PROCESS LIFECYCLE VALIDATION - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 199

TABLE 8.8 Risk Analysis of Mixing Parameters to Design Small-Scale Studies
Factor that may Impact or Effect on Approach for

Impact Mixing Product Quality Study Design

Type of mixing
equipment

1) Filterability decreases with
long exposure to bottom
mounted magnetically
driven mixers,
2) little or no impact with top
mounted mixers or bottom
mounted shaft driver mixer

Develop scale-down model
for both top mounted shaft
driver and bottom mounted
magnetically driven mixers

Power/volume As agitation rate and

power/volume increases,
filterability decreases

Use worst-case power/volume
target for each type of
mixer

Time As mixing time increases,

filterability decreases

Evaluate the impact of
holding up to and past
validated hold time at
temperature range

Temperature As temperature increases,

filterability decreases

Evaluate the impact of
temperature range at
holding up to and past
validated hold time

Product pool As concentration increases,

downstream filterability
decreases

Use pool with highest product
concentration (e.g., diluted
ultra filtration/diafiltration
(UF/DF) pool)

Known vulnerability to
precipitation caused by pH
and temperature changes

Test pools that have a
tendency toward
precipitation

commercial process and must represent a worst-case scenario with respect to
the solution-container and the air-liquid interfaces.
In a traditional hold time study, the solution is held at a desired condition for a
specific duration in triplicate and samples are collected at the beginning and end.
The validated hold time is then established on the basis of the end points meeting
acceptance criteria, such as 5 hours in Figure 8.8. This study does not provide
any information about the behavior of the solution after the maximum time of 5
h; hence, an additional study is required for instances where any time-validated
hold time is exceeded during manufacturing.
In a risk-based hold time study, the impact of hold on process parameters (e.g.,
time, temperature, concentration, etc.) is analyzed to determine the potential effect
on product or solution characteristics. Then the solution is held at a worst-case
condition (e.g., temperature and mixing speed) for an extended period of time
(i.e., beyond 5 h in this example). Samples are taken at various time points
and a maximum hold time without significant change in output characteristics is
considered the maximum validated hold time (Fig. 8.9). Note that the decision