies should be conducted early to understand the relative stability of
the molecule over a wide pH range. Different protein stability challenges are expected at
different pH regions. For example, aggregation and denaturation are usually more
prevalent at acidic pH whereas deamidation and disulfide scrambling are more pro-
nounced near alkaline pH. Solubility is also an important factor, where protein solubility
is usually at a minimum near its isoelectric point. Lower solubility typically leads to
lower physical stability resulting in aggregation and precipitation challenges. As a result,
it is critical to balance between chemical stability, physical stability, thermal stability,
and solubility to identify the optimal pH range for proper dosage formdevelopment. If an
optimal pH region does not exist for a feasible solution formulation, a freeze-dried
formulation needs to be considered. Alternatively, specific excipients can be added to
address specific instability issue and therefore enhance the probability of identifying an
optimal pH region (see below for an example of physical instability). Once the optimal
pH region has been identified, the effect of buffer also needs to be characterized.
Depending on the pH condition, several common buffer types, such as acetate, citrate,
phosphate, Tris, and histidine, should be studied.
Because proteins are folded into a higher order structure for biological activity, they
are commonly susceptible to aggregation as a result of physical stress of shear and
shaking. Physical instability is often a concern and may be more difficult to control than
chemical instability. In particular, a high degree of hydrophobicity can lead to more
susceptibility to physical instability in the presence of additives that impart ionic
strength, such as sodium chloride. A common approach to resolve the physical
instability is through the use of surfactants. Polysorbates 20 and 80 are commonly used
surfactants that are highly effective stabilizers. Different types of agitation studies that
can simulate the potential stress on the protein molecule both during manufacturing
and shipping/storage should be included in the preformulation studies to identify the
need of a surfactant stabilizer and the appropriate concentration to protect against
physical instability. In some cases, the addition of a surfactant stabilizer can also
expand the pH range of acceptable physical stability. Figure 9.3 shows an example of
balancing multiple analytical properties to identify the optimal region of pH. Each arrow
in Fig. 9.3 represents the acceptable pH range for the particular analytical property.
In this particular case, an optimal pH region does not exist that balances chemical
and physical stability properties. However, addition of a surfactant as stabilizer can
effectively expand the acceptable pH region for physical stability, which is shown as the
gray arrow in Fig. 9.3.
