Understand & Control Product Quality Attributes in Cell Culture

Understand & Control
Product Quality Attributes In Cell Culture

Anli Ouyang,
Bioproduct R&D, Eli Lilly and Company

In preparation for
commercialization of therapeutic protein manufacturing, cell culture process is
developed and characterized to ensure consistent delivery of high quality
protein.  Drug substance and drug product
quality attributes can be impacted by the cell culture process. Two case
studies will be presented to demonstrate how Lilly developed new tools to understand
and control critical quality attributes in cell culture.

In a fusion protein program, a
protein cleavage form was considered as critical quality attribute due to its
lack of potency. This cleavage form cannot be removed by downstream
purification process and presented at relatively large percentage (10%) in drug
substance. It is important to develop a robust cell culture process so that
this product related impurity can be minimized and controlled. Traditional
tools (i.e. protease inhibitors, pH and temperature etc) had limited impact on
this cleavage. However, we found that osmolality and pCO₂ controlswere important to reduce this impurity in drug substance. With
implementation of the new control strategy, the cleavage level reduced by 50%
and was successfully scaled-up.

For the second case study, , we
will share our observations that cell culture process changes had a significant
impact on high protein concentration (> 100 mg/ml) drug products stability
profiles in several molecules. HMW aggregates growth rate in drug product increased
significantly after the cell culture medium change though aggregates level in
drug substance were similar.  Lilly
developed a surrogate assay for drug substance as an indicator to aggregates on
drug product stability. By using this surrogate assay, a large number of cell
culture factors were screened and a few levers (i.e. media components and
process conditions) in cell culture were identified to impact drug product aggregates
growth, which were later confirmed in real time stability studies.