Biomedical Engineering Reference
In-Depth Information
to 22, the correlation coefficient dropped below 0.0. Other results, such as those for
methionine, correlate strongly when 11 lots are included, but when 6 or 22 lots are
included, the correlation is less than 0.0. Correlation coefficients for methionine and
aspartate may be prone to type I errors based on the way the result fluctuates.
Four analytical factors have consistently high correlations with cell performance:
Zn, the score froma PLSmodel based on
1
H
NMR spectra, and the intensity of an LC-MS
peak with m/z 279.17. Further discussion will focus on these three tests.
A QbD strategy for raw materials needs a prospective element that can allow
reassessment of the test strategy with time. In the hydrolysate example, results from the
use test influenced which analytical tests were conducted. Tests that showed a strong
correlation to the use test were performed on additional lots while tests that did not
correlate were dropped from future analysis. Understanding the benefits and costs of an
evolvingmodel that gets updated, as more data are available, will helpmove this example
from the realm of a retrospective data mining into a forward looking QbD tool.
Figure 11.6 illustrates how the analytical testing strategy was refined over the
course of this hydrolysate investigation. The left side of Fig. 11.6 shows that several
tests were done early on, including some that did not correlate to performance of the
cells, like AAA. Periodically, results from the analytical test were compared to the
cell-culture outcome to look for correlations with parameters of interest. As new data
became available, the conclusions were updated.
Sample
Sample
Test
Test 1:
All pass
less
information
Test 2:
Some fail
more
information
Edit
test
list
Update
Score
probability
High
Update
Score
probability
Fail
Reject
Use
test
Pass
Use
test
Reject
Accept
Accept
Figure
11.6.
Flow diagram for the analysis of hydrolysates. The diagram to the left shows the
investigation phase, the diagram on the right shows the final form.
