ISO портал. FOOD AND DRUG ADMINISTRATION

P R O C E E D I N G S

(8:30 a.m.)

DR. BOEHLERT: Good morning, everybody. I'd like to welcome you all to the second day of our subcommittee meeting. We had some very good discussions yesterday. Today we're going to change focus a little and it's more informational. We'll be hearing about two important issues: PAT and aseptic processing.

The first thing I'd like to do this morning is for us to introduce ourselves. First of all, I'll start. My name is Judy Boehlert. I'm a consultant to the pharmaceutical industry in areas of quality, regulatory affairs, and product development.

Efraim.

DR. SHEK: Efraim Shek from Abbott Laboratories.

DR. LAYLOFF: Tom Layloff, Management Sciences for Health, a not-for-profit building health systems in developing countries.

DR. RAJU: G.K. Raju, MIT Pharmaceutical Manufacturing Initiative.

DR. PECK: Garnet Peck, Professor of Industrial Pharmacy, Purdue University.

DR. HOLLENBECK: I am Gary Hollenbeck, Professor of Pharmaceutical Sciences at the University of Maryland.

DR. DeLUCA: Pat DeLuca at the University of Kentucky faculty of pharmaceutical sciences.

DR. TEMPLETON-SOMERS: Karen Templeton-Somers, acting Executive Secretary to the committee.

MR. PHILLIPS: Joe Phillips, regulatory affairs advisor to the International Society of Pharmaceutical Engineering.

MR. SERAFIN: Dick Serafin, consultant in manufacturing.

DR. GOLD: I'm Dan Gold, a consultant to the pharmaceutical industry in the area of compliance, regulatory affairs, and manufacturing.

DR. HUSSAIN: Ajaz Hussain, Office of Pharmaceutical Science, FDA.

DR. D'SA: Abi D'Sa. I'm representing Joe Famulare for the morning session.

DR. BOEHLERT: Thank you. The first order of business today is for Karen to read the conflict of interest statement.

DR. TEMPLETON-SOMERS: The following announcement addresses the issue of conflict of interest with respect to this meeting and is made a part of the record to preclude even the appearance of such at the meeting.

The topics of this meeting are issues of broad applicability. Unlike issues before a committee in which a particular product is discussed, issues of broader applicability involve many industrial sponsors and academic institutions.

All special government employees have been screened for their financial interests as they may apply to the general topics at hand. Because they have reported interests in pharmaceutical companies, the Food and Drug Administration has granted general matters waivers to the following SGEs which permits them to participate in these discussions: Dr. Judy Boehlert, Dr. Patrick DeLuca, Dr. Daniel H. Gold, Dr. R. Gary Hollenbeck, Dr. Thomas Layloff, Dr. Garnet Peck, Dr. G.K. Raju, and Mr. Richard Serafin.

A copy of the waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, room 12A-30 of the Parklawn Building.

In addition, Mr. Joseph Phillips and Dr. Nozer Singpurwalla do not require general matters waivers because they do not have any personal or imputed financial interests in any pharmaceutical firms.

Because general topics impact so many institutions, it is not prudent to recite all potential conflicts of interest as they apply to each member and consultant.

FDA acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussion before the committee, these potential conflicts are mitigated.

With respect to FDA's invited guests, Glenn Wright reports he is employed full-time by Eli Lilly & Company.

We would also like to disclose that Dr. Efraim Shek is participating in this meeting as an acting industry representative, acting on behalf of regulated industry. Dr. Shek reports that he is employed full-time as Divisional Vice President for Abbott Labs.

In the event that the discussions involve any other products or firms not already on the agenda for which FDA participants have a financial interest, the participants' involvement and their exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon.

Thank you.

DR. BOEHLERT: Thank you, Karen.

First on the agenda today is Dr. Ajaz Hussain.

DR. HUSSAIN: Good morning. Before I start, as I mentioned yesterday, what we would like to do is after the morning session, we have three presentations, one talking about how PAT becomes part of the drug quality system for the 21st century initiative. Then you have a presentation from one of the working groups on comparability protocols by Dennis Bensley, and then you have a presentation on risk management. What I would like to do is to start connecting all these things together and start defining the topics for the next subcommittee meeting.

I would like to change the agenda, as I mentioned yesterday, with the permission of Madam Chairperson, to wrap up this discussion and define the subcommittee's next steps and then have an update on aseptic manufacturing. Aseptic manufacturing was designed to be an update for you. You have not been part of that discussion at the previous advisory committee, so it's simply sort of an FYI. So if you agree with that, Madam Chairperson, we'll try to do that. Judy?

DR. BOEHLERT: Yes.

DR. HUSSAIN: Yesterday I think we had very valuable discussions. One of the challenges I see is, as we proceed further, we have to start becoming more specific in terms of discussion topics and so forth. I think you will see that happen starting this morning.

Let me start with the PAT initiative. When we started the PAT initiative, this was a topic that we selected based on many different factors. PAT addressed review issues. It addressed inspection issues. It addressed computer validation issues. Therefore, it became a wedge to open the broader discussion that we have on the drug quality system for the 21st century. So it actually was an example that became the topic of discussion of the entire initiative now.

Some of you are already aware of the evolution of this, but for those who are new to this committee, I would like to trace back some history.

The PAT concept actually got started in '93 with an AOAC workshop in St. Louis that Tom Layloff initiated. At that time I think the consensus was not there, and it really did not progress well.

Tom and I spent several hours discussing these concepts, and I think I brought the industrial pharmacy/chemical engineering perspective with his analytical, so what evolved from those discussions was a presentation in the year 2000 to the FIP Millennium Congress on modern in-process controls. The transition that occurred, what happened at AOAC in '93 to what the PAT is now, is we moved the concept to an on-line in-process focus rather than end product testing. I think if you keep the focus on physical methods for end product testing, the concept really did not fit well. So I think the quality by design concept, building quality in, the basic tenets of the GMP, fit very well there.

Keeping that in mind, we took this discussion as an emerging science issue in pharmaceutical manufacturing to the FDA Science Board, and that was necessary because we realized that we are actually changing the paradigm with this concept and you needed the highest levels at FDA buying into this and providing support for this. So the FDA Science Board essentially is an advisory committee of the Office of the Commissioner.

At the first meeting which occurred in November, we invited several individuals to share their perspective. We had G.K. Raju and Doug Dean who actually identified for us the wonderful opportunities that exist to improving manufacturing efficiencies and actually, by doing so, improving not only the science of manufacturing, but also improving quality as well.

Norm Winskill and Steve Hammond represented their views from an industry perspective and outlined some of the challenges for us. The two phrases that I think I have used often is "don't use" and "don't tell." In a sense, the current system has created a scenario, perceptions and rumors and whatnot, that industry either has adopted a "don't use" scenario for new technologies or for process improvement in general or "don't tell." They would use it but not share that with FDA because of fear of regulatory uncertainty and what type of questions might be asked, a "why open Pandora's box" type of mentality. We felt that was unacceptable from a public health objective, and we wanted to start moving and changing that concept, and that's how the FDA Science Board discussion started and we got an endorsement from the FDA Science Board on two critical issues.

The first question we had posed to the Science Board is this is an emerging science issue and all new technologies that we're talking about should not become a requirement. These need to be adopted or adapted by companies that have the capability, that makes sense from a business perspective, that makes sense from a product perspective and so forth. So this could not become a requirement. So it has to be voluntary. That I think addressed some of the "c" in cGMP issues, and that was the first question we had posed to the FDA Science Board.

The second question that we had posed to the FDA Science Board was the issue of a safe harbor, but more accurately what we call research exemption because there is a significant fear of improving just because you may find something or trends which may suggest that something is not appropriate. But if we use that model, then there will never be continuous improvement, and that went to the discussion yesterday also that you have to start tightening your specifications as you improve your process.

The problem with that concept is that why would a company do that if there is no safety and efficacy justification. Simply ratcheting up requirements from a standards perspective is not a solution for that. Therefore, from a continuous improvement model, you have to bring into consideration broader perspectives and actually make more rational decisions. We have approved the product as safe and effective. It has been on the market as safe and effective. Therefore, continuous improvement in reducing variability, understanding it better should not deter and our focus should be on the safety and efficacy.

Ray Scherzer was part of our second Science Board discussion, and essentially he again highlighted the importance of manufacturing, how manufacturing essentially is a stepchild in this industry, and the technology does exist, but I think if we are willing to move in this direction, the opportunities are humongous. Essentially that was a challenge to the PhRMA industry itself that we should be moving to quality by design. He spoke on behalf of the Consortium for Advancement of Pharmaceutical Manufacturing.

These two Science Board meetings, I think, essentially crystallized our thought process and essentially defined a path forward. This support from the FDA Science Board was essential.

From those early beginnings, we essentially set up a PAT Subcommittee under the Advisory Committee for Pharmaceutical Science. This committee met on three occasions and it worked very efficiently to define several things for us: definitions of what PAT is, benefits and scope; identified perceived and real regulatory hurdles, but also identified significant internal, that is, within-company, hurdles that need to be overcome; need for across-discipline communication, pharmacy, chemistry, engineering, essentially an engineering concept; approaches for removing these hurdles. We also had companies come forward with wonderful case studies. General approach to validation, but also I think most importantly, we developed a PAT training curriculum for FDA staff.

We are in the process of training the individuals on PAT, and the training is being conducted by three schools. We focused on three National Science Foundation centers. The School of Pharmacy, Purdue University. That's the home of the Center for Pharmaceutical Process Research. University of Washington, Seattle, Center for Process Analytical Chemistry. University of Tennessee School of Engineering is the Measurement Control Engineering Center. So we essentially brought in a chemical engineering focus, a pharmacy focus, and a chemistry focus to do this training.

Now, the approach for the PAT initiative was to have a core set of individuals who are trained and certified. We have a PAT Steering Committee within FDA. This initiative is a collaboration between the Office of Regulatory Affairs, the Center for Drugs, and the Center for Veterinary Medicine. So you have a PAT Steering Committee that reflects these three organizations.

We have a PAT Policy Development Team that includes new recruits and available FDA experience, such as Raj Uppoor, an industrial pharmacist with extensive review experience; Chris Watts, a biomedical engineer with a pharmaceutics Ph.D.; Huiquan Wu, a chemical engineer with extensive mathematical skills especially in chemometrics, coming from the semiconductor industry; and more recently Ali Afnan, a person who actually has done all of this for AstraZeneca at the Plankstad facility. We hired him and stole him away from AstraZeneca.

We have a PAT Training and Coordinating Team. John Simmons and Karen Bernard chair that.

But more importantly, the heart of this program is the PAT Review and Inspection Team. We have investigators identified from key districts, and here are the names of those. We have compliance officers and we have reviewers. Now, this team is undergoing training. We hope to finish the training by the end of this year. The next session for training is at the University of Tennessee where they'll focus on process controls. They'll come back to Rockville for a second didactic session, followed by a certification program. So all applications that are considered to be PAT applications will only be handled by these folks who are trained and certified. As this program grows, then we start expanding the training and getting everybody on board.

So why PAT? Why process analytical technologies? We felt there was a gap in the type of measurements we do. We have focused for the last 30 years on chemistry, mainly wet chemistry. Physics was missing. So when you bring physics and chemistry together, actually you have more meaningful measurements that relate to product performance. You actually can predict performance attributes such as dissolution from nondestructive measurements.

Essentially from that basis, we felt that PAT provides an opportunity to move from the current testing to document quality paradigm to a continuous quality assurance paradigm that can improve our ability to ensure quality was built in or was by design. This is actually the ultimate realization of the true spirit of cGMPs. In fact, every guidance we have on cGMP, we state that quality cannot be tested in. But a critical look at the current system would say otherwise. We actually test mainly to document quality today.

PAT provides an opportunity for greater insight and understanding of processes. And this is the heart of the PAT initiative. I'd like to emphasize without process understanding, simply adding new measurements is not a solution. In the words of Ray Scherzer, it's like if you don't understand your process and put on an on-line sensor, it's like putting an earring on a pig.

Also I think right measurements, right time, and moving the measurements to the process, and the measurements being predictive of performance is the key here. So you have greater insight and understanding of processes at, on, or in-line measure of performance attributes, real-time or rapid feedback controls, that is, focus on prevention. This is a missing element, especially in product manufacturing, not so in drug substance. Potential for significant reduction in production and development cycle time. Minimize risk of poor process quality and reduce regulatory concerns.

So from the three meetings of the PAT Subcommittee, we created a conceptual framework for PAT guidance development. We actually held the guidance back for some time for two reasons. One, the Part 11 issues had to be clarified to some degree, and that has occurred. Second, since PAT is becoming part of the drug quality system for the 21st century, we wanted to see how best to position this guidance. So there were two reasons for holding the guidance back, but the guidance is on track and will come out hopefully later this summer.

The conceptual framework for PAT policy development will include these elements. Now, if you look at on your left-hand side, it starts with incoming raw materials. Traditionally we have laboratory tests for identity, purity, potency, and so forth. Those are still there, but I think we would like to see bringing in more modern methods that actually provide you information not only about chemistry but also on physics that relates to processability of that material. Today we have materials that come in that are variable in terms of their physical attributes, but our processes are fixed. So that creates a situation where you have larger reasons for deviations and so forth. I think you really have to move towards adapting a process that can manage the variability of incoming raw materials. We would like to keep as minimal a requirement a specification for processability, but to let companies manage that variability in more intelligent way.

So if you have, for example ‑‑ I'll just give you an example of near infrared. If you bring in the infrared for in-process materials there can be certain advantages. One, you can do the identity of the material. You can do moisture content. You'll get a sense of the particle size differences from lot to lot. You may not get an absolute value, but in many cases an absolute value is not necessary if you know the variability exists and if you learn to manage that variability, that provides a solution.

So with incoming raw material attributes, you bring physics and chemistry together and then use that information to predict or adjust optimal processing parameters. You move away from time, the blend for 10 minutes concept, to blend until it's homogenous, more towards endpoints which are predictive of the next step.

So if you look at this processor, you have incoming raw materials that differ in shape and size, and you have end product coming out. So you have incoming materials. You're gaining more information about that through very nondestructive, very efficient methods in a different sense now, and using that information not only to be proactive, a forward control sort of concept, but also then you're processing to an endpoint. The endpoint would be determined based on the performance. You will blend until it's homogeneous. You'll granulate to get the right moisture content, the right particle size, the right flow, and so forth. There are wonderful case studies on this from, say, GlaxoSmithKline on our web site through the subcommittee.

So the concept also comes in you have measurements on-line or at-line that are now focused on performance attributes. The in-process controls are now performance-based, not just time.

To do this, you have to identify what are the critical process control points, monitor those, and go to an endpoint, but also you have to bring in the control mentality of chemometrics and information technology for real-time controls and decisions.

You also have an approach for direct or inferential assessment of quality and performance that could be at- or on-line. This becomes nondestructive. You actually say you are predicting dissolution. Instead of doing the actual dissolution, you can actually relate all the critical variables that affect dissolution, monitor and control those, and actually start predicting dissolution. We have ourselves done many of these experiments, but also we have done experiments to link it directly to bio instead of going through an intermediate dissolution.

So that's the elements of the PAT, but to make this happen, you really have to think about development optimization and a continuous improvement framework. You have to think about design of experiments. There are many advantages of doing well-designed experiments. So you start predicting at least within the design space.

The concept of evolutionary optimization comes in. Today it is not an approach that works in the pharmaceutical sector. It works in the chemical sector, but through this process, you actually open the door for that discussion.

Clearly improved efficiency is also a driver here, but to make this happen, you really have to think not from a univariate perspective, but from a multivariate perspective. Now, you're not only focused on the drug substance in your tablet, you're focused on the homogeneity of all your raw materials and how that relates to performance. So you really have to move from a focus on a univariate thinking to a multivariate systems thinking to make this happen.

Then comes risk classification and mitigation strategies. Essentially this is the framework that the guidance is going to reflect. So it will be an approach that takes us in that direction.

Now, here is a pyramid. G.K. and I share pyramids. If you notice in my first slide, I have added B.Pharm. What has happened is a lot of people, when I make this presentation, think I'm a chemical engineer and they come up to me and say, you know, these pharmacy types don't know what they're doing. So I have to say I'm a pharmacist. But G.K. and I have quite a bit in common in that.

And here is a pyramid that somehow evolved in such a way that I thought he took mine and he thought I took his, but I think we just came up to the same thing.

Now, if we really look at it, to do product and process quality right, it has to be based on knowledge. When I started using this pyramid, I borrowed it from the information technology folks where they said data, information, knowledge, wisdom, as you go up in that pyramid knowledge structure.

So the question for FDA to assess was quality by design, and then we apply our GMP and CMC review to assess that. From our perspective, what we see in the submission and what is available to us, the impression we get is the data derived for all this is from trial and error type of experiments. There's not much information. That's the reason I think the chemistry perspective is "I know it when I see it." When there's a change, how do I know the bioavailability did not change, the shelf life did not change? The only way to make a decision today is to say do three batches or do a biostudy, and if it is okay, then the decision is it can be made.

So we are in the bottom of this pyramid today where we have to scrutinize every step, and it's difficult for us to assess whether quality was by design and so forth. So change management is difficult.

Also keep in mind the base of this pyramid reflects the volume of documentation needed. As you go up, the volume of documentation needed to do this decreases also.

Now, what PAT does is brings the focus on critical process control points. It also brings in an ability to generalize, but generalization would be limited to a certain design space of what you have studied. But it is going up in this knowledge pyramid, and as you move toward mechanistic understanding and first principles, clearly the process design, design qualification probably becomes sufficient.

So that's how we see science- and risk-based GMPs would be based on knowledge. As companies go up in this knowledge pyramid, they need to get a reward for that, and for companies who do not, we have the current system.

So the regulatory framework for PAT is the modern PAT tools that we're talking about are not a requirement. We'll have a research exemption so that you have continuous improvement without the fear of being considered noncompliant. There are two simple ways of looking at research exemption.

One is when you start applying PAT-based systems or any new systems to an existing product line, until that complete system is validated, all regulatory decisions are only based on the current approved validated methods. So that should allow companies to actually gather more information with new technologies without the fear of being considered noncompliant. So the regulatory decisions, as PAT is being applied, on an existing line will only be based on FDA-approved, validated methods. Every other method would be a research method from that perspective.

The second way to look at that is if a company starts from the right thought process, in terms of PAT, if PAT is process understanding, you have to start from the very beginning, start understanding the raw material and so forth, and move towards your end product. So that way, even if you see deviations and so forth, that can essentially be adjusted and corrected, and you really shouldn't have a problem.

The other aspect is in terms of when you have a new method, the acceptance criteria that you have should be different. If you test 10 tablets to make a decision today and if you test 10,000 tablets to make a decision, that is a different acceptance criteria. Essentially you look forward to receiving sound scientific, statistically based approaches from companies to do that.

So that was actually the first or the second question we posed to the Science Board. Unless we are ready for science-based decisions, this won't happen. So we're ready for science-based decisions.

We're also providing regulatory support and flexibility during development and implementation. We're meeting with companies who are ready for proposals. We've already met with several. In fact, I think the challenge for us is now to accelerate the process in such a way because we didn't anticipate things coming in so quickly, and they have started coming in. That's a good thing, but we have to ramp up our process.

The reason for this is to eliminate the fear of delayed approval, but also instead of dispute resolution, you want to avoid the disputes first. So these meetings are focused on science first, and then we define a regulatory strategy, not the other way around. Here is the regulatory strategy and then the science. The discussions for these meetings are first science, understand what is being done, understand what the issues are, then construct a regulatory part for that.

The last bullet here is science- and risk-based regulatory approach. So what is the incentive for companies to do this? I think one incentive, other than this makes sense from all other perspectives, but from a regulatory perspective, I think companies that understand their processes better essentially we have moving towards a low-risk categorization based on a higher level of process understanding.

So the strategy for moving forward right now. We have conducted several workshops, some of which we have co-sponsored, in both the U.S. and Europe. These workshops have been very valuable, especially in terms of the scientific discussion and debate. Some of these have been emotional. Especially the Arden House Conference was quite an emotional workshop. It was across discipline, pharmacy versus chemical engineering type of debate, R&D versus manufacturing type debate, but we had to get over that debate, and I think we had to move to the shared vision.

The general guidance on PAT is to be released later this summer. We'll have a training workshop on that guidance, and that will bring together different associations.

FDA cannot do this. All we can do is to create champions, and that's what our focus has been. Champions to drive this initiative towards a shared vision or desired state that we discussed yesterday.

Champions that have already been there. We simply supported them. Pfizer, GSK, Bristol-Myers, Aventis, and others.

Academia. MIT and Purdue were the champions that were already on board, but I think now we can see the list of universities growing tremendously in the U.S. and in Europe. But also I think this summer we have discussions to get universities in Japan on board here. PAT has been introduced in pharmaceutical engineering programs at Purdue, Michigan, and Rutgers.

We are moving towards a system where we would like to see all the instrument vendors come together as an association. The reason for this is we are getting so many requests for meetings to say here is our technology, here are the issues, and so forth. We cannot afford to meet with them on a regular basis. So we will issue a Federal Register notice to bring all these vendors together and encourage them to move towards an association so that we can address common issues.

Here I think the framework would be ‑‑ we have been in discussion with the National Center for Manufacturing Science in Michigan. That center was mandated by Congress for the automobile industry. That will probably be a framework for bringing them together.

Strategy for moving forward, continued. Improving FDA knowledge base for technical policy development. We have recruited several experts and I'm getting so many CVs from people who want to come to work for FDA. It's amazing. Many from Pharmacia. No.

(Laughter.)

DR. HUSSAIN: Intramural research refocused to address technical needs and for in-house training. Our research program is moving forward to support that.

We would like to learn from other industries. We are in discussion with ASTM, for example. ASTM has several wonderful guidelines for on-line process analyzers and so forth for the petrochemical industry. I think instead of reinventing the wheel, we would like to put together a working group of industry, academia, and FDA folks together to adapt or adopt some of these guidelines so that we don't reinvent the wheel.

We have a collaborative research and development agreement with Pfizer. I think it's almost signed off right now. This will focus on on-line methods, especially focused on chemical imaging.

We have finished the paperwork now, so this is now almost official. We will be part of the NSF Center for Pharmaceutical Processing Research. NSF invited us to be part of this, to champion this, and this is not the only one. We are in discussions with the bigger center, the National Center for Pharmaceutical Engineering and Research, with NSF. So NSF is very supportive in helping us move in this direction.

But finally, I think the strategy moving forward is to move the PAT initiative as part of the cGMP initiative for 21st century. This becomes an example of every element you see in the cGMP initiative. So it's an example of science- and risk-based systems approach to product quality regulations.

Now, within the framework of the cGMP initiative, which we now call a drug quality system for the 21st century initiative, what we have done is post-approval implementation of PAT. The draft guidance that we issued on comparability protocols ‑‑ and Dennis will talk to you about that soon ‑‑ is the PAT-comparability protocol concept. Now, several companies have already proposed this, and in fact that has become a framework for discussion. I think the main emphasis there is systems thinking, process understanding, risk mitigation strategies focused on manufacturing science.

The PAT Review and Inspection Team is also an example of training and certification, science- and risk-based review and inspection.

Clearly the product specialist on inspection concept is built into the PAT. We have experts who have done this, have hands-on experience in industry. So we have the right expertise. I think I won't be exaggerating if I say we probably are at the 90th percentile in terms of know-how on PAT. I think we do have the right expertise and we're getting more of that right expertise.

I want to emphasize what I mean by moving from testing to document quality to quality by design. I think this is a fundamental paradigm shift. What does this mean?

For example, if I take particle size as an attribute, effective methods for managing and controlling particle size variability to provide consistent performance. That's the thought process. For the last 20 years, we have struggled, especially when it comes to physical attributes, to define public standards. It's difficult. Instead of saying, this method, that method, that comparison, we'd like to focus on test methods for understanding variability and managing variability. There's a different fundamental approach to that and I hope you can see that.

Establishing causal links between material attribute variability and performance. So you're connecting your test measurements to release something which is meaningful.

Reduce reliance on lab-based test methods. That's what we mean when we say move from testing to document quality to quality by design.

It improves focus on process understanding as compared to test to test comparisons, and with particle size, I don't think we have a clear solution in mind if we keep the focus on test to test comparisons, as we have been doing.

Let me change and start setting up for the next two speakers and start setting up the whole concept for the next meeting, the risk and how PAT process understanding can help us move in that direction is my focus now.

Now, change is risk. That has been the focus of the SUPAC debate because change is considered risky because if you have a black box, if you change something in the black box, then how do you know what the impact is unless you do all those tests to find out. That has been the framework under which we have operated, but with a high level of process understanding, change may not be bad. Change is innovation. Change is improvement also. So you really have a means for distinguishing good from bad.

So if you look at section 116 of the Modernization Act, a change can have a potential to have an adverse effect on identity, strength, quality, purity, or potency of a product as they may relate to the safety or effectiveness of the product. That's what the risk is. And the risk categorization that we have today, if there is a substantial potential, we require a prior approval supplement. If we have a moderate potential, we now require a changes being effected-30 days or changes being effected supplement. If you have minimal potential, it's an annual report. The regulatory scrutiny is different. The test required to justify is different.

But through the quality by design concept and process understanding, actually what might be substantial potential now can become minimal potential through process understanding. That's the theme that we would like to think about.

On the review side, I think we are moving towards a quality system for review and creating a risk-based approach to the review process itself. Now, you have to consider this. What is the objective of the review process? Review is to minimize intolerable risk to patient safety. That's essentially what the end goal of that is. So in the review process, what we have to start thinking about is identify risk scenarios, assess likelihood of fault condition, assess severity of impact, assign risk grade, assess probability of detecting fault condition, and determine the mitigation strategy, if it's right or not.

That's what the review process in an ideal way should be in my opinion. But today it's not. It's more on test and these are your batches and so forth. So how do we transition from today to something like this if this is what is desirable and what is necessary?

In a risk scenario perspective, what is risk of unacceptable quality? Again, building on the SUPAC example, releasing an unacceptable quality product is a risk. This could happen because of inadequate controls or specifications where you might have a new impurity that comes in or you may lead to a bioinequivalent situation, or you may have inadequate process validation. Sampling may not be representative is one example of what that risk scenario is. You have stability failures. You have bioinequivalence, and essentially the poor process quality leads to some of this. So these are the typical risk scenarios that SUPAC and other things that we have done have tried to address.

But I think SUPAC is one example. The biopharmaceutics classification system was another example of the risk management that we developed before. And here the biopharmaceutics classification system went to the heart of what is the rate-limiting step in the absorption process and how is the product and drug attributes related to that list.

So when we were developing this guidance, it was fortunate enough that I had the lead on this. I spent a couple of years just on this guidance itself. So how did we approach this? We started looking at what are the risk factors. Manufacturing changes pre- or post-approval we have already defined as minor, moderate, and major changes based on SUPAC.

There's also the issue of poor process capability. This was important in our discussion because most of the decisions we make are based on 6-12 tablets for analysis. How representative is that and how do you really rely on that decision? Plus, you have a test which could be variable itself.

So the real question came back to can we rely on in vitro dissolution tests. Especially when you have a single point specification with the sampling issues, we don't know whether that correlates in vivo or not.

So that was the heart of the BCS classification discussion that we had. And there were other factors that can lead to problems. So when we developed the BCS classification and allowed dissolution to be used only in the case of highly soluble, highly permeable, rapidly dissolving, we were not comfortable with saying you can rely on dissolution if you have not a rapidly dissolving tablet because clearly there are certain elements of the test method itself which are challenging, as well as unpredictability of what it means in vivo.

So the assessment of risk was what is the risk of bioinequivalence between two pharmaceutically equivalent products when in vitro dissolution test comparisons are used for regulatory decisions? That was the heart of the question with the BCS guidance that we developed. So we wanted to look at the likelihood of occurrence and severity of the consequences. So narrow therapeutic index came into that perspective and likelihood of occurrence was an evaluation of the entire database that we had and saying that when the dissolution is not rapid, we were not comfortable with making that decision.

So the regulatory decision came back as whether or not the risks are such that the project can be pursued with or without additional arrangements to mitigate that risk. And all the other arrangements that you see in a bioavailable request were designed to minimize this risk.

The most valuable experience that I had with this guidance was ask the question, is this decision acceptable to society? It took significant effort to make sure that it was.

Now, as you move towards Dennis' presentation and SUPAC-comparability protocol, I would like you to think about the PAT and quality by design and how that will evolve the SUPAC or the change management system that we have. If you look at the SUPAC guidances today, we have three categories of changes, and high, medium, low are the risk levels. To a large degree, the risk levels were determined on the basis of AAPS workshop as consensus risk factors. We did extensive research at the University of Maryland that confirmed that they're fine, but the SUPAC guidance is overly conservative. If you look at the University of Maryland data, we could have made many more changes, and I think it would have happened. We did not go there because of the issue of generalization. Can we generalize the University of Maryland data based on six model compounds to the rest of the population out there? That was the reluctance. That was held us back from that perspective.

Now, in a "make your own SUPAC" concept, when you have a high level of process understanding, we can take the SUPAC to the next level. What I have done here is I have combined the SUPAC, high, medium, low, with GAMP-4, which is an ISPE document which has a risk assessment. Essentially it's based on failure mode/effect analysis.

The next two levels of improvement that we can bring in SUPAC is this. Today we do not talk about risk likelihood. Everything is risk. So we do not have a sophisticated way of saying what is the risk likelihood. When you bring development information and knowledge and quality by design concept into systems thinking, we can actually start talking about risk likelihood. And if the risk likelihood is low, what is high risk today in SUPAC could become low risk based on that.

Example. A manufacturing site change ‑‑ Colin mentioned this to you earlier ‑‑ a change in ZIP code is a major change if it's a controlled-release product. We will require three batches of stability, a biostudy if you don't have in vitro correlation. So just changing ZIP code, no other change is that requirement.

Now, what is the risk likelihood? Because we are treating that as a black box. We don't know what will happen. So if you have process understanding, you know what the critical variables are, you know what the risk likelihood will be in a more sophisticated way. So you start reducing the risk likelihood. If the risk likelihood is low, then what is high risk today in SUPAC could become a low risk.

But that's not enough. We can go one step further. In the previous slide, you have essentially decreased the risk classification in SUPAC. The risk classification has gone down. But now suppose you have a process understanding as well as on-line controls and so forth. Even if there is a fault condition, then you improve the probability of detecting that fault condition. So how do controls allow you to mitigate risk factors? That was the question Gerry had raised to you. So with quality by design systems thinking, right measurements, right time, even if there is a risk factor, if you increase the probability of detecting the risk factor and sort of managing that, then from a regulatory perspective, the risk goes down.

So I will wrap up here. A perspective on PAT is just one piece of the puzzle. It was a wedge to start this process. It becomes an example, but I think the entire system is this. Today I'd like to use this book by John Guaspari, A Modern Fable about Quality. "I know when I see it." In a black box situation, our chemists have to see the stability, have to see the bio to make a decision. So the current situation is "I know when I see it."

Vision 2020: "I can see clearly now" essentially is the direction we want to go. Here quality and performance by design, continuous real-time monitoring, specifications based on mechanistic understanding of how formulation and process factors impact product performance, high efficiency and capacity utilization, science-based regulatory decisions focused on product and process quality. That's the shared vision that we discussed with you yesterday.

I will wrap up with this. We are planning an Arden House 2004 conference. Now, the PAT essentially is a tool for process understanding. And this committee I think will really help us bring this together. How does process understanding link to risk-based regulatory assessment? But then I think process understanding is a function of design, predictability, and capability where design is based on intended use of that product. Predictability is based on first principles modeling and so forth that you're bringing in. Capability is optimization, continuous improvement, including corrective action/preventive action. I think we are trying to create this equation this is the desired state for the future.

And the triple integral is because it has to be across disciplines, clinical, chemistry, biopharm, and so forth. It has to be across time. And as G.K. says, it has to be across space.

Thank you.

(Applause.)

DR. BOEHLERT: Thank you, Ajaz.

Questions from the committee or comments? You did such an excellent job, that they're speechless.

DR. GOLD: Judy, I have a comment. I wanted to thank Ajaz for an excellent presentation. It was very, very well organized and very well presented.

I do have a question that perhaps you can answer. This is an excellent vision for the future. Where are we right now in terms of what is happening? You mentioned that there are several initiatives underway with some of the major PhRMA companies. Are you free to discuss what those initiatives are in general terms?

DR. HUSSAIN: No. These are submissions. We cannot talk about that. But we have proposals being submitted for discussion and we have started moving on that already.

DR. GOLD: Are you free to indicate the type of technology that is contemplated at this point?

DR. HUSSAIN: Not really, no.

DR. GOLD: Not really, okay.

DR. BOEHLERT: Thank you.

Second on the agenda this morning is Dennis Bensley who is going to talk to us from CVM.

DR. BENSLEY: Good morning. My name is Dennis Bensley. I'm from the Center for Veterinary Medicine within the Food and Drug Administration. Yes, the FDA does regulate animal drugs and it's very similar to human drugs. So quality issues for animal drugs are just as important as they are for human drugs.

Before I begin, as you can see my title is "Changes Without Prior Approval: An FDA Perspective." And this is pretty much the same presentation I gave at the PQRI late last month. And some of you were there and have seen this talk already. You're excused, but then again, if I excuse you that will be one-third of the audience gone, so you need to stay.

What this changes without prior approval is, is just another word for supplemental applications. And a little bit of a background before I continue.

When we get an original application for approval, one of the components of the original application is a chemistry and manufacturing control part of it. The chemists or microbiologists, the CMC reviewer will look at that information, review it, find it to be acceptable, and then eventually when the product is approved, that's what's legally binding for the sponsor. It's approved processes, it's approved specifications.

What's in that package can include various things: raw material controls, the formulation, manufacturing process, descriptions for both the drug product and drug substance, analytical controls, validation information on analytical controls, stability information. And once we approve this application, the sponsor is legally bound to follow those items in that application or any commitments they made in that application.

Now, when supplemental applications happen is after the original approval of the drug product. And a manufacturing change is a constant. Chemistry and manufacturing control reviewers within FDA see manufacturing changes for the lifetime of a product, which makes this kind of unique in the pre-market arena because we see supplemental changes on a continuous basis. Our focus here is primarily with those types of supplements that require prior approval from us because those are more burdensome, from a regulatory perspective, for the industry and also somewhat burdensome for us also.

So I'll continue with my talk. A little bit of the outline of my discussion will be just a quick introduction, background which is more of the legal aspect associated with supplemental applications. Our current FDA assessment on the supplemental changes process. Current risk analysis, and Ajaz did touch on that a bit. Somewhat on the comparability protocol, which we're very excited about. Strategic goals that we intend to do for the future regarding this area, and the conclusion.

Now, the Changes Without Prior Review Working Group was established by FDA'S Drug GMP Steering Committee, which was headed by Dr. Woodcock, who's the center director for CDER. The working group members. As you can see here, it's a pretty big cross-representation from the three centers and various offices, and it's co-chaired by Drs. Hussain and Sager.

What is the charge of the working group? It's to examine the current state of the supplemental change approval process, specifically those manufacturing changes requiring prior FDA approval. And it's to identify and recommend implementation of other means to reduce reporting requirements. For example, the use of risk management tools, comparability protocols, product development information, and PAT, which Dr. Hussain just talked about.

The purpose of the workshop, when we presented it, was to present a summary of FDA's current thinking and activities regarding the supplemental change approval process and to stimulate discussion and constructive feedback from the stakeholders.

Background. What are legal requirements regarding supplemental applications? This pretty much started out from what I'm going to talk about, basically from the FDAMA, Food and Drug Administration Modernization Act of 1997. The legal requirements are that the applicant must notify FDA of each manufacturing change in accordance with section 506A of the Federal Food, Drug, and Cosmetic Act and when it's finally finalized within our regulations for both CDER and CVM. CBER has very similar language.

So pretty much, the applicant must report any manufacturing change that was approved in the file. If they make any changes, they must report it to us. But there are different mechanisms of reporting, and as I stated earlier the prior approval supplements are the most burdensome.

As part of the reporting of these changes, the applicant must also assess the effects of any change on the identity, strength, quality, purity, and potency of the drug as they may relate to the safety and effectiveness of the drug before distributing the product made with the change. In layman's terms, that means they can't market the product until they get approval from us. That's for prior approval supplements. And as part of this application, they must provide information to us, data, anything that convinces us that they've done enough studies on this change, that the impact of this change will not have a significant impact on the quality of the drug product and will not impact the safety and effectiveness of the drug product.

There are four legal reporting categories under FDAMA and these include: prior approval, immediate CBEs, CBE-30, and annual reports.

Prior approvals are for major changes, and major changes are those types of changes that have a substantial potential to adversely affect the identity, strength, quality, purity, or potency of a product. Products made with a major change may not be distributed until approval. We have identified a lot of these major changes through guidances. Some are identified in our proposed regulations.

The next category is considered moderate changes and there are two types of moderate changes. Reporting categories: these are immediate CBEs and CBE-30s and these obviously have a moderate potential to adversely affect of the drug product. Now, for immediate CBE-type changes, the product may be distributed at the time that the change is reported to the FDA.

The one that's actually more popular, at least for CVM, what we see more often, is the 30-day CBE. That allows the agency 30 days to determine whether that particular change that they're reporting is either a moderate or minor change or it's a major change. If we feel it's a major change, we notify the sponsor and then we review it as a prior approval and they may not implement the change. However, if we feel that, yes, we agree that it is a moderate change, they may implement the change after 30 days.

Then we have annual reports. This is where all the minor changes are being reported. These obviously have minimal potential to adversely affect the drug product. Obviously, they may be immediately implemented.

Now, the section 116 of FDAMA, which is 506A of the Act now, meet the expectation of providing regulatory relief by lessening the reporting requirements of manufacturing changes without compromising the drug's quality, safety, or effectiveness. I believe the answer is yes, with a caveat. A little bit of background here.

Many of the types of manufacturing changes that you are going to report to the agency are identified through regulation and guidance. Section 506A of the Act and our regulations, at least the proposed regulations, identify major, moderate, and minor changes.

We have what I call changes guidances that are currently published. These are changes to approved NDAs or ANDAs. You see there's one for CBER and also one for CVM. These are fairly harmonized documents between all three of the centers. They do identify in more detail the different types of changes and different categories.

Then we have various PAC and SUPAC guidances that also identify even more types of changes under the different categories, but in addition, they also describe the type of documentation to file in support of that change to the agency.

What was the impact of FDAMA on filing? I have it for all three centers, and since I'm from CVM I have CVM first. As you can see from pre-FDAMA times ‑‑ that's up to 1997 ‑‑ about 95 percent of our manufacturing changes were reported as prior approval supplements. Post-FDAMA, 1999 to present, you can see that it dropped down to about 20 percent for prior approval with a significant increase in CBEs and annual reports.

CDER, for this three-year period from 1999 to 2001, sees the same trend for both pioneer and generic drug applications. As you can see, it's dropped fairly significantly for prior approval supplements, and there's obviously a concurrent increase in the CBEs.

CBER sees the same trend over a six-year period, going from 100 percent for PDUFA products down to, it looks like, about 25 percent for prior approval supplements.

So yes, these are a significant increase and decrease in the number of submissions we're seeing. So FDAMA has significantly reduced the reporting requirements. However, we recognize there could be an additional improvement in the change reporting process.

What are our current concerns regarding the supplemental change process? Though, as I've shown you earlier, the relative percentage of prior approval supplements as compared to the other reporting categories has significantly decreased, however, the number of prior approval supplements are starting to increase because we're talking about relative numbers. So we're getting a lot more supplements based on a lot more original approvals. So we're still seeing a high number of prior approval even though the relative number has decreased.

Though it significantly reduced overall from pre-FDAMA times, the number of reporting prior approval changes remain high for certain product types and processes. For example, sterile products is specifically more in the aseptic processing, which will be a very difficult issue to tackle because with all the models we've used so far or are contemplating, these are considered high-risk products and will likely still remain in the prior approval. But I think we still need to work in that area and try to reduce that burden somewhat.

We recognize that any prior approval change could affect business planning and possibly impede innovation. You have to remember, they require prior approval from us before actually implementing the change, and legally they have up to 180 days, which is six months, to make that change. Obviously, there are some variations because of PDUFA, but on the record legally, it's 180 days and sometimes it takes longer to get the approvals out. So six months is a long time to do business planning to make a change.

There's no guarantee that prior approval supplements will be approved during the first round. It's our experience ‑‑ and I assume it's very similar to the other centers ‑‑ that 40 percent of the first round prior approval supplements are found to be incomplete. The data was not sufficient. The GMPs were not adequate. There could be all kinds of reasons.

We also have a compliance dilemma if we find that a changes being effected for an annual report reports a change either that should be in a higher category or the data that assesses the effects of the change is inadequate. What do we do if the change has already been implemented? Obviously, the act does allow for us halt distribution of a product, but it takes a lot of resources to do that. A lot of times, we like to work with the company to get this resolved, but it is a dilemma and the companies do realize that this is the dilemma that they face, that they need to address when they make these changes. Some companies are actually very reluctant to do CBE changes because of this reason.

What are potential solutions?

Use of comparability protocols. And I'll discuss that a little bit more later, and I think that could address many of the issues I just finished talking about.

Drafting and publishing more PAC, SUPAC guidances.

Identifying potential risk management tools.

And encouraging the use of product development information and process control improvements, for example PAT. For product developmental information, we'd like to see the developmental report because basically the companies know how their product works, what doesn't work. A lot of times we don't see that development work. That's not really part of a requirement to submit that to us as an agency. But if we see that information and they can convince us that this product is rugged, this type of change doesn't affect it, if they have that type of information, then they can propose for future changes alternatives rather than a prior approval supplement or a CBE supplement.

Current risk analysis. Ajaz covered this a bit and it's a very simple model for supplemental changes. We have three potentials for adversely affecting a drug: a significant, moderate and minimal potential. The level of risks are corresponding: high, there is some risk, and there's a low risk. If it's a high risk, yes, you need a prior approval supplement. If it's a moderate risk, no, but you need a CBE supplement. And if it's a minimal risk, it's submitted in the annual report.

Now, how do we determine whether a change is major or requires prior approval? When I originally wrote this up I was thinking ‑‑ because I am a team leader in CVM and I deal with these issues on a daily basis. Companies call me up, I get 30-day CBEs and I have to make that determination whether it's major or minor. These are the types of questions I would go through, and it's pretty much I think what the agency does go through, too.

The first question that would come up, what is the likely impact of the change on the identity, strength, quality, purity, and/or potency of the drug product? And obviously, we have some changes that are actually identified in the act that they must submit as major changes, but if we believe that it has a potential adverse effect then it's likely a major change. So it's important again, in the original application, to build up that knowledge base so that we know that this is not going to have an effect.

Will additional clinical or non-CMC like tox studies be required? If yes, then it's likely a major change.

Is the reported change either not well described, too complex, or is the potential impact on the drug's safety or effectiveness not certain? If yes, then it's likely a major change. And I see this a lot. A lot of companies say, okay, we want to make this change, but there's no justification, no rationale. It's not described very clearly. For example, with a 30-day CBE, I only have 30 days to make the assessment, and I have many other applications to go through. I don't have time to actually do the review and determine whether it's going to be a moderate or a major change, so I'll be very conservative and make that a major change.

If applicable, what is the current GMP status? If unacceptable, then it's likely a major change.

So what's the basic question that we use when we address a risk assessment, when a risk assessment is performed regarding a CMC change? Basically it comes right out of the act. It is, what is the potential ‑‑ or in other words, what is the risk ‑‑ for the change to adversely affect the drug product? The potential risk for a CMC change increases when the knowledge regarding the potential impact of the change decreases.

What is the purpose of a prior approval supplement for specific changes? Well, these are changes that we identified, those having a substantial potential to adversely affect the drug. This is just based on our history and our experiences in reviewing these drug applications. We have these listed in the regulations. We have these listed in the guidance documents. And it allows the FDA time to review and concur or not concur with the proposed major change and its assessment prior to product distribution.

FDA tends to be conservative in regard to accepting levels of risk. If we are not certain about the potential risks, then a higher filing category will likely be required. That goes, again, back to building up that knowledge base for original approvals. PAT will nicely address that also.

FDA employees use risk analysis daily. I think everyone here uses risk analysis daily. For example, deciding whether a change is major or moderate, that's a thirty-day CBE assessment. In CVM, that's a team leader's job. That's what I do. Deciding whether the assessment of the change is satisfactory or not is part of the review process. Deciding whether a GMP inspection is required or not. And you can see CBER has an SOP regarding that.

However, risk assessments for CMC changes are neither formalized nor uniformly structured throughout FDA. It can either be very subjective individually as, for example, myself as team leader, I make a decision. It may not necessarily be what the other team leaders agree to, or as a group. Maybe CDER makes a decision that may not necessarily be what the other centers agree to.

Possible ways to reduce the risk potential include the use of comparability protocols. The premise is the acceptance of proposed assessments of anticipated change will likely lessen risk of implementing the change, which will lead to less burdensome reporting categories.

An applicant may establish their own filing criteria based on developmental information in original or supplemental applications. The premise is increase in scientific understanding or knowledge of a change's impact may lessen risk for implementing the change and could lead to a less burdensome reporting category.

Incorporating significant process control improvements. For example, PAT. Improvement in process controls may lessen risk for producing poor products and could lead to less burdensome reporting categories.

Can other risk analysis models be used to identify the level of risk for implementing CMC changes? For example, can we identify through risk assessment low-risk drugs, dosage forms, processes, et cetera, and significantly reduce the number of changes requiring prior approval before implementation?

Now, on to comparability protocols. What is a comparability protocol? A comparability protocol is a well-defined, detailed, written plan that prospectively specifies the test and studies that will be performed, analytical procedures that will be used, and acceptance criteria that will be achieved to assess the effects of specific changes for specific products.

A draft guidance for CPs has been published recently, for what I call the small molecules, and the public comment ends by the end of next month. A CP is described in the proposed regulations, and actually in the current regulations too, and FDA believes that additional prior approval changes can be reported in CBEs or annual reports through the use of a comparability protocol.

What are the uses and benefits of a comparability protocol? If you recall, a comparability protocol is actually submitted to us as either a supplemental application ‑‑ so it is a prior approval, so we do have a prospective analysis of that ‑‑ or it can also be submitted as part of an original application.

What are the uses and benefits? It can allow for a reduced reporting category of CMC changes covered by the approved CP. The CP can describe single or multiple related CMC changes, including those that may occur sequentially over a period of time.

Earlier implementation of manufacturing changes. Likely reduction in incomplete deficiency letters issued by FDA, more first-round approvals, because the means of assessing the change has been approved in the CP. This gets back to my earlier slide when I said 40 percent of the prior approval supplements are found to be deficient. If we had a prospective analysis of those types of changes, and we agreed to the type of testing they will do, then likely that would be reduced significantly and we could get more approvals out.

They allow a sponsor to design his own changes filing and documentation criteria based on experience with the drug product or similar drug products. For example, developmental studies. Ajaz coined the term, "make your own SUPAC" concept.

It allows sponsors to continually improve manufacturing processes without necessarily requiring prior FDA approval, potential for PAT implementation. I can see PAT being introduced as part of a comparability protocol.

Reduces the potential risk for the change to adversely affect the drug.

And it's the potential win-win situation for a public, industry, and FDA. You get timely products. The quality in many cases actually improves if you use PAT, and it actually reduces some of the burden of reviewing from our end.

Unfortunately, for CPs, there's limited CDER experience, and absolutely no experience for CVM, so I'm the perfect person to talk about this subject. CBER has most of the experience because I believe the comparability protocol is a concept that was devised by them. Currently they have more than 100 comparability protocols that have been successfully used for CMC changes for all product classes since 1997, and a submission of developmental information of CPs has convinced CBER to accept reduced reporting categories for some CMC changes.

This is very good news, I thought, because CBER tends to have more of the complex products, the biologics and so forth, as compared to CDER and CVM. So if they're able to do this then I'm certain that CDER and CVM can just as easily do it.

What are our goals? We're going to publish another draft comparability protocol called Large Molecules. That's primarily the protein molecules. Finalize both the comparability protocols, continue to amend or introduce new PAC/SUPAC guidances, and hopefully publish the final regulations for all three centers. Conduct studies. This is part of our working groups' jobs. Conduct studies evaluating existing data on prior approval changes and identify opportunities for further reducing of reporting categories. That includes determination of the number and types of prior approval supplements submitted to each center over a designated time period. To a small degree CVM has already done some of the studies, and we shared that with CDER and CBER. Identify other potential risk models or other means for reducing reporting categories, and consider additional ideas as the result of discussion and feedback received during workshops.

And these were the following discussion points that we had during the workshop. Scientific risk-based approaches for identifying low-risk manufacturing changes, the comparability protocols, and effective use of developmental data and other information to justify less burdensome filing requirements.

And that's it. Thank you.

DR. BOEHLERT: Thank you. Questions, comments? Tom?

DR. LAYLOFF: Yes. I had one question on it. This is a harmonization activity on CP, and is CBER involved in harmonization also?

DR. BENSLEY: Yes.

DR. LAYLOFF: So you're going to have a single regulation for CVM, CDER and CBER as to how ‑‑

DR. BENSLEY: We're going to have the same guidance, yes. All three centers are on the same guidance, yes.

DR. LAYLOFF: How many different guidances are there in this harmonization process?

DR. BENSLEY: In the comparability protocol? In the other ones? Well, we have what I call the changes guidances. CDER has their own. We have our own because our products are a little bit different from theirs, so we sort of have to adjust it differently, but the language is very similar. CBER has their own. SUPAC/PAC documents. I don't believe CBER has any of those, but CVM is harmonizing with CDER on a number of those. It's mostly CDER's.

DR. LAYLOFF: So the agency is moving to harmonize.

DR. BENSLEY: Yes.

DR. BOEHLERT: Any other questions or comments from the committee members? Efraim?

DR. SHEK: I have a question with regard to the statistics you have shown and the change, I believe, moving from preapproval supplements to CBEs. And I believe those changes are for the better to improve the product or the process. I wonder whether the total request for changes has increased as well because what you have shown is the relative. Are more companies submitting more requests for changes than they used to do before?

DR. BENSLEY: Yes, it's a little more difficult to define because we base it on applications. Our metrics is based on the applications. There could be multiple changes within an application, or annual reports could have dozens and dozens of changes reported in those. So it's kind of difficult to make an assessment. But it seems, from a personal experience, I think there are more changes being reported in CBEs and definitely a lot more reported in annual reports. So we're seeing less and less prior approval supplements, in general.

DR. HUSSAIN: We looked at some of the statistics on the CDER side in terms of number of supplements coming in. Since the number of applications being approved are increasing, I think the number of supplements are on the increase also. At the last count when we did that for the Science Board, I think we were over 4,000 supplements a year.

DR. GOLD: Dennis, a question. On the length of time that it takes on average to approve a prior approval supplement, has there been any change in that time period during these numbers of years?

DR. BENSLEY: I think with CDER I think they can respond to that from, I guess, the PDUFA funding. They have 120-day cycle for prior approval? I don't know.

DR. HUSSAIN: 180.

DR. BENSLEY: It's 180 days? Okay.

DR. GOLD: That's the allowed time. What I'm asking for is, do you have any statistics on the actual time for approvals?

DR. BENSLEY: I can only speak for CVM, and we're seeing a reduced time in reporting now.

DR. GOLD: Let me just say, that would be a very interesting number for perhaps this committee. Certainly it would be a very interesting number for us to look at, I think.

DR. BOEHLERT: Pat?

DR. DeLUCA: Yes, Pat DeLuca. Your slide 52 mentioned there were 100 comparability protocols that CBER had successfully processed.

DR. BENSLEY: Yes.

DR. DeLUCA: What was the number that was submitted? Do you have an idea?

DR. BENSLEY: No, they didn't share that with me, so I don't know. I would assume it would be over 100.

DR. GOLD: I have another comment. I've heard from various practitioners that in the drug product area that the preparation submission of comparability protocols is not a very attractive opportunity because they're really not able to predict the type of change well ahead of time that they may want to make. And that may largely be the reason why you have reported no comparability protocols in the CDER area.

DR. BENSLEY: I think it's a misunderstanding too, from industry. With our industry, they just didn't read it close enough. They just thought it was another protocol, and it had to be submitted as a prior approval supplement. They didn't understand what they could do with that protocol. So basically if they have a plan change in the future and they know about it, or they have changes that are constant, maybe across product lines that they know it's going to happen, then those are ideal cases to be submitted as a comparability protocol.

A lot of the companies, after the PQRI, especially for our stakeholders, they'll say, we're going to be submitting something to you now, now that we understand it. It's just a matter of getting the word out there and having them understand it.

DR. GOLD: Dennis, I hope you're correct.

DR. BOEHLERT: Any other comments or questions? G.K.?

DR. RAJU: Dennis, to what extent do the phase IV data from the world out there help you decide your risk as you go forward deciding when something should be prior approval? It seems like that's real data around safety and efficacy. Does that come into your database somewhere?

DR. BENSLEY: Yes. I mean, I only can speak for CVM. We don't have phase IV. We have clinical studies and it's based on the marketed drug product. So we don't have the same phases as CDER has. But yes, we consider the safety and effectiveness, and we do consult the appropriate people within our center.

DR. HUSSAIN: Well, I think in terms of phase IV commitment, these are predominantly clinical studies, extra studies, different populations and so forth. First of all, I don't think we have truly gone out to say what value that does add. We haven't done that analysis. And so the answer is probably not much. The clinical studies keep coming in, and I had an opportunity just recently to go through one application, all the phase IV commitment. I did not see any connection on that particular application back to the CMC process. My guess is, not much.

DR. BENSLEY: And it's even less for us.

DR. RAJU: Do you have the recalls and FIR kind of data?

DR. HUSSAIN: That's not phase IV commitment.

Let me share with you. I think this is an important point, and as part of the systems thinking, at some point we want to sort of bring in the CA/PA concept, this corrective action/preventive action. What is happening today is these reports come in in different parts of the agency and so forth. So, first of all, we don't have those connected well enough.

The second is, some of the categories we collect this information is not truly ideal. So David Horowitz and the Office of Compliance actually are moving towards a better way of managing that. I think that would really help.

I have sort of been struggling with this because I chair a committee called Therapeutic Inequivalence Action Coordinating Committee, assessing all the reports that come in on therapeutic inequivalence of generic drugs, and try to sort of connect the loop on that as part of systems thinking. We struggle a lot because the quality of information available in some of these reports do not really allow us to really get to the root cause and so forth. So there is an element of improvement for that, and what the Office of Compliance is doing with their surveillance and their databases I think will be a step in the right direction.

At some point I think we really need to go back and look at how are we capturing this, what are the categories, and so forth. I think we'll have to improve that process also.

DR. BOEHLERT: Any other questions or comments? If not, thanks, Dennis. We're now scheduled for a break and we'll reconvene promptly at 10:15.

(Recess.)

DR. BOEHLERT: We'll get started. Our next speaker is Gregg Claycamp, who's going to talk on risk analysis.

DR. CLAYCAMP: Thank you, and good morning.

I have come to the FDA only two years ago from academia, and so I am offering the GMP initiative as a more generic and theoretical approach to how risk analysis is done in a variety of fields and how it might be brought to bear on this problem.

I'm also at CVM, and one of the opportunities at CVM is that we do have a side that is an animal drug side, but we also track the human health risk through the fact that we eat food animals, and so we're looking at a broad range of risk-based issues.

This talk will start with some premise and questions. We'll spend a little time on basic risk analysis, and that is a very broad overview. It's not going to be a probability calculus exercise or anything like that. At the same time, I hope I don't talk under anyone in trying to capture a wide range of backgrounds here.

The talk will then go on to some possible ways of bringing risk assessment into this initiative, and risk management. Risk ranking is a possible way of doing that, and we'll talk a little bit about that, then conclude with some other ideas on pilot scales. And, of course, these ideas are only discussion at this point. There isn't a guidance that I'm either presenting or promoting at this point.

The way that I've looked at this problem and heard it from a variety of work groups that I've had an opportunity to visit and work with is that the in GMP process, from an inspectional point of view, there's a variety of risks, and those might be linked to actual items in the GMPs or not, but they're kind of all over the map in terms of the actual risk to public health. And at the other side there is the risk to the patient and, more generally speaking, the risk in public health terms. These two factors are really out of alignment in the current conception of this issue.

What we would like to do is to line up the actual inspection part of GMP and the concepts in GMP risk assessment with the actual patient risk and/or public health risk in a broader sense. That's certainly not an easy task to do. Like many have said, it's a process of getting together and deciding who's going to make first steps at this very difficult and tricky area to work in.

Somewhere back in history we can assume that each one of the GMPs had a risk basis for it in the first place, but things change over time and we need to think about how to reassess those risks and realign the GMP risk with the actual public health risk.

So the question, as I see it, is can risk management theory tools or practice be employed in this process, and secondly, there's a broader need of how can we share a common language about risk and risk management, and ultimately science-based decision making so that we can develop a high quality risk management model in this area.

What theories and tools and lessons have been learned in risk analysis that can help address these questions? Well, there are off-the-shelf models and tools that might be used, for example, and there are other questions that we might ask about which risk management processes can foster the changes needed in both the regulatory and industrial arenas.

Well, starting with some basics, as I taught for quite a while in academics, the first question I brought to a course the first day of every semester in a risk course was, how many of you out there do risk assessment? It's surprising that even in a graduate school of public health you don't get very many hands going up. In fact, risk and its concept is extremely broadly based, and it's something that everybody does all of the time. So in that sense it can be something that's extremely intuitive. That is to say, you do it without any conscious forethought. And at the same time, most of us can think