The International Foundation Process Analytical Chemistry (IFPAC) completed the first day of their 22nd International Forum on Process Analytical Technology covering a full cross-section of subjects focused on the application of Process Analytical Technology to QbD. Leading the Plenary lectures was Dr. Janet Woodcock, Deputy Commissioner, FDA on the subject of the FDA’s Critical Path Initiative.
Woodcock provided new, sobering statistics on the state of today’s pharmaceutical industry including:
- Mergers and acquisitions have decreased the number of new drug candidates because post-merger, similar candidates are dropped.
- New compounds entering Phase I clinical trials have only an 8% chance of reaching the market versus a 14% chance 15 years ago.
- More worrisome is the fact, even after significant investment and “sunk costs,” the Phase III failure rate is now 50% versus 20% a decade ago.
- Costs continue to escalate and companies are less willing and able to bring new candidates forward.
- Today 65% of all prescriptions are generics and there are tremendous challenges in getting them to market and ensuring that they are truly equivalent to brand-name drugs.
- Although there has been huge private and public investment in basic research and specific product development, there has only been minor investment in tools and public standards to aid development.
Woodcock indicated that in 2004, the FDA concluded that “…basic research isn’t enough. We have to look at the critical path that a product must follow before it is introduced to market...The science required to evaluate new product safety and efficacy and to enable manufacture is different from basic discovery science.” The outgrowth of that effort was the Critical Path concept, with quality-by-design as a core feature.
Woodcock made a number of suggestions for insuring the success of the Critical Path concept including:
- We need to build a generalized knowledge base of manufacturing science.
- Industry needs to share their existing knowledge and databases. This information should not stay within the walls of one organization, but must be shared to develop generalized knowledge.
- Sharing will be required in order to develop public standards that will enable evolution of the field for everyone to use.
Woodcock explained, the 21st Century GMPs document was a prototype for the larger Critical Path Initiative. “We are accelerating the pace of introduction of new science and technology,” she said. “PAT was the poster child. It may be a small piece of the picture, but is emblematic of the problems facing the industry.” She added, “We want to move from empirically derived trial and error methods (e.g., formulation, excipient selection) to rigorous, mechanistically based and statistically run processes. We need to break down silos between R&D and production and to be less conservative.”
She noted that the challenge of linking product attributes to clinical outcomes continues. There remains “a disconnect” between clinical and manufacturing sides, Woodcock said, adding, “We still don’t know how the attributes that you measure and control for pharmaceuticals actually control the clinical performance, or the extent to which manufacturing failures adversely affect clinical outcomes.”
Today, the drug safety debate is centered on intrinsic safety problems inherent to the drug itself, rather than errors in manufacturing. However, Woodcock said that suboptimal formulations occasionally get to market and fail to improve over time. She noted that “…for science-based manufacturing, you need to have a better idea of how parameters impact clinical performance and to exercise tighter controls.”