Quality by Enforcement

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-09-02-2009, Volume 33, Issue 9

After years of promomting QbD concepts, FDA's ready to take action on nonconformers.

"Pfizer drank the [quality-by-design] Kool-Aid," commented Gerry Migliaccio, Pfizer's vice-president of quality, in his keynote address at PharmTech's annual conference last month, and then he wondered aloud why some other companies hadn't done the same. Which got me thinking that now, several years after the US Food and Drug Administration launched the initiative—how many companies actually are implementing quality-by-design (QbD) principles, and why or why not?

Michelle Hoffman

We've conducted a few surveys during the past year that address aspects of that question. For example, nearly 60% of respondents to our December 2008 Innovation Survey reported that either they work on projects directly or for companies that have implemented projects incorporating QbD. More recently, about 70% of respondents to our July 2009 Bioprocessing Survey reported incorporating QbD into their processes. About 50% of those not incorporating QbD into their bioprocesses anticipated that QbD would provide no process advantage—which runs contrary to the experiences of those who do. Eighty-one percent said that the use of process analytical technology (PAT)—an important component of the QbD paradigm—resulted in better process understanding. Almost 70% credited PAT implementation with improving their manufacturing efficiency, and an additional 47% percent felt they'd improved their regulatory compliance (multiple answers were allowed, so the total exceeds 100%).

Of those who do not incorporate QbD principles into their bioprocesses, almost 40% said they did not understand the initiative, and almost an equal number felt they lacked appropriate direction from the regulatory agencies. Which brings me to my next point—the role of the regulatory agencies in QbD, FDA in particular.


Participants at the PharmTech conference pointed out that although QbD is not technically mandatory, there seems to be an expectation to implement QbD. This expectation may soon be more than just a feeling among industry as FDA ramps us its vigilance and enforcement.

In an August 6 address to the Food and Drug Law Institute, FDA Commissioner Margaret Hamburg threw down the gauntlet. After listing a litany of attributes of a strong FDA, Dr. Hamburg declared, "And a strong FDA enforces the law," according to a transcript of her remarks posted on the FDA website. The sentence was highlighted in boldface type.

She went on to say that although she was impressed with the commitment that many companies have made to compliance "both in terms of their corporate culture and their investment in compliance systems," FDA's goal is for "all companies to make and implement such a commitment." A key part of this strategy, Dr. Hamburg said, is to support private-sector compliance through "effective enforcement against violations of the law."

Under the new regime, FDA expects "companies will work quickly and thoroughly [to] correct deficiencies and ensure safety." How quickly? The timeline to demonstrate corrections seems to be very short indeed. Noting that "serious violations have gone unaddressed for far too long," Dr. Hamburg challenged industry to deliver a "prompt response," stating that a firm will "generally have no more than 15 working days in which to respond before the FDA moves ahead with a Warning Letter or enforcement action." Furthermore, Dr. Hamburg promised that Warning Letters would be issued with greater speed than before and that "FDA will no loner issue multiple Warning Letters to noncompliant firms before taking enforcement action."

In fact, in the most egregious violations, the agency is prepared to consider "immediate action—even before we have issued a formal Warning Letter," said Dr. Hamburg. She ended her speech by saying, "The solution is a commitment to compliance backed by a strong compliance program. Now is a good time to reassess whether you have such an effort in place."

I strongly suspect she was talking to the 30% or so of companies not implementing QbD. Because what does that paradigm allow a company to do after all, but to understand its manufacturing processes in such detail that when a product or process does fall out of compliance, the company can address the deficiency and correct it swiftly, say within 15 working days? It's interesting to note that about 50% of respondents to our March 2009 Equipment and Machinery Survey purchase new equipment to remain GMP-compliant. This is an industry motivated most by Federal mandates. So, although FDA may not mandate QbD, it certainly seems that companies practicing it will be in a better position to respond to FDA's increased vigilance and enforcement stance. In other words, I think many more pharmaceutical companies will be serving up Kool-Aid very soon.

Michelle Hoffman is editor-in-chief of Pharmaceutical Technology. Send your thoughts and story ideas to mhoffman@advanstar.com