Formulation of biopharmaceuticals poses numerous challenges related to the chemical and physical properties of drugs, and the fact that nearly all such products are injected.
Formulation development is a “big piece of the drug development puzzle,” says M. Byron Kneller, Ph.D., associate director for analytical and formulation development at contract manufacturer and development firm CMC Biologics. The company specializes in early- and production-stage formulation development, not only for its manufacturing clients but also through standalone contract work.
Most of CMC’s customers are early-stage developers of biotherapeutics preparing for their first clinical cGMP batches. With such “young” projects, the key hurdles are logistical.
“Our main challenges are acquiring enough material to conduct all the formulation and stability studies,” notes Dr. Kneller. Material demand is particularly high for studies on highly concentrated protein drugs.
In many instances, when customers ask CMC to redesign the process from the cell line up, there is no material at all to work with. Formulation development may even stall until CMC’s manufacturing team can prepare sufficient material and work out upstream and downstream steps.
A related issue involves the stage at which defining formulation studies occur. “We try to do as much as we can early in development, but we attempt to save our pivotal studies for the end, when we have lots of material and the process is more or less locked. The final material we use should be representative of the drug substance produced during Phase III and beyond,” explains Dr. Kneller.
Even when material is scarce, or not representative of the final process output, it is possible to perform stress-degrading studies and to obtain some idea of factors that promote stability, and those that don’t. “For some molecules it might be oxidation, for others pH or heat,” continues Dr. Kneller. Such “preformulation” studies also help identify suitable analytical methods, and even guide downstream processing.
CMC has employed high-throughput and design-of-experiment approaches to obtain the most data, in timely fashion, from the smallest quantity of material. This strategy applies to liquid formulation as well as lyophilization.
Recent articles in GEN have highlighted the power of design-of-experiment and high-throughput approaches to formulation development. CMC is capable of conducting formulation development in that manner.
But because of development time constraints, the final formulation may not have been thoroughly and systematically optimized for that particular protein. “Sometimes customers only have time for a formulation that is good enough, that is suitable for clinical testing” admits Dr. Kneller. “They want a formulation that will serve them in Phases I and II, but in many cases it’s perfectly fine beyond that as well.”