BioPharm: In implementing QbD, what would you identify as the critical process parameters (CPPs) in a typical upstream bioprocess using
McKnight (Genentech): Among cell-culture parameters, culture pH is typically the most difficult to control relative to its impact on cell-culture
performance and product quality. This is generally the case for both mAbs and other products.
Johanning (QAtor): Common CQAs in an upstream bioprocess (i.e., bio formulation process) using cell-culture include sterility and bioactivity.
Rathore (IIT Delhi): Typical CPPs for a fermentation step would be pH, sparge rate, agitation rate, and temperature. These are typically easy to
control. Issues arise when one goes to volumes greater than 1000 L and when it increasingly becomes more difficult to strip
off the CO2 generated by the cells and in ensuring uniform supply of O2 and other critical nutrients to the cells. Another set of challenges comes from raw materials that are complex and not well
characterized (such as yeastolates) as these can result in significant variation in the CQAs from lot to lot. For mAbs, besides
the afore-mentioned factors, concentration of critical nutrients has been known to affect the glycoxylation pattern of the
product, thereby impacting product efficacy.
Vanden Boom (Hospira): Parameters such as temperature, pH, osmolality, and dissolved oxygen have the potential to impact the CQAs of mAbs and other
mammalian cell-culture derived products. However, with current bioreactor engineering controls, these parameters may be tightly
and confidently controlled within the design space of the manufacturing process permitting these parameters to be downgraded
from a CPP to a key process parameter (or other lower parameter designation used by different drug sponsors).
Weber (CMC Biologics): For an upstream process, the process of expanding the cells is the primary purpose until the culture goes into the production
bioreactor. Because the majority of product produced is in the production bioreactor, the expansion process is considered
to have minimal impact on the final product. Additionally, most products have shown the ability to recover from suboptimal
conditions during expansion without serious product quality impact. Therefore, for a typical upstream process, CPPs are identified
at the production bioreactor stage. CPPs for the production bioreactor may include seed density, temperature, and process
duration. Initial seed density can impact the overall growth profile and viability. Temperature is critical in maintaining
viability and may impact the quality of product being produced by the cells. Process duration will impact the viability of
the culture at harvest, which can be tied to product quality.
Among the most difficult parameters to control in an upstream process is CO2 concentration. The difficulty of controlling this parameter depends on the complexity of the aeration control strategy and
availability of dissolved CO2 probes. Though there can be typically broad ranges of acceptable CO2 during production, very high CO2 concentrations can impact the product quality. A balance needs to be maintained between lowering CO2 and maintaining pH at a set point. Furthermore, these conclusions seem to be supportive of most cell-culture processes, not
just mAb production.