Therapeutic Dose: Who's on First?

When it comes to QbD, we keep using that word, but does it mean what we think it means?

By Emil W. Ciurczak, Contributing Editor

I have been following a number of conversations on LinkedIn that are driving me to imbibe large amounts of adult beverages. The number of people who disagree on what various terms mean is astounding. For example, we all think we know what PAT means, no? Apparently, no. Having been in on the meetings leading up to the PAT (Process Analytical Technology) Guidance, I thought I knew what PAT meant.

To read the columns, I have seen comments range from, “We don’t need any new instruments to do PAT,” to “the instruments are PAT.” The arguments seem to center around the hardware and, some of the more enlightened comments, on the software. What is lost is the reason for the measurements. Many seem to think that simply placing something electronic, somewhere in a process, is PAT!

Perhaps the PAT mission statement wasn’t clear enough: “This guidance is intended to describe a regulatory framework that will encourage the voluntary development and implementation of innovative pharmaceutical development, manufacturing, and quality assurance.” OK, so let’s look at the key terms (using Wikipedia):

  1. Voluntary: referring to a choice being made of a person's free will, as opposed to being made as the result of coercion or duress (or force of law)
  2. Development: (when combined with research) work aiming to increase knowledge
  3. Innovative, from Innovation: the creation of better or more effective products, processes, services, technologies, or ideas that are accepted by markets, governments, and society

Voluntary isn’t that hard a concept to accept. In the future, the concept of PAT may be forced on companies by economic necessities and competition, but for now, it is not mandatory. Development is a little more involved, I suppose. However, “increasing knowledge” sounds pretty clear to me; after all, the Guidance does not say “to make the FDA happy” or “simply substitute one method with another” or “just stick a probe in the kettle and see what happens.” Increasing knowledge implies learning and, since we have been doing the same things for decades and haven’t seemed to learn much about controlling the process, perhaps it’s time for something different?

Now, “innovative” seems to be a major sticking point. There are those who argue that making the same measurements at the same points of a line with different instruments is innovation. Well, it is different. Does the “new” measurement give us data or knowledge? Numbers such as pH, relative humidity, and the like are, indeed, data, but useless unless they allow us to understand and control a process...then, they are information.
Now for the really interesting part: what does QbD mean? This is where the game of 3-D chess (as played on Star Trek) begins to appear simple. On LinkedIn, many of our peers and coworkers state, “We design our drugs now” or “GMP is the same thing.”

The most interesting comment was, “We use QbD to design our products, so we don’t need PAT to control them.” That is similar (to quote Ali Afnan) to “knowing” the way to your job, but driving there with your eyes closed.

And the Design Space? According to many bloggers, we already have that, in the form of the control numbers we use to produce a product. Of course, those have been based on “hut-and-peck” and tradition, but some insist that having them constitutes “designing” the parameters.

OK, some people will allow that we have to control the process and maybe have some type of feedback, but don’t think it is worthwhile to characterize the raw materials or their interactions. And, add to that, they seem to think the tests we perform now are good enough; friability, hardness, disintegration, weight, and color. Most of our ideas are often based on the three development batches, so things like blend uniformity are inferred, not measured, as in true QbD.

Until we recognize that “denial” isn’t just a river in Egypt, there will be no general acceptance of the new paradigm. If we can’t even agree on the definitions, we will be like Mr. Kissinger toward the end of the Vietnam War, when weeks were spent deciding the shape of the table to be used for the negotiation meetings. We are attempting to, as an ex-president once famously said, “define what ‘is’ is.”

So, as Joan Rivers says, “Can we talk?” And, maybe all use the same definitions?

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