Ciurczak Interviews Nasr on QbD and the Need for Robust Processes

In this interview with Emil Ciurczak during IFPAC 2007, Dr. Nasr discusses Agency activities and challenges, and what we might see in the future.

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Click here to download an audio file of Part 1 of this interview. To hear Part 2 of this interview, click the Download Now button at the end of the transcript that follows.

Emil Ciurczak: We’re talking with Dr. Moheb Nasr, director of CDER’s office of new drug assessment. You may have heard some of his remarks at the plenary session, but there are a few things that we’d also want to talk about.

We were just mentioning before we went "on the air," that Dr. Nasr was "ahead of the curve." At San Diego’s IFPAC meeting in 1999, he had already spoken at the session that I put together on process analysis, long before the FDA subcommittee was formed.

When a director at FDA calls someone at a drug company, the only questions you ask are: "How high, and when do you want me to come down?" And so Ajaz [Hussain] hooked me for that, but long before then, you were already preaching the virtues of process and trying to figure out what was going on. To give you your street creds, you were leading the fight before anyone even heard of Ajaz.

You’ve been championing QbD. Do you think that these recent industry layoffs and cutbacks (such as those recently announced at Pfizer) may hurt this effort? Also, PAT and QbD call for patience money and time. But often when you have a squeeze for profits and time, none of those three are given you by management. What’s your take?

Moheb Nasr: I think it may or may not hurt the effort. It will all depend on where the cuts are made. If the cuts are in development, it may hurt efforts at Pfizer and other companies that do submission. If the cuts are in manufacturing, it may have an impact on process improvement and post-marketing changes, innovations and changes of that sort. It depends on where the cuts are. Any time there are cuts in industry it hurts the economy. If cuts are in marketing it will not hurt.

EC: This question is a close parallel: A number of people say, "Why do we hear about PAT in meetings?" My experience with NIR back in the 1980s we had, for example, at a conferences, e.g. in New Orleans, we had so many people in some sessions that the fire marshals asked us to open the door and make more room, because people were standing five and six deep along the back we were overflowing with people.

Then suddenly in the late '90s it petered away. Not that people lost interest, but lawyers for the companies suddenly decided, "Hey, this is a useful technique."

Now I know, from talking to people, that J&J and Hoffman-Laroche are doing PAT but you never see them at meetings. It is possible that this is a good sign that we’re not hearing, that people are so busy doing PAT that they don’t have time for "PowerPoint PAT?"

MN: I think that’s an excellent point. I do IR with many industry sponsors in a formal way through the drug review process. In meetings like IFPAC and a lot of public workshops. I also get invited to speak at corporate meetings at companies like Pfizer, Merck, Wyeth ... I know myself there are other folks who are not present at these meetings who are doing as much and doing very good work on PAT.

Last October, I visited a company that had not been a vocal PAT proponent. They shared with me what they are doing in different aspects of development and mfg, and how PAT was being used and impacting their whole quality operations. I was most impressed. I had no idea, before I went to visit them in New Jersey, because they are not as vocal.

Every company has its own strategy. When I went to that company I met with the CEO and I asked him point blank how come they had not been supportive of discussion. He said “On the contrary. We have different business strategies. We try to see where [new approaches for us such as PAT] fit within existing business needs rather than creating a new additional program, where the need might be questionable.”

Some companies with an abundance of resources create a new program, then they think later on where that program can help. With other companies where resources aren’t abundant, where they implement more business practices, they find issues first and then find the solutions.

EC: There are also a number of people who are still looking for the second shooter in the Kennedy Assassination, people who believe in the conspiracy theory. They don’t want to give aid and comfort to either their competitors or to generics manufacturers. They’re just waiting until major products go offline to suddenly drop prices because they have a PAT process, to try to blindside a generics company. There’s probably some truth in it. Obviously any price reduction will help the general population.

At ISPE you talked about adopting technology for continuous processing – there are validaton concerns, but also questions of process recalls. When you’re running a process for 5-6 weeks you make 80 million tablets and have a recall, how do you define batch?

MN: Your question has several parts. First, do we need new technologies to fully implement QbD? Yes. With existing infrastructure and platforms, QbD fits. It can be done, but it works much better with new platforms.

To be fully realized, new manufacturing platforms need to be there, when you think about a higher level of development, the design space, you cannot model what you don’t understand. You can do scale up experiments with equipment and it will help you, but it doesn’t really get you to a mechanistic understanding. In summary, I think new technologies are needed.

Now, with new technologies, there will be some associated regulatory challenges. Because of that, we at the Agency are currently revisiting our process validation guidance where the traditional "three batches" approach may not be appropriate and it will not be appropriate for these types of new technologies.

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