Automation & Control / cGMPs / QRM Process

CPAC's Mel Koch on Future Frontiers for Pharmaceutical PAT

Emil Ciurczak spoke with Mel Koch, who received an IFPAC Achievement Award recognizing his seminal work on process analytics development. For an audio file of the interview, click the Download Now button below the transcript.

EC: I’m talking with Mel Koch, director of CPAC at the University of Washington. First of all, congratulations on your IFPAC award. If anyone deserves this recognition it is you. Where do you see the process industries, specifically pharmaceutical manufacturing, going with PAT? What will be some of the changes in the next 10 years?

MK: PAT is already an established approach in other industries. Food is going into it now because of heightened interest in safety and security. Within pharma, we’re still in a definition mode. What I hear at the conference is a lot about companies that are structuring PAT organizations, and approaches, not a lot of strong case studies in terms of, “Here’s a successful submission.”

It’s being compromised somewhat by a change in what FDA is looking now, in migrating from PAT. It’s not that they are departing from PAT but they’re now emphasizing process understanding and QbD and saying “you need to use PAT to achieve this,” but really moving to Quality by Design.

I still pick up some confusion in the industry. A company just put together a PAT group, and now they ask whether they should they be assembling a QbD group instead. And should the PAT group then be addressing what QbD thinks they should do? There’s still sorting out and defining.

And then there’s the low hanging fruit of final dosage forms, tableting, mixing...

EC: And raw materials?

MK: What do you mean?

EC: Well, that’s just it. They’re not sure. There’s just the ID for the chemistry, then there’s the quality and they’re not sure about which quality. There’s a lot of talk about using physical parameters… terms such as flowability, crushability. If you do NIR or Raman you get some, but not all, of this info.

MK: And that’s giving you things like content uniformity and consistent delivery to final dosage form. When I think of raw materials, I think further back. I think that the next PAT frontier for pharma will be excipients.

EC: Things like lactose and talcs?

MK: I’ve been working with the food industry, and they see the need to alter their processing based on the quality of raw materials. You come off a year of drought and you may have a different protein or fat value in the product than you had last year.

When you think of it, I don’t know the actual number but it’s approaching 90% of excipients are naturally derived… starch, lactose, stearates… the industry will need to correct their processes based on periodic changes in these excipients. So you go back to formulary to pharmacopoeia which defines quality.

EC: They haven’t been updated since the Dark Ages.

MK: Then you take the next step into nutrients for biotech. You could buy pharmacopoeia grade molasses, but you will find that the quality will differ and results will too. Even from the same supplier, due to seasonal differences, performance will be different.

EC: Also yeast extracts… The Pharmacopeia only tells you about absence of heavy metals and action, but not how fast it will ferment.

MK: I don’t want to minimize the API and some of the content uniformity and those things but some of these will be influenced by changes in the excipient.

EC: So, please tell me about your little shindig in Italy.

MK: This is only the second year. But it will be difficult to continue it in Italy. What we’ve done has come out of our summer institute at CPAC in Seatlle. What we’ve focused on for over 12 years is on a theme of miniaturization being important for unit ops and also the sensors and analyzers that control those operations.

We got a request to take this concept and parts of it such as process intensification (growing rapidly in chemical industry), and high process throughput, and take them elsewhere, so we decided to take it to Rome. We have historical ties there.

We wound up with 40 people coming from Europe and North America Idea was to rotate it throughout Europe. Folks in UK wanted to host it for second year. But it went so well in Rome that they asked if they could postpone it for another year.

So this year we’re going to do it in Rome, but it will be hosted by three UK universities: Hull, Strathclyde and Newcastle, as well as Eindhoven in Holland.

Plan still is to do it in UK next year, but maybe they’ll want to go back to Rome.

EC: As they say, "held over by popular demand." For the 11 people out there who don’t know what CPAC is, what do you do?

MK: Well it’s a consortium drawing together multi-industrial representatives together with government agencies in a multidisciplinary environment. We’ll have as many as 10 academic disciplines involved.

We have most industries coming and the reason for continuing to focus on the multi-industrial approach, is the fact that there are so many cases showing how advances in one industry can apply to solve problems in other industries.

Consider the paper industry. They have their own association and a group of vendors that track developments in that trade group. Paper people aren’t thinking about what’s going on in biotech, yet the approaches that they are using are very similar.

Consider another example. We’ve developed a way for Boeing to monitor the coatings on the wings of airplanes. Exposing that to a multidisciplinary group, we found that same technology could be used for tablet coatings, for monitoring photographic film coatings, paints and other applications. Moving things between industries is one of our strengths.

EC: Science is science and it shouldn’t be compartmentalized.

MK: Well the interesting thing is that 12 years ago I put together a list of industry needs, within the pharma group that we had. List had 10 things… we planned to go to other industries and get their lists, compile them all and prioritize.

In 12 years, nothing has been added to that list. And, as it turns out, pharma’s problems exist in every industry: particle size, moisture, composition, cleaning validation, bioassay. All of these things have different applications and terminology, e.g. vapor characterization, for odors or environmental. If you develop a particle size technology, you can apply it anywhere.

Developing generic approaches to meet general needs can work across industries. Electrical engineering, mechanical, chemistry health science, physics all have their niches as far as approaches go.

MK: The way the academics say… in mechanical engineering, we’ll be working on a polymer melt flow technique and not realize that the application could be used in a number of industries. So that’s why we’ve taken the multi-industry, multidisciplinary approach. Any one university doesn’t have all the answers, so we’ve tried to bring in other universities to the program. We now operate across 10 universities, and are broadening the program out into European institutes and universities.

EC: I read that 130 PhDs have come out of CPAC?

MK: Yes, but that’s over a period of 22 years.

EC: Still, to have a doctorate in process analysis indicates that you’re seeding the future.

MK: It’s interesting that the degree isn’t in process analytics. It is in electrical engineering or chemical engineering or whatever the branch of engineering is, with an emphasis on process analytics in their thesis. But some 80% of those graduates have gone to work for member companies. I’ll get calls about job opening asking for lists of future grads. Companies who are members and attend semiannual meetings start recruiting the students during their second or third years and have them pretty well ticketed. Usually, three or four companies trying for each student. It’s hard for non-member companies to run in and demand people

EC: Using a trickle down effect approach , that’s good for recruiting new companies and new students… like a baseball farm team. A win/win situation.

MK: Something worth mentioning, I was on the industrial side for over 10 years, was industrial rep to CPAC from Dow and hiring six CPAC grads, I found that all of them made it to the higher levels of performance within the first three or four years. We had a ranking system that took into account teamwork, multidisciplinary activities, presentation skills, etc. Doesn’t mean they’re all guaranteed to have brilliant careers, the template is set.

Our students do presentations at semiannual meetings. They stand by the posters and people like yourself will throw some tough questions at them, as in “Why did you do this, and not that?” They’ll go back and study… It’s been a real trial by fire for many of them, and they tend to do well in industrial situation.

EC: I’ve found, too, that in all universities that have work study programs offering practical experience, students do much better… they have the academic smarts but also practical skills. They know what will and won’t work, ahead of time, and can find their way to the stock room.

MK: People coming out of program are a lot better prepared than typical graduates.

EC: Did CPAC train any of the FDA investigators?

MK: For the initial PATriot team, we taught a course and introduced general concepts. Later, 15 reviewers and others from the Office of Pharmaceutical Science saw the development of a sensor and how data from it could be used to make decisions.

Unfortunately, the second wave has been delayed due to cost constraints.

An interesting thing happened during that first exercise, though. These investigators were exposed to emerging technologies, and afterward felt so much better about going out to actual situations and making suggestions re: Raman or particle size analysis. The class increased their confidence, and the respect with which they were treated. Some of them still keep in touch with us.

EC: On a personal note, you’ve been doing this since the Coolidge Administration? How much longer do you plan to continue at CPAC?

MK: It’s still a lot of fun. I enjoy the visioning and there’s a lot that’s unfolding in this world of process optimization enhanced by micro-instrumentation…

EC: So, the world can look forward to the benefit of your knowledge for some years to come? You’re part of the repository of knowledge that these young kids need.

MK: I enjoy what’s starting to unfold.

EC: And it’s exciting. I know, as a teacher, that being with young people keeps you young.

MK: It’s not so much the teaching, it’s talking with them about new things like the NESSI program… it’s all happened within the last seven years.

Our next thrust will be into biologics, and that’s no longer just biotech, but things like vaccine-related needs, biofuels, biobased sustainable chemistry. There are number of things that will require the process analytics advances that have been made in chemicals. By that time, pharma will be well along.

EC: Sounds exciting. Thank you.

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