BioPharm: Can you discuss the concept of manufacturability as it applies to a biological product? When developing a cell-culture process,
what parameters should a developer be considering to ensure manufacturability?
Ng: The end goal of cell culture process development is a robust manufacturing process that generates quality products through
the cultivation of cells to meet the market demand. The keywords in that statement are 'quality products' and 'market demand,'
and there are multiple ways to deliver the end goal. Nevertheless, considerations for manufacturability should be heavily
assessed during process development. The concept of manufacturability will ensure that the process being developed can in
fact be safely and appropriately applied in a large-scale manufacturing facility.
A developer should always keep the process simple and consider the operational limitations and equipment required or involved
in large-scale manufacturing. Facility fit is a key aspect in manufacturability. A process should be developed with the final
state in mind and the developer should also be prepared for the expected differences in large-scale manufacturing. Those differences
may include osmolality, pCO2 level, some metabolite levels, shear level, and hydrodynamics across scales. Another factor to consider is the availability
of GMP-grade raw materials for culture media additives. Any of these expected differences should be properly assessed, documented,
BioPharm: What advice would you offer to someone who is starting out in cell culture process development?
Ng: The cell-culture process is a fairly complex process that includes several activities and development constraints from the
business and regulatory sides, as well as timeline considerations. Consideration for process safety should always be the top
priority. One piece of advice I have for a process developer is to know the end point and know the development system well.
Among the end points are target yield, desired product quality attributes, timeline, business, or regulatory needs. The development
system will include not only the upstream process development, but also downstream, analytical, as well as formulation development.
The developer needs to use reasonable risk assessment tools that are scientifically based to guide the development process
and decision making. Last but not least, a developer should consider the extended effect of the process as far forward as
possible and as early as possible during development. Remember that each process is unique with its own requirements as well
Robin Ng, PhD is a senior bioengineer in process development at Shire Pharmaceuticals in Lexington, MA.