FDA's Chris Watts on New Directions for PAT at FDA

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EC: I’m talking with Dr. Chris Watts of the FDA. What’s your title?

CW: Team Leader for standards and technology, Office of Pharmaceutical Sciences (OPS).

EC: All these changes keep coming. OK now, here’s a real tough question to start off with. How do you like your new digs over at the old Office of Naval Research facility?

CW: They’re fantastic. I really like having most of our people in one location, especially for OPS.

EC: Instead of having people running around and telecommuting?

CW: Yes. We’re waiting for generics to get out there and biotech products. But most of the CDER people are already there.

EC: I’ve heard the laboratory facilities there are really outstanding.

CW: Yes, the laboratories are right there and we have a great lab space… where we can do the process-based research using process equipment, not just lab-scale equipment.

EC: I was just telling Moheb [Nasr] that most people in the industry only see the regulatory face of FDA, but they don’t realize, or never knew, the quality of people that you have working in the labs.

CW: True, and that’s where Moheb came from.

EC: You could take any of these people and they’d be at home anywhere, at any university or industrial or academic research center anywhere in the world. I remember a fellow in Laurel a few years back doing MS MS MS work on estrogens, female replacement hormone research work… At the time, MIT didn’t have some of the equipment that he was using. It was really cutting-edge.

CW: Our labs, some of the people in St. Louis, we're going to present some great posters. Robbe has done some good work, and Chris Ellis, and the entire OTR lab staff. And did you know that we now have a new OTR director, too: Vince Vilker?

EC: Now everyone else will know, too. I get CDER’s daily newsletter. It is a wonderful resource, especially for me as a consultant. I love to mine the CDER web site. I can’t tell you how many excellent slides I’ve found up there and referred to in my courses.

CW: And it’s all public information.

EC: Making the law transparent gives people a lot more confidence.

CW: It really helps do away with “podium policies.”

EC: Last year when you and Ali were kind enough to be interviewed for this magazine… I guess he’s off somewhere else in the world on another mission… We can’t be selfish and keep everyone from FDA here. There have been some changes… I’m assuming that a large number of other companies have given intent to do PAT. You’d said there were no plans to change the guidance or to reissue another PAT guidance. But I guess “do it the best you can scientifically” doesn’t need to be improved.

CW: Absolutely. But we did get a lot of questions about PAT vs. QbD and whether the Agency was losing interest in PAT. If anything, we’re more interested in PAT than ever before. And it’s not just the new drugs. The most encouraging thing to me is… well, consider IFPAC. In the four or five years that I’ve been coming to this conference, the progression in the discussion on PAT in pharma has gone far beyond the academic exercise … "This is what we could do, and this is what we may do” to “This is what we’ve done and this is what we’re going to do tomorrow and this, the next day.”

EC: So we’re not doing what I’ve always referred to as “PAT by PowerPoint”?

CW: Exactly. And, by the way, we use that phrase all the time. David Radspinner and I did a session just this morning. We said, when we put this session together, pharma’s made significant progressions in applying PAT. We said, “We know PAT by PowerPoint,” but we want good, strong examples of what has actually been done. It was a good session, and there have been a couple of really strong sessions at this year’s conference.

EC: Originally in 1998 — I was reminiscing with Moheb — he was in an IFPAC session that I was organizing in San Diego. In those days, I had one session in the morning, and Rick Cooley had one in the afternoon, and that was it for the week. Everyone went off to the gaming tables or to Lake Las Vegas in between. But look at the program now, with all the three, four, five concurrent sessions. Large as I am, I can’t split myself up to attend them all. It is almost frustrating. It has really exploded.

CW: You can’t keep up with everything that’s happening. The excitement for us is the variety of PAT projects. The perception in the industry is that the large pharma companies are the only ones doing PAT. In fact, while the large ones are obviously very active, we have some really great examples of PAT being done by smaller companies, by generics manufacturers.

EC: Other than by Ajaz's team at Sandoz?

CW: We also see more biotech examples. It’s encouraging to see the breadth and depth of activity in the pharma industry.

EC: I see biotech more and more and am getting contacts here and abroad. I used to laugh about NIR. People used to ask me about three uses… but PAT has given it new life. Tell me about EMEA. They seem to be pretty neutral regarding PAT. They’re not against it, but they’re not pushing it like FDA.

CW: I know they’re active in it. We’re all on the same page re: discussions of ICH Q8.There are no philosophical differences. They’re supporting it, but different regions may have different regulations by which they have to operate. Moheb and Helen have both been very active in maintaining links with EMEA, meeting with EMEA and discussing PAT with them. On more than one occasion, PAT has been the specific subject of meetings.

EC: Tell me about E55. Helen Winkle had, at one point, talked about extending E55 to cover pharmaceutical manufacturing more broadly.

CW: I don’t think we’re looking at standards in general but focusing on PAT for now. I’m not sure we expected it to address every pharmaceutical manufacturing need.

EC: It’s not a magic committee.

CW: ASTM is one of several organizations with which we’re establishing standards. We’re developing processes in house so that we can do this…We have limited resources just like everyone else, so the question for us is, “How do we prioritize our efforts?” That doesn’t mean that Standard A from committee XYZ won’t be useful. It may be something that is exactly what the industry needs, but there aren’t any regulatory implications.

We’re trying to follow the example of some of our sister organizations here in FDA, like the Center for Foods and the Center for Devices. Devices probably has the most noted consensus standards setting program of any at FDA. We’re trying to bring all that to pharma.

Janet Woodcock heads the Council of Pharmaceutical Quality. A standard working group is part of that Council and is working on standards setting and the development of procedures for pharma products. We need to maintain not only the spirit but the action of the NTTAA A 19 1 circular.

EC: You know me as a bit of a gadfly and an impatient person. Someone invited me to join that group and my response was, “I understand that there are openings now because several key people on that committee had been run down by a glacier.” In all seriousness, given my temperament and the fact that I’m not 50 or even 60 anymore I may not be getting directly involved, long term, but I enjoy talking to people like you and Moheb and learning what is going on...

CW: E55 is focusing specifically on standards for implementing PAT. I ‘m kind of like you. I want things to be done yesterday. But the advantage that E55 offers is the open discussion of issues. It’s not just one corner of the industry, or just industry, the academics, or just regulators. Everyone, including consumer groups, are involved and decide what we need in order to move forward and how to develop standards so that we minimize the work for ourselves.

EC: After all, we’re not talking about Frisbees here, we’re talking about drugs and people’s health, so these standards are important. One of the most encouraging things for people who used to think of FDA as the stodgy old policeman is the fact that they’re seeing young people like you and Ali, the younger faces, out there pushing these programs. It’s encouraging. I’ve been very impressed by the quality of personnel they’re getting — the people at CDER, the Agency’s younger scientists, mathematicians and chemometricians. It’s a newer face. It’s not, "Well, I can’t do anything else, so let me work for FDA." Or “I”ve retired let me go to USP.” It’s a real career and you, as a group, seem to take an active approach that, “We can do something.”

CW: Thank you for including me in that “younger group.” I can’t tell you how much I’ve learned from my colleagues, including new colleagues, within OPS. I’ve had the good fortune and pleasure of working very closely with seasoned investigators, who have seen what’s happening and how things are changing specifically regarding PAT. We are really dedicated to the public health mission. I know that it may sound corny at times, but I can’t speak highly enough of my colleagues.

It’s like I always tell people in the industry who work in the QC function (which is usually described as a routine dull job)… "You’re the last line of defense. You are our protectors." But at FDA, you set the standards and encourage the QA and QC people to make sure standards are met.

EC: So, are you seeing things happen faster and faster with regard to PAT, or is activity leveling out?

CW: I’m encouraged by the level of activity. I try not to put numbers on anything because they’re not the best metric. Some of the things that we’re talking about you may not see in commercial products tomorrow or the next day. But the basic principles and understanding are being gained from implementing QbD and PAT in the R&D environment and you just can’t put a number on that.

EC: Companies are doing it gladly?

CW: Exactly. Some of what we’ve approved won’t necessarily see the light of day. There are some wonderful examples.

EC: You can’t talk about it unless the company does. But you gave some numbers last year at Colgate?

CW: We’ve amended those numbers. To call them “approvals” is a bit of a leap. We’re at seven or eight, and some are in pilot program. All pilot program projects have incorporated PAT QbD pieces, the metrics, the understanding and the active control. It’s blossoming, as you see in meetings like IFPAC. It’s no longer theoretical. We’re seeing really practical examples of what’s happening in the industry.

EC: If it’s just a piece, we don’t count it. So there may be 100 more companies doing raw materials by NIR and another 50 companies just doing moisture or blend uniformity which doesn’t qualify as full PAT program, but still show that industry is assembling the building blocks that it will need for PAT programs in the future.

CW: That’s just it. We’ve been encouraging people, telling people in the industry for some time that they don’t have to eat the elephant in one bite. We suggest that they implement PAT in a piecemeal way.

We have Sanofi Aventis’ example as a great case history on implementing PAT for the entire manufacturing process from end to end, but others are just as good and they focus on specific unit operations or a problem that they’re having. For instance, they’re interrogating the unit operation to understand fully what’s happening as they’re processing their materials.

EC: Moheb and I talked briefly about layoffs in some of the bigger companies recently in the industry. Over the years, I’ve seen that pharma corporate management is hesitant to come up with bucks for something that they haven’t heard of. And I remember butting heads with Ajaz, who had come from academia and sometimes advocated eating the elephant. Having come from industry, I knew that if you can prove the concept to management with moisture or blending or raw materials, then you get approval and funding for the next step. Prove it then move on from there.

CW: Low hanging fruit is one good way to characterize it. Looking at moisture with spectroscopic techniques may not be new and novel in and of itself, but it’s novel to us, as an industry, to use that information to actively control a manufacturing process.

EC: If you can get rid of a Karl Fischer with all its inherent chemical waste, why not?

CW: We hear the characterization all the time that we’ve “dropped this test” or “dropped that test,” and that’s not the case at all. We’ve not dropped anything but simply moved the analysis and control on line or in line. You don’t necessarily need the lab analysis.

EC: You’re doing 1000 where you used to do three. When I hear people saying “Gee, I’m afraid of doing something new,” my response is always, “Trust me on this. FDA is always happier when you do more tests. So if you now go to 5000 online tests instead of 10 tablets, they’ll be happy if you do it right. More testing has never hurt FDA’s feelings.”

CW: Not just more, but the right analysis, is critical. Some companies have been giving us some great case studies, but we still may be looking at some things unnecessarily. For instance, they’ll throw an analyzer on line and give us data from that analyzer, just because someone else has used that type of analyzer. It may not give us the info we need to control the quality of this product. So it’s focused analysis and control, rather than just doing a lot of different things because we can.

EC: It appears that we still need to dispel a lot of PAT urban legends. Someone just yesterday asked whether FDA were mandating PAT, and “If I use it on one process, will I have to use it on all of them?"

CW: Those questions are legitimate, and we still hear them from time to time, but the program is still completely voluntary. There’s no mandate whatsoever, and we’re actively encouraging people to “piecemeal” their PAT implementations.

You don’t have to do everything from soup to nuts, from raw material and API to finished product. There are great examples that take that approach, but you can just focus on a key unit operation, or a specific issue, and the limited approach can work very well too.

EC: The other myth I had to settle was that some people at a client company believed that if they put any kind of a monitor on equipment in a production setting, they’d have to immediately report every single data point to the Agency. I had to convince them that R&D data are not reported every day.

CW: Oh, yes. The whole concept of research data. That topic was the subject of much discussion in advisory committee meetings. We tried to be as clear as possible on the guidance documents. Even though it’s being used on an existing manufacturing process, as long as you do the risk assessment, and the analysis being done in line or on line doesn’t have a negative impact on product quality, you don’t have to come back to the Agency with all that data. After all, at that point, you don’t even know whether the analyzer will give you the info you’re looking for.

EC: I’ve used the following analogy. “It’s like installing a new HPLC column. You don’t have to report it if you don’t use it.”

CW: People ask: "If I put it on, and the information is useful, does that mean that I can’t use it?" If you want to use the information from the R&D stage to justify an approach that you’re taking, that’s exactly the way things should evolve.

EC: So, tell me, is QbD easier for existing or new products?

CW: For existing products, we're really talking about Quality by Redesign. With true QbD we’re talking about products being developed now, and we may not see applications in four, five, six or seven years. We expect the implementation to take a while.

EC: Industry is used to seven-year timelines, anyway.

CW: But it’s not that principles don’t apply to existing products. We’ve seen from the pilot program, good and hard examples of practical implications of Q8 and Q9 that show how it translates for existing products and processes. But that’s more like a redesign, and part of the "continual improvement" process.

EC: I guess we’ll have our little tete-a-tete again next year?

CW: I will look forward to it.