Retrospection and Introspection at FDA

I have often gotten the impression that FDA's quality-by-design (QbD) initiative remains somewhat mysterious to pharmaceutical manufacturers, even though it's been about seven years since FDA first introduced the concept in its 2004 report, Pharmaceutical Quality for the 21st Century: A Risk-Based Approach. FDA must have had that impression as well because the agency commissioned a study to gauge the industry's rate of adoption of the concept as well as its understanding of it, the results of which FDA officials present in the September 2011 issue of Pharmaceutical Technology. The study findings support anecdotal accounts of industry attitudes towards QbD.

Michelle Hoffman

The report quantifies the degree of adoption among different industry sectors. Not surprisingly, innovator companies (called "New Drug" in the report) have embraced the program most fully. Twenty-two percent of new drug companies are categorized as "fully implemented" in the report, meaning that these companies incorporate QbD principles in almost all of their development programs. These companies also have a "systematic, comprehensive review and redesign of in-line products." In contrast, no generics or biologicals manufacturers fall under the fully implemented category.

At the other end of the spectrum, generic-drug manufacturers appear to be most resistant to the program, with 40% of them being characterized as "novice," which is defined as a company "that is skeptical about the value of QbD," and uses "conventional development practices and has no QbD platforming." In other words, they're non-adopters. Biological manufacturers lie somewhere in the middle, with an impressive 67% venturing tentatively into "pilot" territory, defined as companies trying it out, but uncertainly. These results mirror responses Pharmaceutical Technology obtained in its 2011 Equipment and Machinery Survey (the results of which were published in PharmTech's March 2011 issue), where approximately 58% of innovator companies, and 55% of biotech companies, but only 35% of generic-drug manufacturers reported that QbD had a "high" or "medium" impact on their equipment-purchasing decisions.

The reasons for skepticism cited in the FDA article also mirror what we've heard anecdotally. Quality professionals have a hard time getting management to buy into the concept—what the report referred to as a "disconnect between leadership and middle management." An additional misconception, which the report attempts to squelch—is that QbD is costly to apply.

But there's also great uncertainty within industry, bordering on frustration, about what FDA wants. The report notes—and we've heard this ourselves—that industry perceives internal inconsistencies within FDA as to how the agency assesses a company's QbD efforts. Companies also express some degree of discomfort about talking with FDA at all. And again, I've heard individuals say that FDA might ask people to implement QbD in theory, but gives them a hard time when they try to put it into practice. FDA for its part intends to spend the next five years developing more internal consistency and clarifying expectations both within FDA and the industry.

At its core, the QbD initiative asks manufacturers to understand how variables—temperature, pressure, humidity, for example—govern the behavior of their reagents and their effects on product quality, principles we all learned in our high school science classes when we were first introduced to the experimental method. And that's the most mysterious thing of all. How did a science-based industry manage to unlearn these concepts in the first place?

Michelle Hoffman is the editorial director of BioPharm International.