Therapeutic Dose: Wishing Won’t Make It So

A new generation of scientists and engineers will be needed to make PAT and QbD a reality, both within companies and regulatory agencies. Training will be the key.

By Emil Ciurczak, Contributing Editor

“There is nothing more difficult to plan, more doubtful of success,
or more dangerous to manage than the creation of a new system. For the initiator has the enmity of all who profit by preservation
of the old institutions and merely lukewarm defenders
in those who should gain by the new ones.”

—Niccolò Machiavelli, 1527


Listening to Ajaz Hussain at the recent IFPAC meeting reminded me of a question that he asked me just before he left the FDA to join Sandoz. “Why aren’t more companies implementing PAT?” I kept my answer short, but my first thought was that the industry needed an example: for instance, Ajaz at a private company. If only the answer were that simple.

Looking back in history, any significant paradigm shift has required a transformation within the workforce. In the 1960s, when President Kennedy promised a man on the moon, universities responded with upgraded programs and delivered engineers and scientists with the required skills within a few years. Vision, together with a healthy dose of government funding, made the dream come true.

The drug industry is undergoing a paradigm shift with process analytical technologies (PAT) and Quality by Design (QbD). Like the space race, these efforts will require better-trained scientists. However, this time there is little government funding available for these efforts, and no national desire.

Currently, the U.S. FDA is the biggest cheerleader for process change. Ironically, it’s also the biggest barrier. Niccolò Machiavelli’s observation (above) remains as true today as it was over 500 years ago. This is not to imply that there is any malice of forethought involved. It’s quite a bit simpler than all that and rooted in the concepts of inertia and entropy. (As a physical chemist, I know that these concepts can be used to explain any problem.)

Let’s go back to the early 1970s, when I started my pharmaceutical odyssey at Ciba. At the time, I was surprised that the art/science of liquid chromatography was not setting the pharma world afire. When I accosted the head of the USP at a meeting and asked him about this, I was told that the FDA had asked the USP not to include HPLC methods. The Agency didn’t have the resources or training to review NDAs that included LC methods, and rejected them out-of-hand; it also asked that USP hold off including them in the Pharmacopeia for an issue or two (they were published every five years back then).

That’s where entropy and inertia come in. Even if all (enlightened) pharmaceutical companies took my clarion call to heart and tried to hire materials engineers and physical chemists, where would such specialists be found? If there were a clear indication that real jobs were opening up requiring these skills, it would still take between four and eight years for schools to produce sufficient numbers. And that would require clear “need” signals from industry.

Considering the huge profits that have been generated by doing things the old way, few inherently timid CEOs are about to change the way that their businesses are run. Quite a few companies (and definitely more than the publicized number) are investigating PAT and QbD, but, to use a football analogy, they are making the drive to the post-season with the wrong players.

If we knew what the critical parameters were in a process, we would already be measuring them. The fact that we don’t suggests that our traditional staffing falls short.

But it wouldn’t be fair to ask a traditional pharmacist or analytical chemist to suddenly become proficient in physical chemistry. We will need universities to fill their ranks in a timely fashion.

This is where inertia also comes into play at FDA. It took 20 years for the “old guard” in the FDA to adopt HPLC, and it wasn’t re-education, but replacement, that transformed the Agency. New, college-trained chemists, familiar with chromatography, joined the Agency, which then embraced the new concept.

New ideas seldom are accepted by old minds. This is true in industry or in government. We will have PAT and QbD when a new high tide replaces the old-model scientists now in place.

As the current crop of “traditional” formulators and analysts are supplemented with the new physical pharmacists and chemists, and materials engineers, the approach to developing and producing pharmaceuticals will change. FDA and EMEA will also add more young investigators, train more current investigators and a new partnership will develop in the industry.

While I’m not suggesting that we all hold our breaths for this transformation to occur, I think we should also keep in mind something my father told me back in 1962, “Anything worth having is worth waiting for.”

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