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. My name is Judy Boehlert, and I'm chairing this Subcommittee on Manufacturing of the Advisory Committee for Pharmaceutical Science. I always have to stop. I always say it the wrong way. I say Pharmaceutical Science Advisory Committee.

I welcome you all to today's meeting and tomorrow, hopefully, as well. I'm looking forward to a very productive interchange of ideas. I know we should have that based on the caliber of the committee members I see here, and I'm looking forward to your input.

Our first order of business this morning is to introduce ourselves for the benefit of those on the committee who might not know everybody and for those in the audience. As I said, I'm Judy Boehlert. I am a consultant to the pharmaceutical industry and I consult in areas of quality, regulatory affairs, product development on scientific and compliance issues.

So if we could start around the table, and Efraim, if you would introduce yourself. It's a way to check if the mikes are working as well.

DR. SHEK: Efraim Shek from Abbott Laboratories.

DR. LAYLOFF: Tom Layloff. I'm with Management Sciences for Health, an NGO working developing health systems in less-developed countries.

DR. SINGPURWALLA: I'm Nozer Singpurwalla, George Washington University.

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, Professor of Pharmaceutical Sciences at the University of Kentucky.

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

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

MR. SERAFIN: Dick Serafin, consultant primarily in the manufacturing area.

DR. GOLD: I'm Dan Gold. I'm a consultant from D.H. Gold Associates. We consult with regulatory and manufacturing compliance issues.

MS. WINKLE: I'm Helen Winkle. I'm the Director of the Office of Pharmaceutical Science, Center for Devices ‑‑ Devices.

(Laughter.)

MS. WINKLE: Boy, I'm not too quick this morning. Thank you. I've been on vacation for a couple of days. I forgot where I work. Center for Drugs and Evaluation.

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

DR. BOEHLERT: Thank you.

Our next order of business is Karen Templeton-Somers will 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 this 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. Thomas Peck, Dr. Gokeju 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, Ken Lavin has no financial interest or professional relationship with any pharmaceutical company. Gerry Migliaccio is employed full-time by Pfizer, Incorporated, and is a member of PhRMA GMP Steering Committee. 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.

I would like to back up a little. I think there was a typo here. It's Dr. Garnet Peck. Right? Not Dr. Thomas Peck. Okay, thank you. And he has a general matters waiver.

DR. BOEHLERT: Thank you, Karen.

Our first speaker this morning is Helen Winkle, and she will introduce the topic in today's agenda.

MS. WINKLE: Well, my job this morning is to welcome everyone here on the Manufacturing Subcommittee. It is really nice that we could get together. The last time we were scheduled to meet, which was the first meeting, we had an orange alert. The war was starting, so we had to cancel the meeting or postpone the meeting, and here you all come today and we have another orange alert. So maybe it's the subcommittee.

(Laughter.)

MS. WINKLE: But anyway, I want to welcome everybody.

This is a really exciting time for us in OPS. We're really excited about getting this subcommittee started. I think there are going to be a number of really important issues that are going to come before the group, and we are looking forward to working closely with you on those issues.

I just want to give you a little idea of why we're having the Manufacturing Subcommittee, where it sits in the structure of the Advisory Committee for Pharmaceutical Science, and just an idea of what we anticipate that this subcommittee will do.

Why was the committee established? I think mainly what we were thinking about from the advisory committee standpoint was it was important for us to focus on manufacturing science. It's a real important part of what we do in the Office of Pharmaceutical Science and a real important part of where we're going under the GMP initiative. It affects not only how we do review, but how we do inspection as well. We felt like it would be very helpful to have experts from outside of the agency to work with us so that we could get a better understanding about manufacturing and a better understanding of where we needed to go with our various initiatives.

Basically it's a time to look at what is critical for quality and design in manufacturing. It's really important that the whole agency focus on this, but again, we need some help in looking at what is critical to quality and how we need to go about doing this.

Also, we think it's important that we be open in our communication on this, and through the subcommittee, it is an open public meeting, and there are issues I think that we can talk about publicly here that will help all of us, both in the agency and in industry as well as others, to help understand what we're doing and where we're going and also focus on what we hope to accomplish over the next few years with this subcommittee. I think we're going to look at levels of information and data that are needed in the applications in the review side, and we'll also look at changes to manufacturing and, through the committee, help us understand better what we need to be focused on when we're looking at these changes.

One of the examples of that is comparability protocols. We already have a draft out on comparability protocols. But I think many of you might have been at the GMP workshop a couple of weeks ago. There are still a lot of questions out there that need to be answered both from an agency standpoint, as well as the firms' standpoint. So this will give us an opportunity to take a look at things from the subcommittee and to get some assistance from the subcommittee on where we need to be going.

We need to validate the science behind the review. I think this is very important to all of us in the center. I think there's a lot of science in the review area, but I think that we need to have a better handle on that science and better focus on what it is.

Also, I think the subcommittee can help us address the science that really needs to be validated through research. We have the capabilities of doing that research internally, as well as through our Product Quality Research Institute. So I think the subcommittee can be important to us in thinking about those areas where we need more data, we need more information, and helping us to focus on that.

Basically why now? Why have a subcommittee now for this? I think, first of all, the time is right. We need to look at change as being good. There is a lot of good change out there, and I think the agency has been hesitant to move toward change. We in the agency now realize that we need to do that. We need to change internally, as well as work with industry, to begin to implement change, and we need in the agency to be able to facilitate that change.

And by facilitating that change, I mean understand what is needed, what we need as far as good manufacturing science, what we need as far as good quality built into the design of the products, and we need to have a better understanding of that. We hope to work with every one of the members on the subcommittee to help us think through these changes, to think through what's needed, and to help in facilitating that and what we need to do to facilitate that.

Also, we need to focus on risk management. I think that every place you go now, there's a lot of talk about what's risk management. In some cases, we're not completely certain what are the elements of risk management. So working with the subcommittee, we hope to be able to have a better handle on that. At the next meeting of the subcommittee, in what we hope will be October, we really want to look at some of the risks that are out there and how best to prioritize those when we're looking at taking compliance actions or doing some inspections in the future.

Of course, I've already mentioned the PAT initiative and the GMP initiative. These are two really important initiatives in the center that have been driving us forward for the last almost year-and-a-half/two years, and they are very important to what the subcommittee will be doing. It's a good time to bring the subcommittee together to sort of help facilitate both of these initiatives.

There was a PAT Subcommittee. I think there were several people here on the subcommittee that are on the Manufacturing Subcommittee. There are still areas that we need to pursue, and I'm hoping that the subcommittee can do that.

I mentioned the GMP workshop. There were a lot of issues that came up, a lot of questions that came up at the GMP workshop. A number of these questions still need to be answered internally in the agency. So we're hoping, with the help of the subcommittee, that we can answer some of these questions and begin to put out information and data that will be helpful to industry.

The CDER/CBER merger. There are new therapeutic products, of course, that will be coming under CDER's jurisdiction, and we need to take a look at what best principles are. I think we'll have questions along the line. We really will see a number of elements in both areas, in the CDER products and in the products that are coming over from CBER where we need to answer questions on how best to address review issues with those products. So I think the subcommittee can be very helpful here, and it's very timely the subcommittee is being set up at this time.

Of course, global harmonization continues to be an important part.

And lastly, I have on here better resource utilization. This is important. It's important to us in the center and I know it's important to all of you in the firms, and I hope to work closely with the subcommittee as we think about how best to utilize our resources, especially in the center as we move forward in the 21st century.

The other thing that's important too is we find more and more need to coordinate between some of the issues that we have with generic products, as well as new drug products. There are things that will come up at this subcommittee that will affect both areas of regulation and areas that we need to answer questions on how best to address. So, again, the time is ripe for this subcommittee, and I appreciate all of your participation on it.

Structure. Just to mention real quickly, the relationship to the main advisory committee. This is a subcommittee under the main advisory committee. There are actually five subcommittees that will be under the advisory committee. The other four committees are the Clinical Pharmacology Subcommittee, which has already met; the Biopharmacology Subcommittee, which is scheduled to meet later in the summer; the Pharmacology and Toxicology Subcommittee, which is going to meet for the first time in June; and the Microbiology Subcommittee, which will also meet later in the summer.

We set up this structure because it was very difficult from the perspective of the main committee to focus on the numerous issues that are out there regarding the things that are regulated within OPS and throughout the center. It's very difficult to bring together 13-14 people with diverse backgrounds and have them focus on a specific issue. So we felt like the subcommittee structure was a good structure to have where the subcommittee could then make recommendations to the advisory committee as to specific areas that needed to be changed or specific recommendations for ways to go in the future.

The composition in the Manufacturing Subcommittee. Of course, you met all the members here this morning. Each of you met each other. And I want to thank Judy Boehlert for taking the time out to help us with this subcommittee. She was a member of our advisory committee and very, very helpful to us at looking at various issues having to do with chemistry review and other CMC issues. So we appreciate her helping us.

Based on that, that's all I want to say. I do want to welcome the committee again. I look forward to a really exciting time working together.

Today basically what we're going to focus on is a lot on the GMP initiative. As I said, there are a lot of things under the initiative that I think working together with the subcommittee we can address, questions that we have, areas of manufacturing science that we need to focus on. So we have quite a full agenda.

David Horowitz and I are going to talk a little bit about the initiative this morning, and then we will spend the rest of the morning and part of the afternoon really looking at trying to prioritize how we want to go about working on some of the projects because there are numerous ones.

Again, as I said, at the GMP workshop two weeks ago, a number of issues were identified, a number of questions were asked by industry on how we were going to get things done, and we'd like to start with the committee actually helping plan how we need to tackle some of those things. So Dr. Hussain is going to walk you through this this afternoon after several presentations, beginning to look at how we want to handle this.

Tomorrow we're going to continue along with the GMP, but we're also going to have an update on the PAT and an update on aseptic processing. The subcommittee has not ‑‑ of course, this is the first time it's met ‑‑ heard either one of these issues addressed specifically, but I think the PAT Subcommittee has sunsetted. There are a number of issues that came out of that committee which we'll present tomorrow. And then the aseptic processing update will basically just be an update of what we talked about with the advisory committee, as well as an update of the work that was done at the Product Quality Research Institute. So I realize you all have not been really briefed on this particular initiative that we had ongoing or this particular guidance. So it will just sort of be an update as to where we are and where we're going in the future.

So with that, I'm going to move on to my next presentation. Actually David Horowitz is going to give the first part of the presentation, and fortunately, David is here now. So we will go ahead and start with that. We wanted to, as I said, give you an overview of the GMP, where we are or where we're going. David is going to start out talking about how we got where we are and basically the reasons behind why the initiative came about. So I'll hand it over to David.

MR. HOROWITZ: Good morning. Thank you for having me here. I'm glad to have an opportunity to address this subcommittee of the advisory committee, and I hope we have a chance to interact informally and a chance for me to answer any questions you may have or hear comments you may have.

I wanted to talk to you a little bit today about FDA's GMP initiative, which is really a drug quality initiative. It's broader than just manufacturing inspections and their oversight. I'm going to talk a little bit about some abstractions today, with a few specifics along the way. I'm going to talk about why FDA undertook this initiative, dividing that into some challenges in the environment and some opportunities. And not surprisingly, there's some overlap between those two. I'll talk a little bit about the scope of the initiative, and then I'll talk about the goals of the initiative. I'm not going to talk too much about the specific tasks and projects, but I'll give you a few examples to make it a little bit more concrete. And then Helen will follow up with some more of the specific projects that relate to these goals. Hopefully, I'll provide somewhat of a framework that explains why we're engaging in certain of the specific tasks that we're engaging in.

So I'll talk about external goals, and by that I mean goals for the drug manufacturing and drug development industries, and internal goals for FDA, and then other guiding principles that may not be our major internal goals, but are part of our objectives here.

Why did we undertake this initiative? The first thing is that it's been 25 years since the FDA substantially changed its approach to the oversight of drug quality, and in particular, the last major change was the 1978 revision or comprehensive overhaul of the agency's GMP regulations. There have been other incremental shifts since then, including FDAMA's easing up on some of the requirements associated with manufacturing changes and SUPAC, which you'll hear more about later today.

But not surprisingly, there have been quite significant changes in the environment of pharmaceutical regulation over the last 25 years, and I'll talk about some challenges and some opportunities created by those major environmental changes.

The first challenge I think for us is the dramatically larger role that pharmaceuticals have come to play in health care and will continue to come to play in health care, as well as the larger number of products. Well, what does that mean for FDA? That means we have a larger number of drugs, a wider range of drugs, all different kinds of drugs in different classes. That creates a regulatory challenge for us. We need greater expertise, for example, and greater manpower to deal with that.

This gives you an idea that our resources have not increased with the increase in the rate of drug development and the growth of the pharmaceutical manufacturing sector. What you can see from this is that our ability to conduct GMP inspections, manufacturing oversight inspections, has declined by almost two-thirds over the last 20 years.

So another related factor that's made it even more difficult for us to keep up with our available declining resources is the pharmaceutical industry has become increasingly globalized. There's also been an increase in foreign manufacturing sites. It wasn't true 25 years ago, the way it is now, that about two-thirds to three-quarters of the active pharmaceutical ingredients, really the most important part in many respects of the finished dosage form, are manufactured abroad, often in third world countries that are harder to get to and more expensive to get to and more difficult, therefore, to oversee with the same level of scrutiny.

We've also seen dramatic advances in pharmaceutical science, including the application of biotechnology to drug discovery and manufacturing. As I alluded to a moment ago, drugs have become more complex. Manufacturing, therefore, has become more complex and diverse. That's a regulatory challenge for us. A large number of manufacturing supplements have been submitted to the agency and that number has only increased with the number of drug applications that have been approved. And yet, our resources have not kept up with that.

However, at least in the PDUFA area, to some degree, there's been an increase in resources available on the review side. But that's created somewhat of an imbalance, in my opinion, in the approach that we've taken to the oversight of the quality of pharmaceuticals.

There are some opportunities here as well. There have been major advances not just in the science of drug development, but in manufacturing science and technology throughout all manufacturing sectors. But you'll hear more today and you've probably heard plenty already that there is a great deal of opportunity within the pharmaceutical manufacturing sector and that much of the technological advances that we've seen adopted in other manufacturing segments have not yet been adopted and adapted in the pharmaceutical sector.

We've also seen significant advances in the science of quality management, including quality systems approaches. So 25 years ago, when we rebuilt those pharmaceutical GMPs, concepts of quality systems and quality management were really in their infancy, to say the least. Since that time, we've seen a lot of development in the area, and FDA has made some incremental changes to its approach to regulation. In particular, I think the device regulations do an excellent job of incorporating the state of the knowledge and science when it comes to quality management. HACCP in the food area is a systems-based approach, in essence. More recently, without changing our GMP regulations, we have taken a systems-based approach to applying or overseeing our GMP regulations.

Other opportunities I think that have come from the change in the environment are dramatic changes in our ability to apply risk analysis and risk management. Some of our data analysis capabilities that have enriched risk analysis and risk management come about naturally as a part of the information technology revolution. There is data that we can analyze today that we simply could not have reasonably or easily analyzed 25 years ago, and that creates a wide range of opportunities for FDA and for industry.

Now, again, I think risk analysis and risk management is not foreign to foreign manufacturing, neither is it foreign to FDA. But I do think it's more systematically applied outside of the pharmaceutical sector and outside of FDA. Risk management approaches in government on the regulatory compliance side are really gaining wide acceptance and they have a great deal of experience with this at EPA, at Customs, at OSHA, and everyone's favorite agency, IRS. We are just beginning, I think, to tap into this approach as a regulatory approach, and I think there are also opportunities for industry to focus its energy and resources using risk analysis and risk management.

Let me talk a little bit about the scope of the initiative now. It's not just drugs. You'll hear me using the word "drugs," but what I mean is broader than just drugs. The last bullet there involves all of the pharmaceutical centers, CDER, CBER, CVM, and the component of the agency that encompasses our entire field force of 4,000 or so people, the group that enforces and inspects our GMP regulations.

Going back up here, it involves more than just GMPs. It involves the submission, review, or the application component, chemistry and manufacturing controls, CMC. It certainly involves inspection, and it involves standard setting more broadly. Standard setting I think applies both in the review context and in the inspection context. To the extent we're interpreting and applying GMPs, we're setting standards.

I mentioned that it applies to veterinary pharmaceuticals, as well as human pharmaceuticals and biological drugs.

It's a two-year initiative. It was first announced in August of 2002. We issued a six-month progress report in February of 2003. You'll be able to find that information on the FDA web site in great detail, if there's anything that I say that interests you.

First, I'll talk a little bit about the external goals, and then I'll talk a little bit about our FDA internal goals, and I hope you'll see some parallelism between the two, or at least some connection.

We want to facilitate and encourage the adoption in pharmaceutical manufacturing of the latest advances and innovations in three main areas. These are really the three themes running through the GMP initiative: manufacturing science and technology; quality management, including quality systems approaches; and risk management approaches.

Now, why do we care about that? CDER's mission, which is a part of the agency's mission, is to make safe and effective drugs available to the American public, and we believe that facilitating innovation and availability of safe and effective drugs are consistent with these objectives here.

There are a bunch of working groups that Helen will talk more about that are focused on our internal tasks, and I'll relate those to our internal goals, but I won't stay too long on this slide because I think Helen has it as well.

Primary internal goals. Well, the first piece, not surprisingly, is the quality systems piece. We need an internal quality systems approach. We need to achieve greater coordination and synergy from better integration of the submission review and our facility inspection components. In other words, the application review and the inspection folks need to be integrated in a way that I think we haven't fully accomplished. We need to generally enhance the coordination between the field and the centers and among the centers that regulate pharmaceuticals.

Now, these are all consistent, we believe, with a quality systems approach. This kind of integration and looking at the totality of our approach to regulation is important. We need to enhance the consistency in applying science-based standards for both the submission review and the facility inspection programs. We've formed, toward this end, a work group in internal quality systems, and there is a great deal of energy that will be devoted to this task in the coming years.

The second major internal goal, implementing systematic risk management approaches to all aspects of drug quality regulation. That includes standard setting, it includes review, and it includes inspection.

Now, we want to identify the parameters and the processes that are critical for drug quality, as well as those that are insignificant. Now, this is a key piece of risk management for us because this is a risk assessment technique or activity that will allow us to prioritize risks and better focus our energies internally for setting standards and for focusing our resources. We want to ensure that FDA resources are used most effectively and efficiently to address the most significant public health risks. As you saw on that chart, we don't have resources to burn. We need to know what's most important. We can't take the risk that we'll be focusing on some moderate risk and trying to abate that while we're ignoring something that could be more significant, a risk to the quality and safety and effectiveness of drugs.

In general, what we want to accomplish is adjusting the level of regulatory scrutiny so that it is commensurate with the risk, and there a variety of tasks that we're working on that pertain to that.

The first is work planning. We want to look at how we allocate our resources for inspection. We want to have a systematic risk-based model that allows us to prioritize our inspections according to the risks associated with the manufacturing going on at particular inspection sites. So we want to be smart about where we go, but we also want to be smart about what we look at, and that's going to include changing our guidance that we give to investigators, our compliance programs that tell them what to look at when they get there. As we have more sophisticated process knowledge and we better understand what's important and what are the critical parameters, we can focus our investigators, when they get to the high-risk sites, to focus on the high-risk things.

So I mentioned earlier adjusting the level of regulatory scrutiny with the risk. Related to that also on the review side, I think, is the comparability protocols and making sure that the application and supplement requirements for submission are consistent with risk posed by the manufacturing change.

Similarly, changes to the approach to regulating electronic records, known as Part 11, are consistent with this risk management framework. We don't want to have regulatory requirements that are completely out of sync with the risk posed by those topics which the regulatory requirements are intended to address.

The last and perhaps most important internal goal for this group is enhancing the scientific underpinnings of all aspects of the agency's regulation of drug quality. That means, in part, more science and risk-based manufacturing guidance. It means FDA learning through various opportunities from the process knowledge that can be gained from the design and development phase. What we've learned is that industry has a lot of this knowledge and gains it when they're designing and developing new drugs. Sometimes that information isn't shared with FDA because it's not required to be shared with FDA, and we think it would be very useful to have that knowledge shared so we're operating from the same page in understanding about what are some of the critical processes and parameters for manufacturing.

Also consistent with enhancing the science in the agency is providing greater opportunities for specialization, for training, and cross-cutting teams. Tasks that pertain to beefing up our science are developing a specialized core of pharmaceutical investigators in the field, known as the pharmaceutical inspectorate, to adding product specialists when appropriate on inspection teams, and the PAT initiative, which you'll hear much about.

There are some other internal guiding principles which overlap with many of these three internal goals that I talked about, and I'll just speak about these briefly.

The first is improved internal and external coordination. Well, I don't think we can do any of the other three things I talked about unless we can improve those things, and a lot of our activities pertain to improving those communications, like we're here today.

Scientific workshops and advisory committees are crucial to us achieving greater transparency and better communication.

We're developing an easier to use dispute resolution process to raise scientific and technical issues that arise during an inspection where scientific issues and disputes come about.

We want to do what we can to make sure that people better understand what a 483 is. For those of you who don't know that agency phrase, that's the list of inspectional observations that an investigator hands out at the conclusion of an inspection. It has come to our attention that those observations have been widely misinterpreted sometimes because there is not sufficient science-based guidance, and these observations of one investigator are interpreted and applied as though they are the agency's official position on what is required for drug manufacturing.

Finally, center review of GMP warning letters we think will help us improve our internal communications, as well as, to some degree, our external communications. What I mean by that is with the center's being involved in overseeing and working with the districts in the field on the warning letters, there will be greater opportunities for the field and the center to exchange their views, to raise any disagreements, and to resolve them.

The last two items I wanted to talk about that are guiding principles are international harmonization, which has become increasingly important and, from what we learned at the workshop, is quite important to the industry. We're going to be working through the ICH forum and other international fora to make sure that the approach that we're striving toward will be consistent with our goals for international harmonization.

And last and perhaps most important, we're never losing sight of the strong public health protection, which is the main purpose of this initiative and the main purpose of FDA's goals and objectives. We will not take the risk that this initiative will interfere with strong enforcement of existing standards, even while we're examining and revising our approaches. So there's not going to be a moratorium on all quality regulation. We do expect that these principles will immediately infuse our thinking, as I think they have for many months now.

Thank you very much. If you have any questions, I'll be glad to answer them when there's an opportunity.

DR. BOEHLERT: David, I think we have an opportunity right now, if there are any committee members who have specific questions, because we're well ahead of time on our schedule.

MR. HOROWITZ: Please.

DR. SINGPURWALLA: I have a comment and a question. The comment is on your chart number 5 which shows the proportion of inspections going down.

MR. HOROWITZ: Okay. That one I know by heart.

DR. SINGPURWALLA: I just would like to make a comment that that in itself is not too bad because as things improve, you probably want to monitor less.

MR. HOROWITZ: I think that would be true if we felt that things really had improved dramatically at that rate over the last 25 years, but I agree with you that we ought to get to a point, through these other techniques, that the level of inspectional resources we have are sufficient if we use our resources smartly.

DR. SINGPURWALLA: That's just a comment.

MR. HOROWITZ: I appreciate it.

DR. SINGPURWALLA: The question pertains to my favorite agency. I'm curious. How does the IRS use risk analysis ‑‑

(Laughter.)

MR. HOROWITZ: Well, they wouldn't tell me any trade secrets, so I can't pass them on to you. But in general, what they try to do is similar to what all regulatory agencies who use risk management do. They try to identify risk factors to better target. So, for example, if they determine that through various empirical and experimental methods that people who have home offices are more likely to phony things up, then they would target areas like that. That's obviously an oversimplification on my part, but in general, they devote a great deal of energy to identifying risk factors through various surveillance techniques, which includes data analysis primarily in their case.

DR. SINGPURWALLA: Thank you.

DR. BOEHLERT: Dan.

DR. GOLD: Mr. Horowitz, I also would like to address slide 5. You show a reduction of two-thirds in the number of inspections. I was not aware the field force had decreased by that heavy a percentage. In fact, I'm not aware that they decreased over this period at all. So what would be the explanation for this?

MR. HOROWITZ: Well, I think there are a number of explanations. Over the last 25 years, the agency's legislative mandates and the complexity of the world has grown. The scope of FDA's oversight has grown dramatically over the last 25 years, counterterrorism, biotechnology. Many of these resources have been pulled away to other things that were not on the horizon in 1980.

However, there's one other important factor. Some of these drug inspectional resources have been shifted to the preapproval inspection program. That's covered by PDUFA. As I mentioned earlier, PDUFA has changed the landscape to a large degree of the oversight of drug quality regulation.

There has been a large increase, also related to the 1980s' generic drug scandal I think, in increasing preapproval scrutiny. I think in part it has come at the expense of post-approval, comprehensive, systems-based GMP inspections.

DR. GOLD: But if you were to add preapprovals in and if you were to add the international inspections in, which have increased substantially during this period, what would the normalization figures be?

MR. HOROWITZ: I don't have the exact numbers, but first I can tell you that the number of international inspections has not increased significantly. The number of international drug GMP inspections that are not preapproval inspections is very low, very low indeed. It would be just a small blip on that chart. So if you added the foreign preapproval inspections and the foreign domestic, you would still see the same trend. The line wouldn't be as steep, though.

DR. GOLD: Are you excluding from those international inspections API inspections?

MR. HOROWITZ: Those inspections are just domestic, what I put up, the chart ‑‑

DR. GOLD: No. I'm talking about the summary you just gave. You said inspections have not increased dramatically overseas. Are you excluding API inspections from that?

MR. HOROWITZ: API inspections are often part of the preapproval inspections.

DR. GOLD: Yes, I realize that.

MR. HOROWITZ: And those, of course, with PDUFA have increased both domestic and foreign. I am saying that there has not been a dramatic or significant increase in API inspections that are not part of preapproval. We don't have the resources. We don't have the capacity to adequately monitor foreign manufacturing, particularly when it is not part of the preapproval inspection program.

DR. GOLD: Thank you.

DR. DeLUCA: David, it seems that table 5 has drawn some attention here. I guess the question I would ask is the numbers decreased here, but what about the time devoted? If you're spending more time on an inspection, then maybe it's balancing out.

MR. HOROWITZ: Yes. I have heard and I have seen evidence that drug GMP inspections have tended to take a little bit longer over the years, and some of you may have personal knowledge of that. As the complexity of manufacturing has gone up, in part that has resulted in longer inspections, and some have said that there's been regulatory creep in that regard.

But I've seen the numbers. I don't have them charted, but I've seen the numbers and the trend is still the same. The hours that are available or the FTEs that are available for this inspectional program have significantly and consistently declined over the last 20 years, and that's something we need to make up for by being smarter about what we focus on.

DR. BOEHLERT: Gary?

DR. HOLLENBECK: David, this is an impressive agenda. It's very nice to see all of these itemized and laid out in front of the group. I'd just like you to comment on the two-year time frame. You mentioned that it's a two-year initiative.

MR. HOROWITZ: Right.

DR. HOLLENBECK: So what do you mean by that and what do you expect to accomplish during that period?

MR. HOROWITZ: I'm glad you brought that up. I can't put anything over on you guys.

The truth is that this is a two-year initiative and that doesn't mean we'll accomplish all of these goals, stop this, and then go back to what we were doing because we all know this is really a radical shift in what the agency has been and will be doing for many years to come. In two years, we hope to be well along the path and have established the path to continue down these roads to better accomplish all these objectives. We're not going to just shut this down in two years, nor could we.

DR. LAYLOFF: I have a question and a comment. My question is over the 25-year period, how has the official establishment inventory fared as the industry consolidates across the country?

MR. HOROWITZ: Well, that's an interesting question. You'd think with greater consolidation, the establishment inventory would decrease and it would make it easier for FDA. We haven't really seen that. Even though there might be one corporate parent, in many cases they aren't shutting down manufacturing sites. As more and more drugs come to market, they haven't been shutting down the actual site. They've just been putting it under different management.

But the biggest strain for us has been, believe it or not, the growth in medical gas repackers. There are about 6,000 domestic firms that manufacture, repack, or test drugs. About half of them ‑‑ and this was not the case in 1980 ‑‑ are these facilities that take medical gas from large stand tanks and transfill them into smaller tanks, and they're subject to GMPs. In the late '80s, the resources that were being devoted to that were climbing dramatically, and it was taking resources away from the higher risk manufacturing establishments.

Since about 2000, we've significantly cut that back and those resources have been put back into what I might call the traditional pharmaceutical manufacturing oversight.

DR. LAYLOFF: And one comment. I think FDA has been strongly involved in risk management of products since 1938.

MR. HOROWITZ: Correct.

DR. LAYLOFF: Actually we led everybody else.

MR. HOROWITZ: Absolutely.

DR. BOEHLERT: Nozer, did you have another comment?

DR. SINGPURWALLA: Just a general comment. It's based on your very nice presentation. I get the general impression that when you use the words "risk analysis" and "risk management," you're taking a very, very broad-based view. I have difficulty separating it from classical statistical analysis. So I just want to go on the record as saying that when you use the words "risk analysis," it encompasses a very broad spectrum of things, and perhaps we may need to sharpen our understanding and terminology as we move along so that we can all communicate at the same level.

MR. HOROWITZ: Yes, I think that's an excellent point. For the purposes of this presentation, we wanted to sort of give a broad overview and operate on the more general levels. But we recognize internally that a great deal of work still needs to be done on focusing and sharpening our approaches and defining what we mean not just by risk management and risk assessment, but in fact what we mean by risk, what we mean by drug quality. And I think you'll be hearing more about that in the coming months.

DR. SINGPURWALLA: Just to add to that, when people in finance talk about risk, which they use quite a bit, all they mean is variance or volatility. That's the word they use. That's a cause of risk. That itself is not risk.

MR. HOROWITZ: Yes. There's a great deal of academic and industry literature applying risk and risk analysis to the financial field, to the insurance industry, even in the legal field to litigation in health care, for example. In general, one of the common threads is they talk about the severity and the probability of a particular harm. Those are two of the elements we're looking at in risk.

But, of course, one of the challenges in applying risk to drug quality for us is what is the harm. Is the harm risk of violating some regulation? Probably not. Is the harm the risk of reduction in drug quality, and if so, what is drug quality? Some have said, well, drug quality is fitness for use. Well, what is fitness for use?

So these are all questions that we're grappling with, and we appreciate your pointing out that a lot more work needs to be done in this area and we expect to have additional public discussions like this one as our thinking evolves.

DR. BOEHLERT: Any other questions? If not, David, thank you very much.

DR. DeLUCA: I'd like to just add one thing.

DR. BOEHLERT: Wait a minute.

DR. DeLUCA: Looking at this, as was already pointed out, this is quite an ambitious agenda. I can't help but think as an academician that we're at a time, over the last 10-15 years, where the area, what we're talking about here, manufacturing science and technology making advances, is an area where in our colleges of pharmacy this emphasis has been declining. Not only has pharmaceutics been declining at the expense of other disciplines in research, but as you start moving in this direction, which I think is very important ‑‑ it's music to my ears ‑‑ I can't help but think how this is declining and there needs to be some effort by the industry and the regulatory agency to try to impress upon our academic institutions that this is an area that is in need of emphasis and maintaining excellence in this area. That's being lost, and I think my colleagues here might add some comments to that.

DR. HUSSAIN: Judy, may I? I think that is a very important point, and one of my hesitations and concerns has been did we start a bit too late because I think in a sense industrial pharmacy infrastructure in academia has dwindled leaving behind a situation where I think we may not have a critical mass today coming out of schools, and that is a concern. The agency is working with the National Science Foundation also highlighting the need for this. In fact, I probably will be speaking to the deans of schools of pharmacy to reemphasize the need for this, but also trying to bring chemical engineering departments into this. So I think we are very much aware of this challenge, and I think we will seek your help to bring awareness to the right people.

DR. PECK: The point is well taken, Pat. We have been approached by several industrial units within the Midwest to try to blend pharmaceutics and regulatory affairs, and we have recently established some sort of academic approach to bridge the gap of understanding regulatory affairs and drug product design, process design.

Ajaz was with us last week as we did some specific training on PAT. It came out of that that we need to look at centers of excellence in pharmaceutics that we have left, one.

And two, we have to get others to realize the importance of pharmaceutics. I think in our educational programs over the years, we've emphasized the product and where it goes, and it goes to a patient. We have to relook at that as we approach the manufacture of products and have a true appreciation of this effort for quality. So we have a challenge for those of us who are still active in this kind of education to make certain that people understand where the product goes.

DR. BOEHLERT: Any other discussion?

(No response.)

DR. BOEHLERT: If not, I thank the committee members. I think we brought up a number of issues today that came to my mind, at least when I reviewed the background material, not the least of which is defining what we mean by risk management. So it's a good start to our discussions. Thank you.

Helen has been standing in the wings.

MS. WINKLE: While he's working on the computer, I'm just going to start a little bit. I'm going to just continue with FDA's perspective and where we are with the GMP initiative and try to go through the various task groups and just give you a quick update.

First of all, I want to thank David for coming today and talking a little about the initiative with us. I think it's really important, as the subcommittee moves forward, to realize the need for all different parts of the agency to work closely together with the committee as we look at manufacturing science and at other aspects of the initiative, as well as other aspects of how we're doing manufacturing. The Office of Compliance and the Office of Pharmaceutical Science are working very closely together to make the GMP initiative happen, but we're also working very closely to try to make other parts of the regulatory process work better within the center.

But we've worked closely too with the field organization, with the Office of Regulatory Affairs. We had hoped that John Taylor could join us today to talk a little bit to the subcommittee. Unfortunately, the timing was bad. But as the subcommittee continues to meet over the next few years, I think you will see a lot of input from the Office of Regulatory Affairs, as well as from both the Office of Compliance and the Office of Pharmaceutical Science. So I wanted to really again thank David for helping us introduce this subject this morning.

As I said, I'm just going to catch you up as to where we are and we can probably do it without the slides.

This is again the slide that David showed on the various GMP task groups. I wanted to put it back up again because I think it's important to at least keep these groups in mind as we talk about the initiative and how we're going to focus on it with the Manufacturing Subcommittee.

As you can see, basically the group is made up of a steering committee. The steering committee is across the agency. It includes all of the different centers who are involved in pharmaceutical manufacturing and regulation, and also Dr. Woodcock is the chair of that committee.

There are 14 task groups within the committee. Some of these task groups are not completely active. I'll talk a little bit about them, though. As you can see, there's a training task group on here, and all of the other task groups I think in some way will contribute to the training task group. So until they've really completely identified their working plans and where they're going, we won't have much from the training task group.

Also the evaluation group. Every initiative needs an evaluation group, and this group, although it has met, will of course not focus until some of the other tasks are completed.

The question that came up was how long the entire initiative is slated for. Obviously, there's a lot of work here. As I go through these various task groups, you'll see all that we're working on. David has already touched on several of them, but obviously two years isn't enough to complete every one of the tasks. This is a continuing improvement process I think both within the center, as well as in industry, and we'll be working hand in hand for many years out to make these improvements.

The first task group I wanted to talk about is the Part 11. I think David already touched on this quite well. Basically the goal is to change the approach to 21 C.F.R., Part 11 and incorporate the principles of the cGMP for the 21st century.

Again, there is a lot we haven't done in the last 25 years that has focused on this area except put out, I think, regulations which was confusing to everyone. So we're trying to now go back. We have put out a new guidance on this to industry. We want to amend 21 C.F.R., Part 11, both the rule and the preamble, and actually have a narrow interpretation of the scope, making sure that everyone understands that it doesn't cover systems incidental to creating paper records. It's really focused on the e-records, and we're trying to clarify that. We realize that that clarification is very necessary. Joe Famulare, who is sitting at the table, actually is heading up this work group and has done quite a bit already to help clarify in this area.

Manufacturing science. The goal here is to ensure high efficiency and quality of pharmaceutical manufacturing and associated regulatory processes and to enhance FDA's expertise in engineering and technology. I think that it's very important, the second part of this goal, from the subcommittee's perspective, to help us in the agency to have a better understanding of what we need to know in the area of manufacturing science and to help us to understand those technologies that we need to have a better understanding of and be able to apply those in the regulatory scheme.

We did have a workshop in April of 2003. I'm sure many of the people in this room, as well as people on the committee, were at that workshop. It was a very important milestone, I think, for us in the agency because it was one of the first times we've really gotten a lot of information from industry and other stakeholders on what really we need to focus on. And we are in the process now of going through that information that came out of the workshop and evaluating the information and trying to determine where that fits in our planning for the next stages of the initiative.

Also, we've talked about manufacturing some at the advisory committee, and as a result of that, we have set up this subcommittee. As I said earlier, the subcommittee I think is going to be very valuable to the agency in helping address many of the issues on manufacturing science.

Changes without prior approval. The goal is basically here to identify the opportunities to allow post-approval manufacturing changes without FDA review and approval prior to implementation. This is very important for a number of reasons, I think, resources being the main reason both on the industry side and on the agency side. But there are other important aspects of this as well. Hopefully, we'll be able to look at this, both at the subcommittee level and more at the agency level, to find other things that we can do to help simplify, as well as make changes more effectively.

We already have the comparability protocol guidance, the draft that's come out. At the workshop, we heard a lot of questions on this. So there's a lot of clarification we need to have here. That guidance is up on the web.

483 communications. David spoke to this as well. The goal here is to determine proper mechanism for communicating deficiencies and inspectional observations to industry. In many of the conversations I've had with various groups on the GMP initiative and what it means to industry and other stakeholders, there have been a lot of questions on how we really communicate the observations on the 483, a lot of questions as to what kind of effect they have on our manufacturing processes, as well as on how we regulate internally. So we really need to clarify that. We have written internally additional language for the 483s to help clarify that they are observations that are made by the inspector, but there's a lot more education and training that needs to get out there to the industry on what these communications actually need to be. So we'll be working a lot on this in the area.

This group has actually been folded into the dispute resolution group, and I'll talk a little bit about that in a minute.

But this has been important because, again, there are a lot of questions in this area on what we're saying in the observations, and I've heard from industry that many of the companies will read through the observations and actually make changes in anticipation of inspections to accommodate to the observations that have been made in other firms. So it's an area where we really need to think more about how best to get this information out.

Warning letters. The goal here is more scientific review of warning letters before they're issued to the firms and to ensure consistent application of policies and procedures. We're in the process now of implementing a new internal process so that we can get more scientific review of warning letters before they're issued. In the past, there has not been input from the scientific side or actually in CDER from the CDER side as to what the letters may say and whether they're really focused on relevant scientific issues that need to be addressed. So we're going to go back, look at that process. We'll start a process where, in fact, some of the reviewers can actually have an opportunity to look at the warning letters, along with our compliance folks in the center, to make sure that we're really addressing significant problems that need to be addressed.

Dispute resolution. I already mentioned this. The goal here is to develop consistent policies and procedures for formally resolving scientific and technical GMP issues and improving transparency of such procedures. We're in the process of developing the guidance. Actually David and I chair this working group. This was one of the things that people call low hanging fruit, and actually it's at the top of the tree.

(Laughter.)

MS. WINKLE: We're having more trouble with this particular working group than we ever anticipated.

But I think we're to the point where we do have a process identified, where we'll be putting a guidance out hopefully in the next few months. What we plan to do is have a 12-month pilot with the dispute resolution process in order that we can evaluate the process and determine where best to make improvements to it. It's been very difficult. Again, we were looking at having both an informal process, as well as a formal process, and basically we're focusing now more on the formal process so that we can get something out there that everyone can take advantage of.

Risk management. I think the questions here were very good. I have had problems myself because I think when we talk risk management, every one of us is talking something different. But as David tried to explain, we definitely need to better define risk management. But as far as this particular working group is concerned, they really have a goal to ensure that systematic risk management approaches are applied, whatever we identify as being the real risk, that we can apply so that we can better allocate resources, actually select sites for inspections based on those risks, and determine the scope of the GMP programs for both human and veterinary drugs. This is really important.

It's a big area for us and one that's going to be, I think, very complicated for us to really determine where to focus our resources. We hope to work with this group a lot in being able to help us to identify and maybe even define risk management and help us to identify what we need to be focused on as we try to apply this to actual inspections.

Pharmaceutical inspectorate. The goal here was to establish a staff of highly trained inspectors who will spend the majority of the time doing drug inspections on high-risk firms and have a close working relationship with the centers. This has not been the case. When we talked about the decrease in the number of drug inspections, as David said, there's a number of reasons why this has happened. We need to have a better handle on directing these inspections and really sort of get the bang for our buck when we send our people out. So having an inspectorate will make it possible for us to have better trained people who can do inspections more efficiently, more effectively and facilitate the opportunity to work closely with the center. This doesn't happen as much as we'd like to see it happen. I think it's very important that you have that interaction between the inspectorate and the people who are doing the reviews, the people who are in the center working them from the regulatory aspect. So this is one of the things we hope to accomplish.

We're looking at approximately 50 people. Where we are now with this initiative is that we have been working on an expert PD for the members of the inspectorate and an agreement between the centers and the field. We're looking at approximately 50 people in this inspectorate. We will probably, in the next year, have identified 25 of these people and we'll begin to work with them to do more training. What we will do is come up with a curriculum for additional courses, additional information that they really need to be able to do an adequate job in doing inspections.

Product specialist. In order to sort of supplement the inspectorate, we'd like to be able to utilize some of the people we have in the center who have a lot of knowledge in particular areas. Obviously, every inspector can't be trained in every aspect of manufacturing science, but we have experts in the center in a variety of places that we're hoping to be able to include on an inspection team that can help in strengthening the consistency of the reviews and to ensure that submission reviews and inspections are better coordinated and are synergistic. We're still in the process of identifying who these people will be. In the review areas, we've tried to narrow down who some of the specialists that we have are, people who have particular expertise in certain areas of manufacturing, and begin to utilize these people more in looking at some of the applications, as well as getting involved in the inspections. We have developed a concept paper which is up on the web.

Team biologics. I didn't want to talk much about this because I really don't know a whole lot. David is probably in a better position, but there's already been a lot of work that's been going on with the team biologics program. The improvements to this program started before the GMP initiative. It's basically been rolled into the initiative, but with taking on the new products into CDER from CBER, it really is going to be necessary for us to be more involved in this program and to have a better feel for how we need to interact with the program and adopt some of the principles of this program into our own inspectional area.

Basically the team biologics program is already in the process of adopting an internal quality management system and developing metrics to determine the impact on industry. I think this is really important. This is something we need to think more about in the center, these metrics. Standardized training and qualifications of core team members. They've implemented a risk-based work planning, and they've increased their communication between headquarters and the field. As I said, there are several things from here, I think, that we can learn and incorporate into the CDER program.

Quality systems. This is an area that still needs a lot of work with the working groups. We actually have two working groups, an external and an internal working group. We're still trying to determine how best to apply the internal knowledge that we have to be able to see where we're going with this. Some of it is we've been looking at whether we need to rewrite our regulations, whether we should leave the GMP regulations the way they are. Maybe there are parts of it we need to do. We also are looking at getting guidances out in this area. So we really know that there's a broader implementation process that needs to be incorporated, but also when we look at that, it goes beyond the scope of the GMP initiative. It actually affects how all of us do our work in the agency. So it's difficult to narrow down on that part that we need to focus on.

We have, though, as a part of this, begun to implement a quality systems approach in how we conduct CMC reviews. I hope at one of the future meetings that we can talk more about some of the things that we've done as far as the quality systems approach in our Office of New Drug Chemistry and actually get some feedback from you. So this is an area I think you're going to see more and more. As we in the center and in the agency get a better handle on what the quality systems approach is and how we plan to implement it as far as GMPs, I know that we'll be coming back to the subcommittee.

International. David has already talked about this. The goal here is to have internationally harmonized approaches to assure drug product quality and encourage technological innovation. He mentioned ICH in July where we'll begin to talk about some of these approaches. Also, there are other venues too that we'll begin to look through. We actually probably even appreciate recommendations from the committee as to where we might want to look in the future to improve that international harmonization.

There is a task group on here, contracts management. Basically this group was set up to expedite external studies of key issues to be addressed by the GMP initiative. We have several contracts that are currently being researched in the agency. One is for effective quality systems practices. We actually had planned to have a number of briefings on what we think are effective systems and to better educate our people in this direction. We also are looking at some benchmarking projects. But neither one of these contracts has been let as of right now. So we're still in the process of talking about them internally within the agency.

Other. I already mentioned evaluation and training. Both of these will be based on what comes out of the other working groups.

Next steps. I talked about these, and when I talked earlier this morning, I talked about the role of the Manufacturing Subcommittee. I think there are a number of things the subcommittee can help us in doing to move forward. Obviously, there are numerous activities that you all can help us in supporting and helping us better think through them. I mentioned today that in the agenda we're going to begin to work out a plan for the subcommittee. Working together, I think we can determine what we need to prioritize.

Also, I'd like to ask the subcommittee to help us recognize other areas that we might want to consider that we may not have thought about. When we sat down and originally set up the initiative, we looked at those things that we felt were the most relevant to helping us make changes in how we looked at issues, but I know there are things that we probably haven't touched base on, and I think over the next few meetings, we can begin to identify a number of those issues as well.

Again, I think it's an important group here. I look forward to working with you all in this area. This morning David and I have given the FDA perspective. Dr. Raju is going to give an academic perspective, and then Mr. Lavin will give the industry perspective from GPhA, and Gerry Migliaccio from the PhRMA perspective. I think this will help us all think through where we need to be going, how we need to plan out the next steps. I think they will all begin to weave together and we can begin to see the issues and identify those issues that we feel that this subcommittee can really give us some answers to.

So with that, I'll turn it back over to Judy. If anybody has any questions, I'll be glad to answer them.

DR. BOEHLERT: Any questions or comments? Dan?

DR. GOLD: Helen, one area that would leverage the available resources within the agency that you did not mention or David did not mention are mutual recognition agreements. I haven't heard anything about them recently. They would obviously relieve some of the inspectional burden. Why are they not part of this group of initiatives that you've mentioned?

MS. WINKLE: I'm going to let David or Joe answer that. They probably have a much better answer than I do.

MR. FAMULARE: As you're probably well aware, we were well on the task of a mutual recognition agreement with the European Union, and that is a very resource-intensive effort in and of itself in terms of finding each other's authority's equivalent. In terms of saving resources, the actual equivalence determination itself is a very resource-intensive task which, to this date, has not been able to be finished because of that resource involvement.

But all is not lost there. We are looking for other approaches in terms of taking advantage of what we can from our international partners. Some of that was even brought up generally at the PQRI/FDA joint meeting several weeks ago in Washington in terms of how we could harmonize, how we could take advantage of other organizations such as the pharmaceutical inspection cooperation scheme and so forth which could make us get to some of that information sharing in maybe a less burdensome way. So there's more to come in that area, but right now mutual recognition is burdened by the resource strain.

MR. HOROWITZ: If I could just add to that. The spirit that motivated the MRA, I think, is alive and well. The problem is that the equivalency determination proved to be so burdensome, and the implementation of the MRA that the EU insisted on required that all of the EU nations be found equivalent before the agency could gain any of the resource benefits of starting to implement on a country-by-country basis the MRA. Particularly now that the EU has expanded with several additional less-developed countries, that approach is not workable.

So at the moment, we're looking at other ways and other opportunities to leverage the results and oversight of other foreign inspectional bodies and working through harmonization and other techniques to accomplish the same objectives.

DR. LAYLOFF: Another thing, Dan. I think that products in the United States are part of a web which involves the FDA, but it also involves very heavily tort law. So you can't look at it from a monolithic point of view that the FDA is the sole controller of product quality. It's actually the whole legislative and societal environment that controls it, and I don't think we have that in other parts of the world.

DR. BOEHLERT: Nozer?

DR. SINGPURWALLA: Question. When you issue a 483 communication, is this open to the public or does it only go to the particular organization? Because there is a risk-benefit in that. If you tell everyone, then the others are aware that this has happened and so they will take action. But at the same time, the particular industry that has received the 483 suffers because their reputation could be tarnished. So what is the disposition of a 483? Is it public?

MS. WINKLE: It is public, and you couldn't have said it better than we would say it here. I think that industry would agree with you that this is why there are a lot of questions on the 483 is because their reputation can be tarnished, as well as what I was saying. A lot of people take advantage of that information to utilize as a way of trying to see what direction the agency is going as far as their inspections are concerned and what are some of the scientific and technological areas that they're focused on. So, yes, they are public.

MR. FAMULARE: If I could add to that, I think one of the important issues that the work group looked at was the fact that these are the investigators' observations just as they're doing the inspection, and they haven't gotten the review of the agency or been determined to be actual violations of the law, the advantage being, of course, the fact that they are available to the general public from the perspective that you looked at it, but the disadvantage is that many companies feel that once that observation is there, that they will implement it, not only in that company but in other companies, without a full airing of the issues to see if it's actually appropriate at the end of the day. So that's the problem that's being grappled with.

MS. WINKLE: One of the things I failed to mention is at least many of these different task groups are sort of intertwined with one another, and one of the things with the 483 group and how we communicate sort of intertwines with what we're doing in dispute resolution. It's to give now industry a mechanism for being able to come in and dispute some of those observations, the science behind the observations. And what's going to be very important to us in the agency is then to be able to communicate that information out publicly as well so that industry has a better opportunity to see why we have made certain decisions or observations.

DR. BOEHLERT: I think next on the list was Efraim and then Tom.

DR. SHEK: Yes, but I wanted to talk about the international ‑‑

DR. BOEHLERT: Okay. Tom, do you want to make a comment to that? Then go ahead.

DR. LAYLOFF: The dispute resolution provides a CA/PA procedure which is an internal quality system on your training of investigators. By reviewing 483s and going through the dispute resolution process, it gives you a closed loop to train the investigators not to do that again.

DR. BOEHLERT: Before Efraim, Pat, you wanted to comment?

DR. DeLUCA: Yes, on the 483. I just would follow up what Tom said.

When I teach my course in parenteral technology, I use the 483 as a springboard because you can cover an awful lot of territory just by going through a 483 covering a number of issues.

I guess one of the things that I would like ‑‑ and I thought Helen had said something about really understanding the 483 ‑‑ is that what are observations and what are violations. And I don't think that comes out too clear. I'm just wondering if that could be a focus. Is it an observation or is it a bona fide violation?

MR. FAMULARE: Anything on the 483 is an observation. Whether it rises to the level of a bona fide violation can only be determined once the agency further reviews that and makes a determination. For example, I don't have a representative. Well, we have Mike here from ORA. But one of the efforts that ORA at least made in the past towards this effort is to send a letter to each firm after the inspection and review to tell you what the outcome of the inspection was. Now, that wasn't a line-by-line listing of how you made out on each 483 observation.

But the issue and the fact still remains, as Helen brought out, that it is a public document so that if something on the 483 turns out to be, after evaluation of that initial observation, really not appropriate, as Helen said, all of industry may see this and say, well, this must be the way to go and follow along that way. So one of the things that was done by this 483 committee folded into the other committee was to put a statement further explaining the observation nature, that it's not a final agency conclusion.

DR. DeLUCA: Is there some link in the public record here or availability between the 483, what's written by the inspector, the letter from the FDA, and the response by the industry? It seems there should be some kind of linkage there to tell the whole story.

MR. FAMULARE: Well, the documents are available through FOI. The thing is that they're not all released in sequence. One thing about the 483, when it's given to the firm, it's releasable except for certain information, confidential, commercial, and trade secrets so that it's out there before the company has responded and so forth. So it's out there at the very beginning of the process.

MS. WINKLE: Two points I'd like to make is we've had this discussion ourselves within the dispute resolution working group quite a bit. One of the things we feel is very necessary in the whole process is that when an observation is determined by the field, before it even goes into dispute resolution, to not be a viable or accurate observation, that they will also put something out as an addendum to the 483 that says that this observation has been removed or it didn't have the scientific validity or whatever. We haven't come up with any words or how we're going to do it. But I think it's really important that we indicate that when an observation comes off a 483, that everyone knows it, and we don't publicize that now. The firm may know that that observation is no longer on the 483 or it's been agreed to by the district to remove it, but the public doesn't. So that's one part of it.

But I think it's really going to be important for us to find better ways to communicate with industry about the observations, that these are observations, the importance of that, because I think that the interpretation is they are violations in many cases. And I think that's why industry goes to the extreme that they do go to to try and make corrections because they don't want those same violations or those same observations when inspections are done. So we have not done a good job, I think, internally within the agency of really communicating what these observations mean.

So I think when we talk 483 communications, we're talking much more than the 483 itself. We're talking about how to get better information out to the stakeholders on what we mean by the document.

DR. BOEHLERT: Efraim.

DR. SHEK: To get back a little bit to the international initiative, I believe it's a great opportunity for society both for the regulatory agencies, as well as for industry.

As all of us know, we are spending a lot of energy on what we call the common technical documents, but if you look at them really critically, there are not too many documents that don't have to be rewritten between requirements in the U.S. and international requirements. What is basically left many times is just the frame, the outside frame, and it's worthwhile to try to harmonize. Maybe that will be an easier step than to get the mutual recognition to harmonize, as much as we can, the regulatory requirements which will enable us to come to better agreement and use the common technical documents.

MS. WINKLE: I agree. Thank you. I think there's a lot that we have to do here. It's going to be determining where we need to focus our efforts. That's why I put other venues on there because I think we have not completely determined ourselves how best to make some of the international changes we need to focus on.

DR. BOEHLERT: Gary?

DR. HOLLENBECK: Helen, I'd like to focus on the empty box there, the training box. I heard your explanation, and I think it was something like we'll see where the other boxes end up and then we'll do the training initiative. I guess my perspective you should start now. Maybe I'd like to hear your comments as to why the training and education aspects of this initiative haven't been started yet.

MS. WINKLE: Well, in some ways I think they have. I just don't think we have an identified task group yet. I think each one of the working groups has some type of education process going on. Identifying, though, who we need to train besides industry is going to come very shortly through the various working groups. I think each group is going to have specific programs that they need to incorporate as far as training is concerned.

But again, I think we have started training. I think the workshop two weeks ago was the beginning of that training. I think we'll have a number of other workshops in the very near future. David mentioned risk management. I think there are several other groups that are looking to have workshops. We may even decide to have some more stuff on dispute resolution because we feel we need to get information out there on the process very soon.

We have in dispute resolution too done a session with industry that was a smaller session than the workshop to begin to get input but to help them have a better understanding of what we were trying to accomplish.

I think, to answer your question, it has started. It doesn't have a specific working group, and I think that that will be developed very soon.

We're also talking about actually having a specific working group on communications as well because there are a lot of things, besides just actual training, that need to be better communicated as far as what we're doing.

DR. HUSSAIN: Just from a PAT perspective, I think that becomes an example for the overall initiative. You'll recall that we actually developed a curriculum and training and certification program for the PAT review and inspection team. So that is an example, but that is probably a higher level training that we are conducting right now. Last week we were at Purdue doing that. So in that sense, the training is happening from different angles. But as Helen said, I think the training group will focus more on the starting level of training and then specialization and so forth. So you'll see bits and pieces that will come together soon.

DR. BOEHLERT: Other questions or comments from the committee? Gary?

DR. HOLLENBECK: I guess my perspective is it's a big job, and if initiatives have already been started, I think coordination of these initiatives would really be ‑‑ in my previous involvement with training, history has shown it to be a big job. It's an effort which requires coordination of groups that have been highlighted in your plan so far, and I think having a group step back and take the larger perspective would be something to give consideration to.

MS. WINKLE: I think we all appreciate that comment. We need to focus there and we realize that. Thank you.

DR. HUSSAIN: I remember working with you and the University of Maryland going through the SUPAC training and the challenges that we faced there. I think the challenges are great, but I think there's one aspect that we haven't discussed here which is having the right people to start with. That is another part of this initiative. We're trying to hire people with engineering and industrial pharmacy background also at the same time. So that's a combination effort that will have to come also.

DR. BOEHLERT: Gary, did you have a response to Ajaz?

DR. HOLLENBECK: No, but at the risk of ruining my career, I would like to point out that the box that says "evaluation of the initiative" is chaired by the same person who's in charge of the entire steering committee.

(Laughter.)

DR. HOLLENBECK: I have the utmost respect for Dr. Woodcock, but I think there's an inherent conflict of interest there, and you might want to give that consideration as well.

MS. WINKLE: Thank you. What can I say without risking my career?

(Laughter.)

DR. BOEHLERT: Nozer, did you want to add something or have a question?

DR. SINGPURWALLA: Well, if there is time, I'd like to ask a question for clarification.

In one of your slides titled "Risk Management," you laid out in a very clear way what your goal is. It says to ensure systematic risk management approaches are applied to allocating resources, selecting sites and so on and so forth. That's very clear, but that is from the perspective of the FDA's operation. Is it my understanding that this initiative also involves a reciprocal attitude towards what the industry itself does towards risk management?

If so, then the two risk management tasks are adversarial. What you would like industry to do would be, in a sense, adversarial to what industry would like to do. For example, industry would prefer that you don't come and do any inspections. You would like to go and do the inspection from your point of view. So there is an adversarial situation.

What I'd like to know is, does this initiative apply both to the FDA and to the industry or does it only apply to the FDA?

MS. WINKLE: I'm going to let David address that question.

DR. SINGPURWALLA: Is that clear? Is my question clear?

MR. HOROWITZ: Yes. I understand what you're getting.

I think the initiative really has two main pieces to it. One is changing FDA's behavior and approaches, but ultimately the goal is to change things that industry does. The two will work together.

So, more specifically, what Helen referred to there on the slide, those are the short-term goals of a working group on risk management that is focusing on the internal piece as its first goal, and that doesn't mean that we're not interested in the broader approach to risk management. But that group is really focusing applying risk management concepts and principles to work planning of our own internal FDA work. That means what do we fund, where do we go, and what do we look at.

Now, that last question, what do we look at, I think actually has crossover potential. When we have greater process knowledge and greater understanding of the critical parameters and the variables that are predictive or associated with problems, that information I think is just as valuable, if not more valuable, to industry to focus its own resources and to improve and control its own quality.

So in many ways, when FDA figures out or has a better understanding of how to better focus its inspectional resources, that information will automatically be very useful to industry. F