(IMAGE: GREGOR SCHUSTER/PHOTOGRAPHER'S CHOICE RF/GETTY IMAGES)
|
Platform technology is becoming a popular industry approach for bioprocessing, but just how are companies using it? Pharmaceutical Technology talked to industry experts to gain insight: Morrey Atkinson, PhD, CSO and vice-president of R&D and Drug-Substance Manufacturing
at Cook Pharmica; Peter Moesta, PhD, senior vice-president of Biologics Manufacturing and Process Development at Bristol-Myers
Squibb; and Jim Powell, business development manager at Ashai Kasei Bioprocess.
PharmTech:
How might platform technologies be applied to upstream and downstream processes? Is one easier than the other?
Atkinson (Cook):
It is not easier to develop platforms for either upstream or downstream, it is just different. The main difference in developing
platform processes for either is that, in most cases, one develops upstream processes for the cell line and the expression
system, while downstream processes are tailored to the molecule itself. If the molecules are of a similar type, then the downstream
process becomes easy to develop.
In terms of difficulty, the cell lines and expression systems are inherently variable, and clone-to-clone variability adds
to the complexity. Scale factors are also more difficult to control in cell culture and fermentation. In general, upstream
therefore probably poses a slightly greater challenge, assuming that the molecules are in a given class or category.
Moesta (Bristol-Myers):
With today's level of know-how in molecular biology and expression, platform technologies are easier to develop for upstream
processes. Identification of a preferred strain or cell line for microbial or mammalian expression, combined with a well-developed
expression vector, is the first step in establishing a production platform. This step allows for the use of standardized fermentation
or cell-culture conditions requiring limited media and feed optimization. The use of platform expression systems and upstream
conditions allow for the generation of significant process experience and forms the basis for developing downstream platforms
to the extent possible.
It is easiest to develop a standardized process for initial downstream steps (e.g., centrifugation and depth filtration for
cell-culture products). For monoclonal antibodies (mAbs), where the Fc protein domain–Protein A interaction can be exploited
to capture the protein from clarified cell-culture broths, additional platform steps are possible (e.g., Protein A-based
affinity chromatography and viral inactivation and filtration steps). The final purification steps (i.e., polishing) need
to be tailored to the particular antibody at hand and usually require individual optimization. For other proteins, downstream
processing becomes less amenable to the platform approach. Individual process steps can be standardized, but will need to
be pieced together and optimized on a case-by-case basis.
BMS is developing molecules to which we apply platform-based approaches, including antibodies and adnectins. But even when
dealing with well-defined classes of proteins, key challenges for establishing production platforms result from unique properties
of individual proteins, such as charge heterogeneity, differences caused by post-translational modifications, and stability.
These unique properties can impact both the cell's ability to express a correctly folded and stable protein as well as purification
of a homogeneous drug substance.
PharmTech:
Could a platform for purification accommodate variations between mAbs? Is it possible to develop a purification platform
for various classes of products (e.g., mAbs and enzyme products)?
Atkinson (Cook):
Platform purification processes must deal with both process- and product-related impurities. With antibody processes, the
process-related impurities tend to dominate the development of the platform. Removal of host cell proteins (HCP), in particular,
is usually a primary driver.
For the product-related impurities, most antibody processes are usually dominated by the removal of higher-molecular weight
aggregates, followed by clipped forms and other charge variants. This is why so many platforms use an affinity step, followed
by some combination of ion-exchange and/or mixed-mode separation.
