Biomedical Engineering Reference
In-Depth Information
TABL E 9.2. An Example Summary of Forced Degradation Results
Mode of Forced Degradation
Summary of Results
Temperature
Variable region
Significant effect on oxidation
Constant region
Significant effect on deamidation and oxidation
Moderate effect on soluble aggregate formation
pH
Acidic pH
Significant effect on soluble aggregate formation
Alkaline pH
Significant effect on deamidation in constant region
Trace metals, peroxide,
Variable region
and light
Significant effect on cleavage and oxidation
Constant region
Significant effect on oxidation
Moderate effect on soluble aggregate formation
Headspace
No significant effect on stability properties
understanding of stability properties and are used to aid in the optimization and selection
of the solution formulation.
9.5 ACTIVE PHARMACEUTICAL INGREDIENT (API)
CRITICAL PROPERTIES
A critical prerequisite for developing a stable solution formulation is to understand the
critical properties of the API. Upstream cell culture and/or other processing steps may
generate a variety of chemical modifications. The stability growth potential of these
modifications could cause significant solution instability that cannot be easily corrected
during formulation development. In particular, there could be large lot-to-lot variability
of these chemically modified forms during API process development. If this is discov-
ered early in development, significant purification efforts should be devoted to focus on
the removal and/or proper control of these chemically modified forms during API
process development. Therefore, it is critical to assess solution stability of multiple API
lots with an aim to establish a correlation between API process and subsequent
formulation development studies and drug product stability properties. Short-term
accelerated stability study should be conducted on multiple lots of API to assess and
benchmark critical solution stability properties during formulation development and
optimization. In particular, it is extremely useful to establish a correlation between
the timing of API lot history and the various formulation development studies, such as
forced degradation, preformulation, formulation design of experiment (DOE), and
prototype stability studies. As a result, the risk of potentially significant lot-to-lot
variability of API critical properties is minimized and provides some assurance that
