I have been following a number of strings on LinkedIn about PAT and QbD where many doubts are expressed as to the application (and success) of PAT and QbD. Listening to some of the (often uninformed) comments by contributors, I am reminded of a famous quote from “Princess Bride” by the prophet, Inigo Montoya: “You keep using that word; I do not think it means what you think it means.” They seem to be totally misunderstanding what PAT and QbD are.
In addition, many more have taken baby-steps thinking that is “good enough.” There is no immediate apparent ROI (return on investment), so the comments include, “why waste so much money for so little profit.” The calculation of “immediate” payback is specious, at best, in many cases. I compare the estimates with trying to prove that fire insurance is a waste of money, because the house didn’t burn. It is difficult to estimate how much was saved on (potential) recalls, when there were no recalls to analyze. All too often, the “bean-counters” need to see an increase in the income and seldom consider the reduction in COGS (cost of goods sold).
Nonetheless, the old guard is fighting a losing battle; they are the “Neigh-Sayers” (sorry about that), who like the supporters of horses, are defending the status quo against the “new-fangled” horseless carriages appearing on the streets. The arguments are that they are noisy, smoky, break down a lot, unfamiliar, confusing and, worst of all, new. And, in many cases, they were correct; the early cars were nowhere near perfect and neither were the first PAT instruments.
While we all like to think that we are all open to new ideas, even people of science tend to stick to that which they are familiar. [“Science advances one death at a time.” - Max Planck] Only as new people enter the fray are massive changes made. My favorite example has always been HPLC: including it in a NDA in 1970 meant automatic rejection, now, it is almost the only analytical method used in Pharma. Why? All the new people entering the industry were exposed to it in school, so it seemed natural to use routinely.
The big difference in the case of PAT/QbD is that we don’t need 40 years to move from a “no HPLC/all HPLC” condition; economic forces will “encourage” companies to lower the COGS. Economic Darwinism will prove effective in willowing the “horse-lovers.” However, in a movement that parallels the rapid increase in development of computers and data storage (tape to disks to CDs to solid-state to…?), well before the majority of Pharma companies adopt the 10-year-old model of PAT, a number of companies are jumping over the intermediates and going to the latest Mustang GT… continuous processing.
A number of companies (Vertex, GSK and Merck, to name a few) are moving to continuous processing, jumping well beyond the (now) conventional PAT approach. Why? As good as PAT may be, too many people get hung up on the “Analytical” part of the title and overlook the “understanding” and “control”; the PAT Guidance encourages continuous improvements.
The smaller batches inherent in continuous processing immediately show many financial benefits:
• With smaller “lots,” design of experiments is FAR less expensive (as much as 90% less API needed for a regimen) and may be completed in days, not weeks.
• Since the size of the production lots are the same as development lots, there is no scale-up time needed (estimated at between 12-18 months; 6-8% of patent time, based on a 17-year patent life).
• The production hardware and instruments used will be less costly, since fewer of each will be needed in any one production plant.
• Then there is the physical plant: smaller production facilities (smaller buildings, lower HVAC, electric, etc.) and fewer warehouses… less lab space and chemicals, too.
Thus, many of the complaints about (what is currently called PAT) will be addressed and the 2004 Guidance’s dream will be fulfilled. So, while many are still bringing apples to work for their horses and denying that the Earth is round, the rest of us will embrace the 21st century. (To quote a button I have, “The meek will inherit the Earth; the rest of us will go into space.”)