FOOD AND DRUG ADMINISTRATION














                        Tuesday, April 13, 2004


                               8:30 a.m.




             Advisors and Consultants Staff Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland






      Arthur H. Kibbe, Ph.D., Chair

      Hilda F. Scharen, M.S., Executive Secretary




                Charles Cooney, Ph.D.

                Patrick P. DeLuca, Ph.D.

                Meryl H. Karol, Ph.D.

                Melvin V. Koch, Ph.D.

                Marvin C. Meyer, Ph.D.

                Gerald P. Migliaccio (Industry


                Cynthia R.D. Selassie, Ph.D.

                Nozer Singpurwalla, Ph.D.

                Marc Swadener, Ed.D. (Consumer


                Jurgen Venitz, M.D., Ph.D.




                Judy Boehlert, Ph.D.

                Paul H. Fackler, Ph.D., (Acting Industry


                Thomas P. Layloff, Jr., Ph.D.




                Ajaz Hussain, Ph.D.

                Chris Joneckis, Ph.D.

                Robert O'Neill, Ph.D.

                Keith Webber, Ph.D.

                Helen Winkle




                            C O N T E N T S



      Call to Order:

                Arthur Kibbe, Ph.D.                              4


      Conflict of Interest Statement:

                Hilda Scharen, M.S.                              4


      Introduction to Meeting:

                Helen Winkle                                     8


      Subcommittee Reports:

                Jurgen Venitz, M.D., Ph.D.                      34


      Parametric Tolerance Interval Test

      for Dose Content Uniformity:

                Ajaz Hussain, Ph.D.                             44


      Moving Forward--An Approach for Resolution:

                Robert O'Neill, Ph.D.                           46


      Committee Discussions and Recommendations                 53


      Process Analytic Technology (PAT)--Next Steps:

                Ajaz Hussain, Ph.D.                             70


      Finalizing PAT Guidance, Training and


                Chris Watts, Ph.D.                              89


      Standards Development:

                Ali Afnan, Ph.D.                               100


      Rapid Microbial Methods:

                Bryan Riley, Ph.D.                             110


      Committee Discussions and Recommendations                135


      Open Public Hearing

                Leo Lucisano, GlaxoSmithKline                  135

                Parrish M. Galliher, Xcellerex                 145

                Troy J. Logan, Siemens                         174

                Robert Mattes, Foss-NIRSystems                 185


      PAT Applications for Products in the Office of

      Biotechnology Products (OBP): Overview and Issues:

                Keith Webber, Ph.D.                            194

                Christopher Joneckis, Ph.D.                    213

                Charles Cooney, Ph.D.                          224

                Kevin Koch, Ph.D.                              248

                Tom Layloff, Ph.D.                             271


      Committee Discussions and Recommendations                279




  1                      P R O C E E D I N G S


  2                          Call to Order


  3             DR. KIBBE:  Ladies and gentlemen, shall we


  4   begin. This is the Advisory Committee for


  5   Pharmaceutical Science. Today is April 13th.  Those


  6   of you who have not done your taxes, because you


  7   are here working for us and the Federal Government,


  8   you will get exactly no compensation to allow you


  9   to do your taxes late.


 10             Hilda.


 11                  Conflict of Interest Statement


 12             MS. SCHAREN:  Good morning.  I am going to


 13   start reading the Conflict of Interest Statement


 14   for the Advisory Committee for Pharmaceutical


 15   Science.  I am Hilda Scharen with the Center for


 16   Drugs, FDA.  I am the Executive Secretary for this


 17   committee.


 18             The following announcement addresses the


 19   issue of conflict of interest with respect to this


 20   meeting and is made a part of the record to


 21   preclude even the appearance of such at this


 22   meeting.


 23             Based on the agenda, it has been


 24   determined that the topics of today's meeting are


 25   issues of broad applicability and there are no




  1   products being approved at this meeting.  Unlike


  2   issues before a committee in which a particular


  3   product is discussed, issues of broader


  4   applicability involve many industrial sponsors and


  5   academic institutions.


  6             All Special Government Employees have been


  7   screened for their financial interests as they may


  8   apply to the general topics at hand.  To determine


  9   if any conflict of interest existed, the Agency has


 10   reviewed the agenda and all relevant financial


 11   interests reported by the meeting participants.


 12             The Food and Drug Administration has


 13   granted general matter waivers to the Special


 14   Government Employees participating in this meeting


 15   who require a waiver under Title 18, United States


 16   Code, Section 208.


 17             A copy of the waiver statements may be


 18   obtained by submitting a written request to the


 19   Agency's Freedom of Information Office, Room 12A-30


 20   of the Parklawn Building.


 21             Because general topics impact so many


 22   entities, it is not prudent to recite all potential


 23   conflicts of interest as they apply to each member


 24   and consultant and guest speaker.


 25             FDA acknowledges that there may be




  1   potential conflicts of interest, but because of the


  2   general nature of the discussion before the


  3   committee, these potential conflicts are mitigated.


  4             With respect to FDA's invited industry


  5   representatives, we would like to disclose that


  6   Gerald Migliaccio is participating in this meeting


  7   as an industry representative acting on behalf of


  8   regulated industry.  Mr. Migliaccio is employed by


  9   Pfizer.  Dr. Paul Fackler is participating in this


 10   meeting as an acting industry representative.  Dr.


 11   Fackler is employed by Teva Pharmaceuticals U.S.A.


 12             In the event that the discussions involve


 13   any other products or firms not already on the


 14   agenda for which FDA participants have a financial


 15   interest, the participants' involvement and their


 16   exclusion will be noted for the record.


 17             With respect to all other participants, we


 18   ask in the interest of fairness that they address


 19   any current or previous financial involvement with


 20   any firm whose product they may wish to comment


 21   upon.


 22             Thank you.


 23             DR. KIBBE:  Thank you.  I am Art Kibbe.  I


 24   am Chairman of the Pharmaceutical Science's


 25   Department at Wilkes University.




  1             We have a tradition of introducing


  2   everyone around the table, so, Dr. O'Neill, if you


  3   will start.


  4             DR. O'NEILL:  I am Bob O'Neill.  I am


  5   Director of the Office of Biostatistics in CDER.


  6              DR. HUSSAIN:  Ajaz Hussain, Deputy


  7   Director, Office of Pharmaceutical Science.


  8             MS. WINKLE:  Helen Winkle, Director,


  9   Office of Pharmaceutical Science.


 10             DR. VENITZ:  Jurgen Venitz, Clinical


 11   Pharmacologist, Virginia Commonwealth University.


 12             DR. SELASSIE:  Cynthia Selassie, Professor


 13   of Chemistry, Pomona College.


 14             DR. BOEHLERT:  Judy Boehlert.  I have my


 15   own pharmaceutical consulting business.


 16             DR. SWADENER:  Marc Swadener, retired from


 17   the University of Colorado at Boulder.


 18             DR. MEYER:  Marvin Meyer, Emeritus


 19   Professor, University of Tennessee, now a


 20   consultant in Boca Raton, Florida.


 21             DR. KAROL:  Meryl Karol, a Professor at


 22   the University of Pittsburgh in Environmental and


 23   Occupational Health.


 24             DR. LAYLOFF:  Tom Layloff, Management


 25   Sciences for Health, a nonprofit, working primarily




  1   in Africa on drug quality.


  2             DR. KOCH:  Mel Koch, Director of the


  3   Center for Process Analytical Chemistry at the


  4   University of Washington.


  5             DR. COONEY:  Charles Cooney, Department of


  6   Chemical Engineering at MIT.


  7             DR. DeLUCA:  Pat DeLuca, Professor of


  8   Pharmacy at the University of Kentucky.


  9             MR. MIGLIACCIO:  Gerry Migliaccio, Vice


 10   President of Global Quality Operations for Pfizer.


 11             DR. FACKLER:  Paul Fackler, Teva


 12   Pharmaceuticals.


 13             DR. KIBBE:  Thank you.


 14             Next on our agenda is an Introduction to


 15   the Meeting.  Ms. Winkle.


 16                     Introduction to Meeting


 17             MS. WINKLE:  Thank you and good morning to


 18   all the committee members.  I especially want to


 19   welcome the members who have not attended before or


 20   are just joining us for the first time.


 21             That includes Dr. Cooney, Dr. Koch, and


 22   Dr. Singpurwalla, who is not here yet, but will be


 23   joining us later today, and also to Gerry and Paul


 24   for helping us out as industry reps.  We are really


 25   pleased to have both of them here working with us.




  1             [Slide.]


  2             Today, I just want to give a short


  3   update--it will probably be longer than short, but


  4   it is supposed to be short--update on some of the


  5   things that we are doing in OPS.


  6             [Slide.]


  7             Today, I want to talk a little bit about


  8   the OPS mission, vision, and goals.  I think it is


  9   really important for me to go over these with the


 10   committee because it helps all of us understand a


 11   little bit more about where OPS is going in the


 12   future.  I think that as we talk about various


 13   scientific issues, it will help put things in a


 14   better perspective for the committee.


 15             We have just recently finalized the


 16   mission, vision, and goals, so I think it is


 17   important that I share them.


 18             I also want to talk a little bit about


 19   what we are doing in OPS in developing a new


 20   paradigm for CMC review in our Office of New Drug


 21   Chemistry.  This is really an exciting effort that


 22   we have undergone, and I think there are a lot of


 23   things that will be very beneficial to talk about a


 24   little bit here.


 25             A lot of this is built on the




  1   Pharmaceutical Quality Initiative for the 21st


  2   Century, so it helps put that in perspective, as


  3   well as to what we are doing in the future in OPS.


  4             I also want to mention some of the new


  5   personnel that we have in OPS and then talk a few


  6   minutes about the meeting agenda.


  7             [Slide.]


  8             The mission statement.  Again, I think


  9   this is very important because it sets forth what


 10   OPS is currently focused on, and it is important


 11   not only to those activities that we are engaged in


 12   and working on very diligently in the organization,


 13   they are also very important in supporting the


 14   overall mission of the Center and mission of the


 15   Agency.


 16             Basically, our mission statement is to


 17   ensure timely availability of high quality drug


 18   products to U.S. patients.  We are doing this


 19   through effective and efficient scientific


 20   assessment of relevant pharmaceutical and


 21   biotechnology information in the submissions, and


 22   by facilitating those scientific and technological


 23   innovation that improve understanding of product


 24   performance, quality, and efficiency of


 25   development, manufacturing, and quality assurance




  1   processes.


  2             Many of these things that we have talked


  3   about at past meetings, that we will talk about in


  4   the future, fall very much within this mission


  5   statement and some of the things that we are trying


  6   to accomplish.


  7             [Slide.]


  8             Our vision is to be an international


  9   champion.  I think it is very important that we


 10   talk about where OPS is going from an international


 11   perspective because things are more global.


 12             Obviously, now industry, many of the


 13   things that we work on are global, and we need to


 14   be part of that overall global involvement in


 15   pharmaceutical science, but we really want to be


 16   champions and leaders in the regulatory application


 17   of contemporary scientific knowledge, and that


 18   knowledge that affects the design, development,


 19   manufacture, and clinical performance of


 20   pharmaceutical and biotechnology products.


 21             [Slide.]


 22             Basically, the goals are for OPS programs


 23   and projects to support the achievement of the


 24   following attributes of drug products:


 25              The drug quality and performance is




  1   achieved and assured through design of effective


  2   and efficient development and manufacturing


  3   processes;


  4             That regulatory specifications are based


  5   on a mechanistic understanding of how product and


  6   process factors impact product performance;


  7             And that there is continuous "real time"


  8   assurance of quality.


  9             These are all very important objectives


 10   that we are striving toward.


 11             [Slide.]


 12             Also, OPS will implement a review quality


 13   system and procedures throughout the organization


 14   that will:


 15             Recognize the level of scientific


 16   knowledge supporting product applications, process


 17   validation, and process capability;


 18             Apply a risk-based regulatory scrutiny


 19   that will relate to the level of scientific


 20   understanding of how formulation and manufacturing


 21   process factors affect product performance, and the


 22   capability of process control strategies to prevent


 23   or mitigate risk of poor product performance.


 24             [Slide.]


 25             I wanted to talk a few minutes now that I




  1   have talked about sort of the mission and the


  2   goals, and you have a feel for where we are going,


  3   I want to talk about some of the changes that we


  4   are making.  Specifically, I want to talk about the


  5   changes we are making in CMC review.


  6             To help set the stage for the future, I


  7   wanted to go quickly through the FDA Strategic


  8   Action Plan that Dr. McClellan initiated when he


  9   came on board, I want to talk about the


 10   Pharmaceutical Quality for the 21st century, which


 11   is a really important initiative that is taking


 12   place in the Agency, and is very important to us as


 13   we move ahead in the Office of Pharmaceutical


 14   Science and some of the things that we are trying


 15   to accomplish.


 16             I want to talk just a second about


 17   resources in our CMC area, because I think without


 18   mentioning the resources and the problems that we


 19   have in resources, it is hard to understand why the


 20   changes are necessary that need to be made in order


 21   to improve on how we do review.


 22             Also, I want to talk about a few other


 23   influences that have happened since the


 24   organization was first established in 1995.


 25             [Slide.]




  1             The FDA Strategic Plan - Responding to


  2   Challenges and Opportunities.  Again, as I said,


  3   Dr. McClellan introduced this plan several months


  4   after he entered the Agency.  He was very focused


  5   while he was here at the Agency on accomplishing


  6   these particular aspects of all of the products


  7   that are regulated by FDA.


  8             Mainly, he focused on efficient risk


  9   management, so that we were sure we were going to


 10   get the most public health bang for our regulatory


 11   buck.


 12             He wanted empowering consumers.  He felt


 13   that I think all of us understand there is a lot of


 14   interest on the part of consumers in their own


 15   health care, and he wanted to be able to improve


 16   health through better information to consumers, so


 17   as they make decisions, as they look at their own


 18   health care, as they even deal with their


 19   physicians, et cetera, that they have a better


 20   understanding of the medications, food, et cetera,


 21   et cetera, that they need to take or use.


 22             He wanted to improve patient and consumer


 23   safety, protect America from terrorism, and more


 24   effective regulation through a stronger workforce.


 25             So, as we make changes in OPS, and we look




  1   toward the future of things that we want to do


  2   differently, and how we want to do those, we are


  3   trying to incorporate many of the things that Dr.


  4   McClellan incorporated in his strategic plan.


  5             [Slide.]


  6             Also, as I mentioned, the FDA Initiative


  7   on Pharmaceutical Quality is an important


  8   groundwork for some of the things that we are doing


  9   now and in the future in OPS.


 10             This particular chart is very helpful


 11   because it shows the particular dimensions of the


 12   plan for strong public health protection, for


 13   international cooperation, for risk-based


 14   orientation, science-based policy and standards,


 15   and integrated quality systems orientation.  These


 16   are the really important aspects of the initiative


 17   and where we are going.


 18             [Slide.]


 19             There are various directional vectors that


 20   came with the initiative, and I won't go through


 21   each of these.  I think you can look through them,


 22   but I think they are important as we look at OPS


 23   and where we are going for OPS in the future, so


 24   looking at our regulatory policies, making sure


 25   that we incorporate new technology advances when we




  1   do our regulation, that we are able to work with


  2   industry, et cetera, in doing some of these, and


  3   that we have consistency and coordination


  4   throughout the whole drug quality regulatory


  5   program.


  6             [Slide.]


  7             Here is basically the directional vectors


  8   and many of the things that are being worked on


  9   under the GMP initiative agencywide.


 10             These include looking at a preapproval


 11   inspection compliance program, dispute resolution


 12   processes being established, a pharmaceutical


 13   inspectorate that focuses specifically on


 14   pharmaceutical products during the inspection


 15   process that is being set up.  We are hoping to


 16   have product specialists on inspection process, and


 17   we hope to start that very soon.


 18             We have set guidance on CFR Part 11,


 19   aseptic processing guidance, a comparability


 20   protocol guidance.  We have been doing a lot of


 21   stuff with risk management and quality by design,


 22   and, of course, PAT, which we have talked about.


 23   But you can see where each of these sits on the


 24   whole vector between risk and science.  These are


 25   all important aspects of the initiative.




  1             [Slide.]


  2             But the most important thing to me about


  3   the initiative is it afforded us in OPS, a lot of


  4   opportunities to change the way that we do


  5   business.  It has opened up a window of time for us


  6   to really look at how we do business and make the


  7   changes that are necessary to move forward into the


  8   21st century.


  9             This is not easy, and I will go through


 10   some of the challenges what we have had, but first


 11   of all, I want to talk about some of these


 12   opportunities and just mention them to you, because


 13   I think they are really important.


 14             We really have the opportunity now to


 15   strategize more on how we are going to ensure


 16   product quality.  This is ensuring product quality


 17   across all of the Center, and it is the first time


 18   we really have thought about the whole aspect of


 19   product quality and what needs to be done to ensure


 20   in  the future that we are focused on the right


 21   aspects of that.


 22             We need to revisit our processes.  This is


 23   a really good opportunity for us to do that.  We


 24   have built processes over the last 20, 25 years,


 25   not only in review, but in inspection, as well, and




  1   this gives us an opportunity to look at all of the


  2   processes that fall under pharmaceutical quality


  3   regulation, and to incorporate best practices.


  4             We need to focus more on manufacturing and


  5   associated issues relating to the quality of


  6   products, one of the things that was very apparent


  7   to us when we went in and looked at the review


  8   processes, that we did not pay as much attention to


  9   the actual manufacturing of products and how it


 10   affected the quality of the products.


 11             So, this is a really good opportunity for


 12   us to do that.  We have a lot to learn and we have


 13   to work with a lot of people because obviously, we


 14   don't have as much understanding as we need, but we


 15   are doing a lot and looking at manufacturing


 16   science and trying to get a better understanding of


 17   that.  I think that has been very apparent in some


 18   of the things that you have talked about with PAT,


 19   we will talk about even more today.


 20             We need to focus both on review and


 21   inspection, and we need to put more science into


 22   those.  A lot of times, and it has been said time


 23   and time again, we have not used really good


 24   science in making the decision, and sometimes we


 25   have had a lot of complaints from industry and




  1   others about that lack of really scientific


  2   understanding on inspections, so this is a really


  3   good opportunity for us to ensure that that science


  4   exists, but it is really important that we ensure


  5   that it is part of the review process, as well, and


  6   it is going to take time, but I think working with


  7   our people and others, we will get there in the


  8   future.


  9             We need to enhance the interactions


 10   between review, inspection, and compliance.  One of


 11   the things that was very interesting to me right


 12   before we started the initiative is we met with a


 13   number of people from trade associations, and it


 14   was made very clear, the gap between what happens


 15   in review and what happens in inspection, and who


 16   is sitting in the middle but industry with a lot of


 17   questions on how policy was set or what the policy


 18   means, and dealing with the inspectors day to day


 19   who really don't have an understanding of that


 20   either, so we really need to ensure better


 21   interaction between review and inspection.


 22             We need to foster communication with


 23   industry.  In the review, we have been very


 24   hesitant to talk much to the industry and to work


 25   with the industry, not only on specific




  1   applications, but on science in general, and there


  2   is a lot of science in the industry that can be


  3   very beneficial to us in the Agency to understand


  4   the processes and understand manufacturing and


  5   pharmaceutical quality, and we need to do more of


  6   that.


  7             We need to have early discussion on CMC


  8   questions. As I already mentioned, we have a


  9   dispute resolution process that we are setting up,


 10   which we feel will be very helpful to give industry


 11   an opportunity to talk with us when they have


 12   scientific issues or questions.


 13             We need to leverage resources for the best


 14   bang for the buck.  This is a real problem, and as


 15   I said, I am going to talk a little bit more about


 16   resources.


 17             We need to simplify the regulatory


 18   requirements and we need to be able to find ways to


 19   reduce some of the regulatory burden.  We have


 20   talked here before at the committee about the


 21   number of supplements that we get in the


 22   organization, we are really drowning in


 23   applications in supplements, and all of them are


 24   treated basically the same, and we need to really


 25   step back and look at ways that we can put more




  1   emphasis or more responsibility on industry and try


  2   and work with them to have better understanding of


  3   things, and not get as many applications.


  4             We need to eliminate the "check box"


  5   approach that we have.  What we do basically in


  6   review is we go through and do you have this, do


  7   you have that, do you have this without a real


  8   understanding of what the process is, the


  9   manufacturing, the whole important aspects of


 10   pharmaceutical quality.


 11             [Slide.]


 12             We need to enhance training opportunities,


 13   and we now have this opportunity under the GMP


 14   initiative, as well as some of the things that we


 15   are undertaking in OPS.  We are in the process of


 16   working with several of the pharmaceutical


 17   industries to set up plant residency programs for


 18   some of our chemists.


 19             We have other cross-training opportunities


 20   that we are discussing, and then we have the


 21   pharmaceutical inspectorate, and the reason I put


 22   this here is not only will we be able to train our


 23   inspectors better as far as some of the aspects or


 24   manufacturing science, will it be able to take


 25   advantage of those from the review standpoint, as




  1   well, and I think this will be extremely helpful


  2   and useful to us in our future regulatory


  3   activities.


  4             [Slide.]


  5             We need to enhance FDA's knowledge


  6   regarding new technologies in manufacturing, and we


  7   need to encourage innovation, and again this goes


  8   back to PAT.


  9              We need to develop processes that are


 10   focused more on product risk, which we have not


 11   done.  As I said before, almost every product has


 12   the same weight, same level of review, and we


 13   really need to look more at the risk aspects of the


 14   product.


 15             We need to revisit how quality of products


 16   relate to ensuring safety and efficacy, and


 17   especially ensuring clinical relevance.


 18             We need to alleviate industry's concern


 19   regarding reprisal.  I hate to put this up, it's a


 20   bad word "reprisal," but that thought is out there


 21   often in industry, I hear it time and time again,


 22   and I am hoping through better interactions with


 23   industry, with better understanding of the science


 24   and the ability to discuss the science, we can


 25   begin to eliminate some of these concerns.




  1             We need to enhance our international


  2   involvement. We are working on pharmaceutical


  3   development and risk management in international,


  4   but we need to do more of this, because again it's


  5   a very global world out there, and we need to be


  6   sure that we are involved in everything that is


  7   happening on the international front.


  8             [Slide.]


  9             I did say I wanted to mention resources


 10   real quickly.  I thought this would give you a


 11   better perspective again as to why we want to make


 12   some of the changes in CMC. The workload is really


 13   difficult for our CMC reviewers in new drugs.


 14              We got, in 2003, 159 NDAs, 342 commercial


 15   INDs, 507 research INDs, 1,858 CMC supplements, and


 16   that doesn't include efficacy or labeling


 17   supplements, and 1,132 annual reports.  This is a


 18   lot of work to take on, and this is a lot of work


 19   because we have fewer and fewer review staff.


 20             We have constantly been over the last few


 21   years hit by reductions in resources, so we are


 22   doing more work with less people, and we have


 23   really got to think of ways to streamline the


 24   process and to be able to get some of this done in


 25   a more efficient and effective manner.




  1             [Slide.]


  2             Other influences, though, too, that bring


  3   about the necessity for change, as I said, in 1995,


  4   when ONDC was established, it was collocated with


  5   the clinical divisions, and this seemed to work


  6   really well for a couple of years, but a lot of


  7   things have happened within the Center, within the


  8   Agency, within the world, that really affect how we


  9   do the CMC reviews, so we really need to rethink,


 10   based on these influences and changes, how we do


 11   things.


 12             Some of the influences includes shorter


 13   PDUFA deadlines, FDAMA, again harmonization and


 14   globalization, such changes in our regulatory


 15   processes, such as SUPAC, BACPAC, new technologies


 16   in pharmaceutical manufacturing.


 17             [Slide.]


 18             PAT, counterterrorism, counterfeit


 19   products.  We were just talking about the fact that


 20   we can't even begin to keep up with counterfeiting,


 21   we have to find better ways to do that.


 22             BSE and other crisis, such as that.  There


 23   has been a greater focus on generic drugs, and


 24   tomorrow we will spend a lot of time talking about


 25   some of the issues that we have with regulating




  1   generic products, and it is really important that


  2   we begin to focus more on some of these issues and


  3   how we need to ensure that we incorporate other


  4   thinking from the new drug side into how we are


  5   going to regulate generic products in the future.


  6             There have been a lot of changes in


  7   industry, more globalization mergers, et cetera.


  8   There has been electronic submissions.  We are


  9   working very hard to hopefully enhance the


 10   efficiency of our processes through electronic


 11   submissions, and there has been more focus on risk


 12   management and quality systems.


 13             [Slide.]


 14             So, basically, what we need to do is to


 15   change the paradigm for CMC review.  I have talked


 16   about that we have the opportunity to do this.  The


 17   things that we really need to focus on based on


 18   those opportunities is really to develop a


 19   risk-based CMC review.


 20             I think this is really important, and I


 21   think we are going to need help.  This is not going


 22   to be an easy thing to determine risk.


 23             I think products are going to come and go


 24   that are risky, we see that all the time, products


 25   that you don't expect when it comes on the market




  1   to have any risk, then, things are found out later


  2   on, so it is not going to be an easy process to


  3   develop, and it is going to take a lot of thought


  4   and probably a lot of help even from the committee,


  5   but this is definitely a direction that we need to


  6   head in.


  7             We need to establish quality systems which


  8   help set the framework for ensuring that we do have


  9   a dynamic organization and that we can handle the


 10   complications of the regulatory processes.


 11             We need to focus resources towards efforts


 12   that improve quality, and not hinder and interfere


 13   with innovation, and I think that is very


 14   important, and we need to focus on all aspects of


 15   CMC.


 16             We need to look at chemistry, we need to


 17   look at manufacturing, and we need to look at


 18   controls, and we have not done as good a job of


 19   this in the past.


 20             [Slide.]


 21             The advantages of the new paradigm, for


 22   FDA, we will have more product and process


 23   knowledge, which can be shared by industry, so that


 24   we have a better understanding of the products that


 25   we regulate.




  1              We will have more efficient resource


  2   allocation for review and inspection, and we can


  3   increase our trust and understanding  of industry


  4   decision making.


  5             [Slide.]


  6             The advantages for industry is hopefully,


  7   that we will have fewer, more efficient,


  8   science-based inspections, faster, more consistent


  9   reviews.


 10             There is a potential for reduced


 11   regulatory burden, for managing changes with less


 12   FDA oversight, for focused resources on critical


 13   issues, flexibility to focus on what should be


 14   done, not what can be done, and to improve


 15   communication with FDA.


 16             [Slide.]


 17             But most of all, the ultimate beneficiary


 18   is the public, and we hope through some of the


 19   changes that we make, that we can increase the


 20   availability of drugs on the market, we can have


 21   faster approval of new products, we can have


 22   continued assurance of high quality products, and


 23   we can increase the public's confidence in the work


 24   that we are doing in FDA, and hopefully, reduce


 25   costs, which isn't, of course, our business, but




  1   something we hope is going to come out of some of


  2   the changes that we are making.


  3             [Slide.]


  4             The new paradigm will include developing


  5   strategies to recruit and train reviewers.  One of


  6   the things that we realize is that we have a real


  7   gap in the qualifications that our reviewers have.


  8             We need more that have understanding of


  9   drug discovery, analytical chemistry,


 10   pharmaceutical engineering, and we are going to be


 11   looking at recruiting and training people in these


 12   areas.


 13             We need to build a learning organization,


 14   one that is skilled at creating, acquiring, and


 15   transferring knowledge.  This is one thing we have


 16   not done an adequate job of in the past, and we


 17   really need to work on, probably not only just in


 18   OPS, but throughout the whole Center.


 19             We need to set specifications based on


 20   science and process understanding.  We need to


 21   reengineer the process, so that we have the best


 22   practices, metrics, and that we are customer


 23   oriented.


 24             This is another thing that we have not


 25   paid a lot of attention to in the past, which we




  1   really need to look toward in the future, is who


  2   our customers are and what they need.


  3             [Slide.]


  4             We need to increase emphasis on


  5   manufacturing science, we need to ask the right


  6   questions at the right time.  We need to implement


  7   peer review by FDA scientists and clinicians.


  8             Establish a program to better integrate


  9   review and inspection, develop processes which


 10   ensure regulatory relief based on process


 11   understanding and control, quality systems in


 12   manufacturing, and continuous improvement is very


 13   important, and we need to create a better work


 14   environment and promote job satisfaction within our


 15   organization.


 16             [Slide.]


 17             As I said, there is a lot of challenges.


 18   The current culture, both inside and outside of


 19   FDA, is definitely the biggest challenge we have.


 20   It is very difficult to get people to think


 21   differently.  They have worked in a certain culture


 22   for years and years, and changing that culture is


 23   not easy.  We see that both inside the Agency, as


 24   well as outside.


 25             Hiring is not easy, it is very difficult




  1   to find people with the right skills that want to


  2   come to work for the Government, and this is a big


  3   challenge that we have ahead of us.


  4             Establishing performance metrics is also a


  5   challenge because we have really never had the


  6   metrics to measure anything except for the amount


  7   of work we get, and we are really going to have to


  8   step back and look at this differently.


  9             We need to identify gaps in requirements.


 10   We need to reevaluate the review process again to


 11   be sure we are asking the right questions that


 12   ensure product quality.


 13             We need to understand what is relevant


 14   science.


 15             We need to determine what is needed for


 16   pharmaceutical development data to assist in a


 17   better understanding of manufacturing process.


 18             We need to develop a science-based risk


 19   model,  and we need to integrate better into the


 20   inspection process  including participating on


 21   inspections.


 22             This is a lot of work we have ahead of us,


 23   and the reason I am sharing it is because I think a


 24   lot of these issues are going to come up in the


 25   future where we are going to need the committee's




  1   input on how to tackle some of these challenges,


  2   some of the things that we need to incorporate into


  3   our review and our processes to make sure that we


  4   are doing what is necessary to have the best


  5   regulatory processes available.


  6             Again, I feel that this is important that


  7   you all have an understanding of where we are


  8   going, and we will look forward to talking about


  9   many of these things in the future.


 10             [Slide.]


 11             Before I go into the agenda, I just wanted


 12   to mention some of OPS's new additions that we


 13   have.  We are really fortunate to be acquiring a


 14   lot of new staff lately, and some of the people I


 15   think that are very important, that will be working


 16   with us very closely, I wanted to talk about today.


 17             First, is Dr. Vince Lee.  I think all of


 18   you know Dr. Lee since he was once chair of this


 19   committee.  We are very happy to have Vince with


 20   us, and we feel that there is a lot of things that


 21   he is going to be able to help us work on as we


 22   move towards changing some of our regulatory


 23   paradigms.


 24             Also, we will be adding Dr. Mansor Khan


 25   from Texas to our staff.  He is going to be our




  1   director of our Division for Product Quality


  2   Research in our Office of Testing and Research, and


  3   he will be joining us next month.


  4             We are looking forward, too, to having Dr.


  5   Khan.  I think he is going to add a lot and help us


  6   a lot in some of the areas of research that we need


  7   to be focused on in order to accomplish some of the


  8   things that we want to accomplish.


  9             Also, I wanted to mention that Dr. Moheb


 10   Nasr has become the permanent director of the


 11   Office of New Drug Chemistry.  I think many of you


 12   know Dr. Chiu has retired. Dr. Nasr so kindly came


 13   from St. Louis to take this job, and has been


 14   working very diligently on some of the changes that


 15   we are trying to make.


 16             Dr. Chi Wan Chen has joined him as the


 17   deputy of the office.


 18             Also, I wanted to announce that Dr. Keith


 19   Webber, who is sitting over here, too, is the


 20   Acting Director of the Office of Biotech Products.


 21   We appreciate Dr. Webber stepping in and taking on


 22   this very challenging group that has recently


 23   joined us in the Office of Pharmaceutical Science.


 24             [Slide.]


 25             Just to finalize my presentation, I just




  1   wanted to quickly go through the meeting topics.  I


  2   think this is going to be an extremely exciting


  3   meeting.  I think that the topics tomorrow are


  4   especially stimulating, topics that I think will


  5   add a lot to our future thinking in these areas.


  6             Today, we are going to have subcommittee


  7   reports.   We are going to have a discussion of the


  8   proposal on PTIT.  That is parametric tolerance


  9   interval test for dose content uniformity.  We have


 10   talked about this before.  We have a proposal now


 11   on how we want to finalize our thinking in this


 12   area.


 13             Then, we want to talk about PAT.  We want


 14   to give an update, talk about some of the things


 15   that we have done, and also talk about how PAT is


 16   going to be implemented in our Office of Biotech


 17   Products.


 18             Tomorrow, as I said, I think the topics


 19   are very stimulating, I think we will have some


 20   really good discussion on bioequivalence topics.


 21   We want to talk about highly variable drugs, about


 22   bioINequivalence.  This is very important.


 23             We have a lot of areas here of thought


 24   that we need to bring forward and discuss with the


 25   committee, and we want to talk about topical




  1   products.


  2             Also, time allowing tomorrow, we have an


  3   awareness topic, and this is nanotechnology that we


  4   want to introduce.


  5             With that, I am going to finish up and


  6   hand it over to Dr. Kibbe, and I look forward to


  7   hearing the discussion in the next two days.


  8             Thank you.


  9             DR. KIBBE:  Thank you, Helen.


 10             We are pretty close to being on time, so


 11   we will turn it over now to the subcommittee


 12   reports.  The first one is from Clinical


 13   Pharmacology.  Jurgen is moving rapidly to the


 14   podium, so here we go.


 15                       Subcommittee Reports


 16             DR. VENITZ:  Good morning.  I am here to


 17   report back from a meeting that the Clinical


 18   Pharmacology Subcommittee had last November.


 19             [Slide.]


 20             Just in terms of review, this committee is


 21   serving to provide expertise in three different


 22   areas to this parent committee:  pharmacometrics or


 23   exposure-response modeling, pediatrics, and


 24   pharmacogenetics.  As you see, those were the three


 25   topics that we discussed.




  1             [Slide.]


  2             Our first topic in the November meeting


  3   was a proposal by Dr. Lesko from OCPB to institute


  4   End of Phase 2a Meetings.  Those are meetings that


  5   are currently not recommended or that are currently


  6   not required by the FDA.


  7             He, as well as Dr. Lee, presented the


  8   FDA's perspective, and then we had three FDA


  9   staffers giving us case reports where those


 10   meetings may be helpful in finding optimal doses


 11   early on and identifying key issues.


 12             [Slide.]


 13             The committee appreciated that this was a


 14   pilot program that is intended to improve dose


 15   findings over a few years.  There was some


 16   discussion as to how we assess the success of a


 17   program.


 18             The committee noticed that there would be


 19   additional FDA resources required to implement this


 20   very program, but on the positive end, that this


 21   End of Phase 2 Meeting Program would allow


 22   integration of preclinical information both in the


 23   PK and PD area and particularly to identify early


 24   on the use of biomarkers in Phase 2 and Phase 3


 25   studies that may help streamline the dose finding




  1   process.


  2             The committee also felt that a meeting


  3   such as this would be very useful in identifying


  4   key issues early on and discuss them between the


  5   sponsor and the FDA, as well as define what we call


  6   "utility" functions, which are basically measures


  7   of the potential consequences of either safety or


  8   efficacy issues which are essential to come up with


  9   an optimal dose.


 10             There was, as I said before, some


 11   discussion as to how you would measure the success


 12   of such a program, and the committee felt that


 13   probably the overriding metrics to measure the


 14   success would be customer satisfaction, the


 15   customer being both the sponsor, as well as the


 16   FDA.


 17             Possible, but more difficult to measure


 18   outcome would be the need to have post-approval


 19   dose changes.  Again, if we can minimize that, that


 20   would indicate that there is success in this


 21   program.


 22             So, while the committee was in support of


 23   this program, and as far as I know, it is being


 24   implemented as speak.


 25             [Slide.]




  1             The second issue relating to


  2   exposure-response was the issue about clinical


  3   trial simulations specifically with the intent to


  4   assess the liability of drug products to induce QT


  5   changes which are thought to be associated with


  6   fatal cardiac arrhythmias, we had Dr. Lee give the


  7   introduction, Dr. Bonate from the outside review


  8   modeling that he had done, clinical trial


  9   simulations, and then Dr. Kenna from the FDA review


 10   ongoing project within the FDA.


 11             [Slide.]


 12             There was a lively discussion on this very


 13   topic. The committee I think still felt that the


 14   QTc correction methods, those are ways to correct


 15   the QT interval for change in heart rate, that


 16   those methods are still questionable, we still


 17   don't have a gold standard on that.


 18             We felt that despite the trial simulations


 19   presented to us, it still appears very difficult to


 20   separate drug-induced changes from baseline changes


 21   in those EKG intervals.


 22             There was some discussion as to what


 23   constitutes a meaningful QTc change.  Right now the


 24   perception is that a 6-millisecond average QTc


 25   change would be relevant.  There is some concern in




  1   the committee or there was some concern stated in


  2   the committee that that might be too conservative,


  3   however, there was acknowledgment that using


  4   clinical trial simulation to get to the issue as to


  5   what the QTc liability is of a new product may


  6   provide a more rational risk/benefit assessment.


  7             One issue that was brought up that is


  8   currently not being explored is the fact that some


  9   drugs, not only interact at the kinetic level, but


 10   also the dynamic level, which may lead to QTc


 11   changes on the PD level.


 12             [Slide.]


 13             The second major topic related to the


 14   pediatrics component of the committee, here, we


 15   reviewed the pediatric decision trees.  We had


 16   several speakers.  We had Dr. Hinderling and Dr.


 17   Chen giving case reports.  Those were drugs or drug


 18   products that were reviewed for the pediatric use,


 19   used what is a called a "pediatric decision tree,"


 20   that allows PK or PK/PD studies to support efficacy


 21   and safety.


 22             We had Dr. Machado giving a statistical


 23   overview on what methods might be useful to compare


 24   pediatric exposure-response to see whether there


 25   are any age-related differences.




  1             Then, our committee member Dr. Kearns gave


  2   his perspective on how those studies actually are


  3   being done in practice and what some of the


  4   shortcomings are of the current pediatric decision


  5   tree, and this was followed by Dr. Rodriguez giving


  6   the FDA experience with the decision tree that has


  7   been in place for a few years.


  8             [Slide.]


  9             There was some discussion about the age


 10   appropriateness of some of the endpoints that are


 11   currently required to measure the pharmacology of


 12   drugs in children, whether the endpoints are


 13   related to the mechanism of action of the drug


 14   and/or the pathophysiology of the disease, are


 15   those meaningful endpoints and what do they tell


 16   us.


 17             There was some discussion, because that is


 18   part of the decision tree, as to what evidence


 19   supports that the disease progression in children


 20   is similar to the one in adults, which would then


 21   allow it to transfer information from adults to


 22   children.


 23             There seemed to be consensus that


 24   nonclinical information, such as data from primate


 25   studies or in-vitro studies may be very useful in




  1   supporting the pediatric decision tree.


  2             However, there was extensive discussion on


  3   whether there has to be extensive interaction and


  4   discussion between both the clinical pharmacology,


  5   the OCPB, as well as the reviewing divisions on the


  6   pediatric decision tree and its use in a particular


  7   drug product area.


  8             There was some discussion also on the


  9   limitations of the exposure-response in terms of


 10   some of the PD differences that are very difficult


 11   to be captured in the current paradigm.


 12             I think there was overall an appreciation


 13   that the pediatric decision tree is still


 14   work-in-progress and additional updates may be


 15   necessary to review or start discussing any changes


 16   to it.


 17             [Slide.]


 18             The last area that we discussed related to


 19   the pharmacogenomics and the metabolic drug


 20   interaction area, so we had two outside speakers,


 21   Dr. Flockhart and Dr. Neuvonen talk about two


 22   relatively novel cytochrome p450 isoenzymes that


 23   start to emerge as part of drug metabolizing


 24   enzymes, and the issue was here what is the current


 25   state-of-the-art, what can FDA use as basis of




  1   review for new incoming NDAs.


  2             [Slide.]


  3             There was acceptance by the committee for


  4   cytochrome P4502B6, that we do have both in-vitro,


  5   as well as in-vivo, substrates, model substrates


  6   that can be used for drug interactions.


  7             We don't have, on the other hand, any


  8   specific clinical inhibitors, and somewhat


  9   questionable in-vitro inhibitors.  On the other


 10   hand, for cytochrome P4502C8, we do have both


 11   in-vitro, as well as in-vivo, inhibitors, as well


 12   as substrates, so we can characterize any


 13   interaction potential for cytochrome P4502C8.


 14             Discussion by the committee followed that


 15   went beyond the specific isoenzymes where the


 16   committee emphasized that it is becoming more and


 17   more essential to look at population-based clinical


 18   studies to primarily assess, not the incidence of


 19   drug interactions, but their clinical significance.


 20             In other words, we have enough science to


 21   support the likelihood of drug-drug interactions,


 22   but we are not always sure about what the clinical


 23   consequence would be or consequence would be.


 24             Along the same line, the committee made


 25   the recommendation to encourage sponsors to review




  1   databases that exist, medication-use databases, to


  2   look for this very issue, what are the clinical


  3   consequences of drug-drug interactions especially


  4   if you go beyond two interactions.


  5             [Slide.]


  6             The last topic that we discussed related


  7   to pharmacogenomics.  Again, this is an ongoing


  8   discussion that we had.  In this case, we were


  9   discussing how to integrate that in the drug


 10   development and what kind of labeling may be


 11   necessary to reflect information collected during


 12   the development process.


 13             We had committee member Dr. Flockhart and


 14   Dr. Relling give their academic, as well as


 15   clinical, perspective, and Dr. Hockett give the


 16   industry perspective.


 17             [Slide.]


 18             To summarize the committee discussion, I


 19   think there was acceptance of the fact that we need


 20   additional population-based studies meaning


 21   large-scale studies to look at the prevalence for


 22   some of the rare genetic polymorphisms, in other


 23   words, for some of those polymorphisms that may be


 24   important, we do not know how many patients have


 25   those specific genotypes.




  1             There was recognition that we do have or


  2   at least start to emerge having a lot of


  3   mechanistic and quantitative understanding that is


  4   necessary for labeling.


  5             In other words, we collect a lot of


  6   information and we know a lot about how likely some


  7   of those pharmacogenetic differences are and what


  8   the kinetic or dynamic consequences are.


  9             The discussion then really focused on what


 10   is the impact as far as risk/benefit is concerned,


 11   in other words, how do we translate changes in drug


 12   levels or change in the pharmacology of the drug,


 13   how do we translate that into safety and efficacy


 14   information.


 15             There was, shall we say, a lively


 16   discussion of how to label pharmacogenetic


 17   information in drug package insert, and I don't


 18   think there was any consensus.


 19             We had experts telling us we need to label


 20   very extensively, on the other hand, clinicians


 21   were concerned about overloading information that


 22   is not being used by the ultimate consumer, and


 23   there was recognition that pharmacogenetics or


 24   pharmacogenomics is going to be different from some


 25   of the other clinical covariates in the sense that




  1   it has multidimensional nature, in other words,


  2   there are lots of different pharmacogenetic


  3   polymorphisms that may be relevant for a given drug


  4   product.


  5             I would be happy to entertain any


  6   questions that you may have.


  7             DR. KIBBE:  Okay.  Jurgen will be with us,


  8   so if you want to ask questions later, if topics


  9   come up that we need to get back to him on, we can.


 10             Thank you.


 11             Now, I know you are fumbling through your


 12   things looking for the slides for the next speaker,


 13   but there aren't any, which gives us great hope


 14   that it will be a short and direct presentation.


 15             Dr. Hussain.


 16              Parametric Tolerance Interval Test for


 17                     Dose Content Uniformity


 18             DR. HUSSAIN:  No, I do not have slides for


 19   this part of my introduction.  The topic that will


 20   be discussed as a proposal to you is that of


 21   parametric tolerance interval test.


 22             As we have discussed this several times


 23   with you, in particular at the last meeting, in the


 24   previous meeting that we had, the challenge is how


 25   do you move forward with adopting a more rigorous




  1   scientific, statistically sound approach to dose


  2   content uniformity of inhaled products.


  3             We believe that parametric tolerance


  4   interval test that is being proposed by IPAC-RS is


  5   an improvement over the current method, and we


  6   would like to sort of move forward in sort of


  7   resolving some of those issues which have lingered


  8   on, and sort of adopting it as soon as possible.


  9             But the challenges are not trivial, and I


 10   tried to sort of summarize those challenges to you


 11   in the memorandum along with the paper that we


 12   wrote.


 13             We felt that in order to move this process


 14   faster and move it forward more quickly, the


 15   proposal to you is that we will form a working


 16   group under this advisory committee.


 17             This working group will report to you with


 18   their findings and provide a way forward to


 19   resolving the issues that have lingered on for


 20   three years, and come up with a very well


 21   structured process to resolve in a timely fashion.


 22             So, the proposal is a very straightforward


 23   proposal that this working group will report to


 24   you, and you will define the goals and objectives


 25   for this group, and you will define also the




  1   timeline for this group, and the proposal will be


  2   presented by Bob O'Neill, who is going to head for


  3   FDA working group members.


  4             Bob.


  5           Moving Forward -- An Approach for Resolution


  6             DR. O'NEILL:  Good morning.


  7             [Slide.]


  8             My name is Bob O'Neill, and as I indicated


  9   earlier, I am the Director of the Office of


 10   Biostatistics, and Ajaz and Helen have asked me to


 11   chair this group, which Ajaz has indicated is going


 12   to be reporting to you all.


 13             This is the process for coming to


 14   resolution on what you know to be a discussion that


 15   has been going on at least for three years under


 16   the specifications for delivered dose uniformity


 17   for inhaled and nasal drug products.


 18             [Slide.]


 19             I am going to be proposing how we are


 20   going to be going about doing this and asking for


 21   your advice and concurrence, so we can move forward


 22   on this.


 23             So, what we have thought about, and we


 24   have met several times with the IPAC-RS group, and


 25   this is the proposal.  We will have a joint working




  1   group under this particular committee, and it will


  2   be populated by senior representatives from FDA and


  3   from the Oral and Inhaled Nasal Drug Product


  4   industry, and that is mainly the IPAC group that we


  5   have been working with.


  6             [Slide.]


  7             The folks from FDA, I will get into the


  8   names in a moment, but essentially are representing


  9   sort of the clinical risk side of the house, the


 10   statistical side of the house, the generic drug


 11   side of the house, and the Office of New Drug


 12   Chemistry side of the house, so all the major


 13   players in terms of how this particular solution


 14   impacts the way we go about doing business.


 15             This particular proposal is essentially a


 16   way forward, so that we have a defined process with


 17   identified objectives, with identified ways of how


 18   we are going to communicate with each other, in


 19   terms of the mechanism, some timelines, some


 20   milestones, and how are we going to get some


 21   resolution on some of the issues that might be sort


 22   of sticky or still needing further discussion.


 23             So, the overall working group objective is


 24   to agree on a mutually acceptable parametric


 25   tolerance interval test for delivered dose




  1   uniformity, and these are the folks, and if they


  2   are in the room, I would ask them to stand up.


  3             On the lefthand side are the FDA folks.


  4   It is myself, Dr. Chowdhury, I believe Badrul is


  5   here.  He is the Pulmonary Division Director.


  6   Moheb Nasr, I believe is out of the country, you


  7   probably know him.  And Lawrence Yu, I don't know


  8   if Lawrence is here--there he is, and he is the


  9   Director for Science in Office of Generic Drugs.


 10             On the industry side, I think Michael is


 11   here, Michael Golden from GlaxoSmithKline.  Kristi


 12   Griffiths, I don't know if she is here, from Eli


 13   Lilly.  Bo Olsson from  AstraZeneca.  Dar Rosario


 14   from Aradigm.  Dennis Sandell from AstraZeneca


 15   also.  We have met with these folks and we plan on


 16   meeting in the future, and I will go through the


 17   timeline.


 18             [Slide.]


 19             So, just to reiterate, the objective of


 20   this working group is to develop a mutually


 21   acceptable, standard DDU specification, both the


 22   test and the acceptance criteria, for these


 23   products with a proposal to come back to you folks


 24   by the end of this year, by the end of 2004.


 25             [Slide.]




  1             So, the process that we are going to


  2   follow is pretty much trying to get the


  3   communication and the coordination of this effort,


  4   which is not going to be trivial, straight among


  5   all of us.


  6             We have identified that we will have a


  7   project manager that will help us as a working


  8   group stick to agendas, minutes, meeting materials.


  9   We plan on having monthly meetings at FDA beginning


 10   in May.


 11             The first one is probably in a few weeks,


 12   and in May, what we will plan to do is to review


 13   the feedback that you all give us today in terms of


 14   your blessing and what other suggestions you might


 15   have for how we would fine-tune this particular


 16   process.


 17             We are going to need to rely on working


 18   groups within the industry and within the FDA to


 19   further deal with the statistical issues here, the


 20   clinical issues, the CMC issues, and whatever else


 21   is on the plate, so there is likely to be some


 22   technical projects that will be assigned to folks,


 23   and the leadership and the project management of


 24   those particular projects will be overseen by the


 25   folks on the working group.




  1             [Slide.]


  2             So, again, just to reiterate the timelines


  3   and  the milestones, we expect to have a status


  4   report back to  you folks in the fall, in the


  5   meeting in the fall, in October, and hopefully to


  6   submit recommendations to you by the end of 2004


  7   that you can act on and come back to us on.


  8             [Slide.]


  9             Here is where we think we are to date.  We


 10   have discussed these issues at length and here is


 11   what we think we have reached consensus on.


 12             That the parametric tolerance interval


 13   approach is an improvement on the current test.  It


 14   is a concept that requires refinement and further


 15   development to address the regulatory requirements.


 16   There are still things that need to be fine tuned.


 17             We believe that there has been a lot of


 18   work, productive work, a lot of understanding, but


 19   it is time to move forward and come to closure


 20   particularly on this particular test.


 21             So the working group is formed to devote


 22   the necessary time and the resources to get this


 23   thing done, and that is through review of


 24   additional data analyses, especially some of the


 25   appropriate statistical procedures.




  1             [Slide.]


  2             We also recognize that there is some stuff


  3   hanging out there that needs consensus.  You have


  4   probably seen a presentation and heard about a


  5   presentation with regard to the different operating


  6   characteristic curves, the parametric tolerance


  7   interval test versus sort of the zero tolerance


  8   test, and there is a gap that essentially is the


  9   difference between the producer and the consumer


 10   risk, and it sort of differs in the middle over


 11   what you might assume to be the standard deviation


 12   of some of the measurements.


 13             That is essentially where a lot of the


 14   discussion has been.  Much of the discussion has


 15   been around what the performance characteristics


 16   are of the different tests under assumed scenarios.


 17   Another way of saying assumed scenarios is the


 18   simulated data, so if this, then that.


 19             So, if the data were to perform this way


 20   or lay itself out this way, then, this is what the


 21   operating characteristics of that particular test


 22   procedure are.


 23             So, we are actually also interested in


 24   seeing what real data is, so there is a number of


 25   issues with regard to actual data that is not in




  1   our hands, not in FDA's hands, which would lead us


  2   to say, well, how many situations are there where


  3   the standard deviations start to push out to 12,


  4   13, 14, 15, because those are the areas where you


  5   may be wanting to have a little more information


  6   because if you are not in the symmetric situation,


  7   your outliers are going to be where your problem


  8   cases are.


  9             So, there is some more work to be done in


 10   this area, so talking about that and marrying both


 11   the zero tolerance interval concept with the


 12   parametric tolerance interval idea is essentially


 13   where the statistical details of the test are


 14   likely to be focused over the next few months.


 15             Obviously, this issue of the applicability


 16   to non-normal distributions, asymmetric bimodal


 17   distributions, which essentially may be very much


 18   characteristic of manufacturing processes of, you


 19   know, large and small particles, and things like


 20   this, which is not an unusual statistical scenario


 21   when you have mixtures of populations, so that is


 22   from the statistical perspective.


 23             [Slide.]


 24             The next steps are to ask you folks to


 25   endorse this idea or to suggest some refinements to




  1   it.  We will come back to you with a status report


  2   as to where we are in October, and the working


  3   group is planning to submit recommendations to you


  4   all by the end of this calendar year.


  5             With that, I think I am done.  I would be


  6   willing to take any questions, and I think anybody


  7   on the working group would also be willing to chime


  8   in.


  9             Committee Discussion and Recommendations


 10             DR. KIBBE:  We have time now for


 11   questions, it's on our schedule, so ask questions.


 12             DR. SINGPURWALLA:  Well, just out of


 13   curiosity, what is the DDU test?


 14             DR. O'NEILL:  Delivered dose uniformity


 15   test.  It is essentially a measurement of, it's


 16   content uniformity, how much of the dose is


 17   delivered in, let's say, a spray or these nasally


 18   inhaled products, so it's a matter of if this was a


 19   pill, you would be crunching it up, you would be


 20   looking at what its content is, you would have a


 21   measure of that, and the test is essentially that


 22   you agree what the goalposts are for an acceptable


 23   amount of variability for the active ingredient,


 24   and if it's in that zone, it's acceptable; if it's


 25   not in that zone, it is not acceptable, so it's a




  1   variant.


  2             That is the whole concept behind the


  3   delivered dose uniformity, that the product has to


  4   have some consistent uniform characteristics to it.


  5             DR. SINGPURWALLA:  So, how would it differ


  6   from the parametric tolerance interval?


  7             DR. O'NEILL:  Well, first of all, it


  8   differs in a number of ways.  I don't want to go


  9   through the test, that there has been a


 10   presentation on this, and there is a lot of


 11   background stuff on this.


 12             The key difference between the zero


 13   tolerance is it's a zero/1 kind of thing, it's


 14   either in or out, and it doesn't take the standard


 15   deviation into account.


 16             The parametric tolerance interval approach


 17   is probably, assuming that you have something close


 18   to normality, and it is essentially basing the test


 19   both on the estimate of the mean and the estimate


 20   of the standard deviation, and then depending upon


 21   the combination of both of those guys, it is


 22   essentially a zone of equivalence, but the


 23   distinction between the two tests is one sort of a


 24   zero/1, you are either all in or all out, but it


 25   doesn't estimate the standard deviation.




  1             The work that has been done on the


  2   parametric tolerance interval approach


  3   statistically is intended to be a more powerful,


  4   more precise, take more of the information into


  5   account.


  6             DR. SINGPURWALLA:  So, would you say that


  7   the DDU test is not a statistical test, it has no


  8   statistical basis?


  9             DR. O'NEILL:  No, I would not say that at


 10   all.  In fact, both of them have statistical bases.


 11   In fact, the zero tolerance test is essentially the


 12   USP test that is used for all content uniformity,


 13   it is a variation on that.


 14             Take 10, see whether they are in the


 15   limits or out of the limits, if not, take another


 16   20.  If they are in the limits or out of the


 17   limits, and you are done, up or down.  That is what


 18   the test has been for years.


 19              What this is, is essentially to say,


 20   well, I am not using all the information, I am not


 21   finding out actually what the variability of the


 22   process is, so I want to get some handle on what


 23   the standard deviation of the process is, so I want


 24   to estimate that also, and I also want to estimate


 25   what the mean is.




  1             So, if you were to back up and sort of


  2   look at this within the mainstream of process


  3   control, you sort of want to look at where you are


  4   in the standard deviation world, where you are in


  5   the mean target close to what the center of the


  6   distribution is.


  7             So, both of these are statistical in the


  8   sense that they have probabilities of consumer risk


  9   and regulatory risk, but it is that part of it that


 10   is the statistical aspect of it.


 11             DR. SINGPURWALLA:  So, if I were to


 12   understand what you are saying, the DDU test seems


 13   like a binary test, it's a sequential binary


 14   process.


 15             DR. O'NEILL:  Well, what we are talking


 16   about, we are talking about the parametric


 17   tolerance interval test versus what is--I don't


 18   know what its best name is--but it would be like


 19   the zero tolerance interval test.  That test is


 20   binary.  The other one is--


 21             DR. SINGPURWALLA:  Is not binary.


 22             DR. O'NEILL:  --is not binary.  It takes


 23   more of the information into account.  That is the


 24   conceptual idea.


 25             DR. KAROL:  Could you tell me how much




  1   real data you have and what is the source of the


  2   real data?


  3             DR. O'NEILL:  Well, we have, our folks, I


  4   know that there are folks maybe in the audience who


  5   have looked at data that we have from the industry,


  6   but it is not necessarily the data that is all the


  7   data.


  8             I mean what we have is data that is


  9   submitted to us in applications and in annual


 10   reports, and often that is data that has already


 11   been screened in the sense that it either passes or


 12   doesn't pass, so in some sense, we are seeing data


 13   that is less variable than the data that these


 14   tests are intended to apply to uniformly.


 15             I believe that is where our comfort level


 16   is in terms of trying to understand how much


 17   variability is in the data, and I think it's a


 18   conceptual thing getting back to the way Helen


 19   talked about.


 20             For years, for years, I think the process


 21   was let's set the goalposts and then see whether we


 22   can manufacture it to fit the goalposts as opposed


 23   to the other way around, sort of saying what is the


 24   process capability and then fix the goalposts for


 25   the process capability.




  1             Under continued process improvement, the


  2   idea is to be closer to the target mean and to be


  3   closer and tighten down your variability.  It may


  4   be if you can't do any better, that's what you are


  5   left with.


  6             So, our situation is understanding that,


  7   and what we are seeing now is I believe, if I am


  8   not speaking for our chemists, our folks are seeing


  9   relatively tight standard deviations in the 5, 6, 7


 10   area, and the idea that there could be some


 11   standard deviations that are hanging out in the 12,


 12   13, 14 area is how come.  We are not necessarily


 13   seeing all of that.


 14             So, we want to see a little more data


 15   along those lines.  So, that is sort of


 16   conceptually where the gap is in terms of trying to


 17   move transitionally from the current test into a


 18   test that we believe has a lot more merit for


 19   several reasons.


 20             One, it captures better a handle on the


 21   variability of the data, and, secondly, you should


 22   be rewarded for taking more samples than less


 23   samples.  So, this test needs to reward you for


 24   having better estimates of what your variability is


 25   rather than less.  That is another conceptual part




  1   of this.


  2             DR. MEYER:  I might be mistaken because I


  3   don't normally read the USP, but it seems from my


  4   recollection there are some tablet products that


  5   have a specification for variability, as well,


  6   warfarin being an example, where you do 10, then


  7   you do 20, but you also look at standard deviation


  8   or coefficient of variation as some marker for


  9   approval or not.


 10             Is that correct?


 11             DR. O'NEILL:  Ajaz.


 12             DR. HUSSAIN:  Right, I think, Marv, you


 13   are right, in the sense the traditional approach,


 14   in the pharmacopeial approach, which are market


 15   standards, and they were never intended to be


 16   release standards, and that is the purpose they


 17   serve, are to maintain the market standard.


 18             In the case of tablets and solid dosage


 19   forms, you have a non-parametric approach to that,


 20   and, say, you have your goalposts 85 to 115 for 10


 21   tablets, and if one is outside that, you go to 75


 22   to 125 with 20 additional ones.


 23             For those, you have an estimate of


 24   standard deviation.  I think it's 6.6 person at the


 25   second stage, so  you have to meet that.




  1             The test we have for dose content


  2   uniformity or delivered dose uniformity for


  3   inhalation products right now, the FDA guidance


  4   doesn't have a value of standard deviations.  It


  5   simply says take, if it's 85 to 115, if one is


  6   outside that, take 20 more, and they all have to be


  7   within 75 to 125.


  8             So, the term "zero tolerance" actually is


  9   not really a meaningful term, and I think we


 10   discussed that at the previous committee, but if


 11   you really look at it, Jurgen had one set of


 12   comments at the end of that meeting, and our


 13   statisticians there had a very different set of


 14   comments on that, so we were very divided on that,


 15   because zero tolerance is for that sample, and that


 16   is, in my opinion, a big hindrance to continuous


 17   improvement because it forces industry to do only


 18   30 tests.


 19             If they do more, they are at risk, so that


 20   is not conducive to PAT, that is not conducive to


 21   the 21st century process that we want to move


 22   forward, so this actually is a model or the


 23   framework for what we would like to do for all


 24   specification, because clearly, the compendia,


 25   there is no movement.




  1             I don't see much movement in the compendia


  2   to change that, so we will have to move forward and


  3   change that, because if the compendia don't change


  4   that, they are going to be hindrance to PAT and


  5   everything else that follows.


  6             DR. BOEHLERT:  Just as a follow-up to


  7   that, I believe under ICH, the compendia are


  8   looking at harmonizing general chapters, and one of


  9   the ones they are looking at is content uniformity


 10   and should there be a tie-in somewhere with that


 11   group and what they are looking at and what they


 12   are doing, so you don't go two separate ways in two


 13   separate directions.


 14             DR. HUSSAIN:  I agree, but compendia are


 15   still a market standard, they are not a release


 16   standard, so from a regulatory perspective, that


 17   has always been the case.


 18             DR. BOEHLERT:  That has always been the


 19   case.


 20             DR. KIBBE:  Tom.


 21             DR. LAYLOFF:  I was going to say also


 22   there is a market standard in the way--you end up


 23   in a contradiction if you test the whole lot, it


 24   will always fail, because of the standard


 25   deviation, so you can't really do that.




  1             But in the regulatory laboratory, what we


  2   used to do is if we found one out of limits, then,


  3   we would submit it for check analysis, and if it


  4   passed check analysis, then, it was okay.  So, you


  5   sort of got around that contradiction in the limit


  6   setting.


  7             DR. KIBBE:  Anybody else?


  8             Is there anyone on the committee who


  9   thinks that moving forward is not necessarily the


 10   way to go?  Is there something that we need to


 11   discuss, because they are essentially asking us to


 12   say, well, yeah, we need to move forward and let's


 13   get the results by the end of the year?


 14             DR. SINGPURWALLA:  Do we have to do this


 15   right now?


 16             DR. KIBBE:  We are not going to decide on


 17   which tests to do right now.  We are just


 18   supporting the concept of having the working group


 19   move forward and give us a report.


 20             DR. SINGPURWALLA:  But one of the things


 21   they wanted is recommendations .


 22             DR. O'NEILL:  No, I don't think so.  We


 23   are just asking you to endorse the idea of moving


 24   forward and having this group, and we will come


 25   back to you with a report.  If  you don't like it,




  1   you can say go do more.


  2             DR. SINGPURWALLA:   I am sorry, you said


  3   suggest refinements in your talk, I made a note of


  4   it, so do you want the refinements now or later on?


  5             DR. O'NEILL:  No, we don't.


  6             DR. SINGPURWALLA:  So, you don't want


  7   refinements.


  8             DR. O'NEILL:  No, it's very high level,


  9   not detail oriented feedback that we would like


 10   from you right now.


 11             DR. SINGPURWALLA:  Because I would like to


 12   suggest refinements, but not at this minute.


 13             DR. O'NEILL:  I am sure we would be very


 14   interested in your refinements, and, in fact, I


 15   would certainly be interested in speaking with you


 16   outside of the meeting in terms of getting some


 17   additional ideas on this particular test, because


 18   again, this is a working group that is under the


 19   umbrella of this committee and essentially is


 20   coming back to the committee on behalf of the


 21   committee saying what do you think, because the


 22   committee is the one who is going to give the


 23   recommendations to the Agency.


 24             So, if you don't like the recommendations,


 25   then, it is totally within the committee's




  1   responsibilities and rights to say, you know, that


  2   is not what we had in mind, or that's not what we


  3   think is right.


  4             DR. KIBBE:  Let me get at some of this a


  5   little bit.  We have, I think, a tentative schedule


  6   to meet in October, and for you, the working group,


  7   to have your best shot prepared for us to look at


  8   and give you feedback on, right?


  9             DR. O'NEILL:  Yes, and it's not that we


 10   haven't thought this isn't ambitious either, but


 11   that's what we are   trying to work on.


 12             DR. KIBBE:  Is it reasonable for a member


 13   of this committee to forward suggestions to you in


 14   the interim and then have you incorporate them in


 15   the working group?  If you have some things that


 16   you would like to think through and then--


 17             DR. SINGPURWALLA:  Honestly, I was


 18   intrigued by the comment made that we invite


 19   suggested refinements, and for me to suggest


 20   refinements, I need to have a better appreciation


 21   for exactly what is going on.


 22             DR. O'NEILL:  I hear what you are saying.


 23   I guess maybe that was meant in terms of


 24   refinements to the process. Part of this is the


 25   process, and part of this is the content that the




  1   working group will be dealing with, and the working


  2   group already has essentially a proposal that they


  3   have been reacting to from IPAC-RS that has been in


  4   the works for a number of years, and it is that


  5   that is trying to be refined, those ideas are


  6   trying to be refined in the context of how do we


  7   understand what is currently sort of the operating


  8   characteristic curve of the current way we do


  9   things versus a new proposed way of doing things,


 10   and are they achieving where we want to be as a


 11   committee.


 12             I think that is the sense of the


 13   refinements.


 14             DR. SINGPURWALLA:  So, if the endorsement


 15   that you seek is for the process, and not for the


 16   inner workings of the process, I have no comments,


 17   go ahead, but if it is for the workings, then, I


 18   would like to think about it.


 19             DR. KIBBE:  I believe we are looking for


 20   moving ahead on the process right now.


 21             DR. O'NEILL:  That is what we are seeking


 22   from you, yes.


 23             DR. KIBBE:  What I hear my colleague


 24   saying is that he would like to have some input on


 25   the actual workings of the committee, with the




  1   thought process of the committee, and that if we


  2   could find some way to do that, to accommodate that


  3   situation within the budget constraints of the FDA,


  4   it would be useful.


  5             It always is good for a subcommittee or a


  6   working group of ours to have somebody from here to


  7   carry water for us.  You might get yourself into


  8   more work than you thought you were going to get


  9   into.


 10             Anybody else?  Jurgen.


 11             DR. VENITZ:  I am obviously in favor of


 12   moving forward, but I would like to give maybe


 13   somewhat of an unwanted recommendation, not


 14   necessarily a refinement.


 15             That is, when I look at the objectives of


 16   the working group, they are basically, primarily


 17   looking at the statistical properties of the test.


 18             I am recommending the group for having


 19   information on it, and I would encourage the


 20   committee to also, the subgroup, I guess, the


 21   working group, to also look at the clinical


 22   significance, in other words, in my mind, we talked


 23   about that last time, the clinical use is part of


 24   what risk-based manufacturing is all about.


 25             So, for example, it may be very different




  1   whether you are comparing inhaled insulin release


  2   to inhaled topical steroids, and I would like for


  3   that to be discussed as part of the working group.


  4             DR. O'NEILL:  I hear you.  Maybe I went


  5   through this a little too fast.  If you look at the


  6   constitution of the working group, Dr. Chowdhury is


  7   our clinical input on that, so that has been


  8   recognized, and that is why he is on the working


  9   group, to essentially put, as an overlay, the


 10   clinical risk structure on this, recognizing very


 11   much it might be product-specific, so that is his


 12   role.


 13             Lawrence Yu's role is also looking at this


 14   from, let's say, the generic drug implication, so I


 15   think the working group has been put together


 16   primarily to be relatively broad-minded.


 17             The statistical component of this is only


 18   one of multiple dimensions to this, but it is


 19   critical to understanding where we are in terms of


 20   the only thing that is not moving right now, which


 21   is the test that is on the table.


 22             DR. KIBBE:  Pat, go ahead.


 23             DR. DeLUCA:  Since this committee is going


 24   to be reporting back to this group, I am just


 25   wondering why a member of this group wasn't put on




  1   that committee, and it sounds like Nozer could have


  2   some real input into it, as well as being a link to


  3   this committee.  There may be some reason why you


  4   didn't do that, but I would certainly consider


  5   that.


  6             MS. WINKLE:  It certainly is an option.


  7   The way that this group is set up is basically a


  8   fact-finding group for the advisory committee, to


  9   give them the facts and the information that they


 10   will need to help make a recommendation on this


 11   test and how we want to move forward with it, but I


 12   think that it would be very helpful to have some


 13   input from Nozer.


 14             I think that he has some knowledge and


 15   some understanding and there is nothing that


 16   prohibits us from doing that, but we tried to set


 17   it up as an independent fact-finding group for the


 18   advisory committee.


 19             DR. SINGPURWALLA:  By the way, I just want


 20   to clarify that I didn't raise the question to


 21   thrust myself into this arena.  I was honestly


 22   asking a question, and since the matter has been


 23   raised by my colleague on the clinician, I would


 24   like to suggest that a Bayesian be on this


 25   particular group.




  1             DR. O'NEILL:  We will certainly be


  2   listening to you.  If you want to get into that


  3   discussion, we could, but one of the critical


  4   discussions we have been having right now is


  5   assumptions versus data, and Bayesians are heavy on


  6   the assumptions, but you have to have the data to


  7   support the assumptions, the game we are in, in the


  8   regulatory game we are in, and that is why we are


  9   trying to sort of get some sense of what does the


 10   waterfront actually look like, because it is very


 11   important to the behavior of the characteristics of


 12   this test.


 13             DR. KIBBE:  It is always fun to have


 14   statisticians discussing statistics.


 15             Do we have any other questions?


 16             Seeing no one's hand or little button lit


 17   up, I want to thank you very much.  We are looking


 18   forward to a very informative and useful report in


 19   October.


 20             My schedule says that we are supposed to


 21   be talking until 10:15, and we could either take a


 22   break now or if Ajaz promises to get finished in


 23   time for a break, we could move forward.  What is


 24   everyone's pleasure?  Naturally, the Bayesian wants


 25   to break.




  1             [Laughter.]


  2             DR. KIBBE:  I will give you all 15 minutes


  3   and then we will have Dr. Hussain.


  4             [Break.]


  5             DR. KIBBE:  Why don't you go ahead and


  6   start, Ajaz.


  7         Process Analytical Technology (PAT) - Next Steps


  8             DR. HUSSAIN:  Thank you.


  9             [Slide.]


 10             What I would like to do today is to give


 11   you a brief progress report on the PAT initiative


 12   and have three speakers.


 13             [Slide.]


 14             I will present a brief history to recap


 15   how we got here, current status and next steps.


 16   There are three topics that we want to share with


 17   you, finalizing PAT guidance, training and


 18   certification.  Chris Watts will make that


 19   presentation.


 20             What we are doing with respect to


 21   standards development.  Ali Afnan will talk about


 22   that.


 23             A topic that we have discussed twice with


 24   you, but we thought we would sort of bring some


 25   closure to that, what we have done with rapid




  1   microbial methods and how that has been a part of


  2   PAT.  Bryan Riley will talk to you about that.


  3             What we are hoping is, we have not really


  4   posed any questions, this is more of a progress


  5   report, status report, and we are moving forward,


  6   but if there is anything that you think we need to


  7   consider, please share this with us.


  8             The questions you might want to consider -


  9   are we on track?  Are there any recommendations for


 10   improving how we have approached PAT and how we


 11   might want to approach PAT in the future?


 12             [Slide.]


 13             The aspect that I often share is I think


 14   the PAT thought process has been in the Agency for


 15   a long time, and, in particular, a focal point for


 16   the discussion occurred in October of 1993.  I was


 17   not at FDA at that time, but Tom Layloff and others


 18   in St. Louis had organized a Symposium on


 19   Pharmaceutical Process Control and Quality


 20   Assurance by Non-traditional Means.


 21             The information I have about that is a lot


 22   of the focus became on near IR, and a lot of the


 23   focus tended to be on endproduct testing although


 24   the title was process control, and the discussion


 25   that led to sort of a very negative view of near IR




  1   and some of this technology came from FDA saying


  2   this cannot be USP methods, therefore, cannot be


  3   regulatory methods, which is probably more blunt,


  4   Tom will correct me if I am wrong.


  5             So, I think that was really an unfortunate


  6   aspect because from an FDA perspective, a lot of


  7   progress did not occur because of that.


  8             Tom and I spent a lot of time together


  9   thinking about this, and we saw this as an


 10   opportunity.  It was more of a discussion between


 11   an analytical chemist and an industrial pharmacy


 12   type, so we were putting our heads together and we


 13   made a presentation in the year 2000, the


 14   Millennium Conference in San Francisco.  I will


 15   just share some slides on that with you.


 16             Another meeting which was very important


 17   in the evolution of this process was the new


 18   technology meeting of Royal Pharmaceutical Society


 19   entitled Process Measurement and Control.  I


 20   actually met Ali Afnan and many other people who


 21   were then associated with the PAT at that meeting.


 22             [Slide.]


 23             The aspect I think which was important is


 24   this was a presentation that Tom and I did together


 25   at FIP meeting.  Tom had left FDA and was part of




  1   the USP at that time.  The title was Advanced


  2   Quality Control of Pharmaceuticals: In-line Process


  3   Controls.


  4             If you look at the outline, what we talked


  5   about then was pharmaceutical product development


  6   and manufacture: Building Quality In, and sort of


  7   design and specifications, how you approach that.


  8             We looked at modern in-line controls,


  9   potential advantages over traditional controls, a


 10   better approach for "building quality in," and


 11   talked about the need for accelerating industry and


 12   regulatory acceptance of modern in-line controls.


 13   That was the thought process before we coined the


 14   term "PAT," and so forth.


 15             [Slide.]


 16             In many sense, if you look at the cartoon


 17   there, that was the art of pharmacy manufacturing


 18   to the science of pharmaceutical manufacturing is


 19   how did we do granulation endpoint.  We reach in


 20   the bowl, grab a handful of granules, and look how


 21   they crumble, and then decided the granulation


 22   endpoint was reached, so we wanted to move from the


 23   art to more of a science-based approach.


 24             Our part of the PAT looked something like


 25   this, so if you look at that other cartoon there,




  1   that is how we saw it in 2000, this is what PAT


  2   might be.


  3             [Slide.]


  4             I think one of the critical meetings that


  5   I attended was a far more technical conclave in


  6   North Carolina.  I happened to walk into that


  7   meeting and G.K. Raju from MIT was talking about


  8   it, and that was a chance meeting that really


  9   provided us some of the critical information


 10   because I think without that, Tom and I could not


 11   have made any points in 2001.


 12             What the CAMP consortium, the MIT


 13   consortium helped us was to really put a value to


 14   this thought process, and based on that, we made a


 15   presentation to the advisory committee, Vince Lee


 16   was the chair then, is to initiate public


 17   discussion on application of process analytical


 18   chemistry tools in pharmaceutical manufacturing.


 19             You gave us strong support to move


 20   forward.  You recommended that we form a PAT


 21   Subcommittee.  We also, at that same meeting,


 22   related discussion on Rapid Microbial Testing,


 23   however, we did not discuss this further at the


 24   advisory committee, we had these discussions at the


 25   subcommittee, and that is the reason I brought




  1   Bryan Riley to come back and share with you that


  2   discussion again.


  3             [Slide.]


  4             But at the same time, I think Helen and


  5   Dr. Woodcock, we were discussing this, we felt this


  6   was much bigger than just an OPS issue, it had to


  7   be an FDA issue, so we took this to the FDA Science


  8   Board, and Dr. Woodcock presented that as emerging


  9   science issues in pharmaceutical manufacturing.


 10             We actually invited--I am not going to go


 11   through all the slides, but just to sort of


 12   illustrate the key presentations that occurred--one


 13   was the opportunity for improving the efficiency


 14   from G.K. Raju and then Doug Bean from


 15   PriceWaterhouseCooper, and we had industry


 16   colleagues from Pfizer who really came and helped


 17   us, saying that Pfizer has adopted a "Don't Use"


 18   and "Don't Tell" approach.


 19             That is the industry approach is to not to


 20   use new science and new technology because of


 21   regulatory uncertainty, or if it is needed, they


 22   will use it, but then they will do something for


 23   the regulators to say here, this is what you want,


 24   but we will control the process this way.


 25             So, we felt that was undesirable from a




  1   public health perspective, and we wanted to move


  2   forward to facilitate introduction of PAT, and we


  3   coined the term PAT. So, we got a very strong and


  4   unanimous endorsement from the FDA Science Board to


  5   move forward.  In fact, the Science Board also said


  6   that they would like to talk and give seminars on


  7   it, but they have not, but we did give them


  8   updates.


  9             [Slide.]


 10             Taking the recommendations of the advisory


 11   committee, this committee's recommendation. we


 12   issued a Federal Register Notice to invite people


 13   to participate on a PAT Subcommittee.


 14             So, we got people to apply.  We selected


 15   those individuals and we formed a PAT Subcommittee.


 16   We brought it back to this advisory committee to


 17   see whether the charter for the subcommittee is


 18   acceptable.


 19             You gave us valuable recommendations.  We


 20   formed the subcommittee, and we had three meetings


 21   - October, June, and February.  Tom Layloff served


 22   as the acting chair for the subcommittee.


 23             [Slide.]


 24             The subcommittee moved so rapidly we did


 25   not have an opportunity to remove the word "Acting"




  1   from these names, so while they were acting, the


  2   work was done, so we never finalized their


  3   positions.


  4             Dr. Kibbe, now the current chair of this


  5   committee, took the responsibility for PAT


  6   Applications Benefits Working Group.  Judy


  7   Boehlert, who is the chair for Manufacturing


  8   Committee, took the lead for Product and Process


  9   Development Working Group.


 10             Leon Lachman focused on Validation.


 11             Dr. Koch, who is now on the advisory


 12   committee, chaired the Working Group on PAT


 13   Chemometrics.


 14             So, these working groups provided us


 15   information, feedback to sort of help create a


 16   framework to write this guidance.


 17             [Slide.]


 18             We also, in parallel, were discussing this


 19   further at the FDA Science Board, and the key


 20   aspect was the PAT initiative was just a starting


 21   point to what was to follow, the 21st Century


 22   Initiative, and so forth.


 23             So, we took this discussion further to the


 24   Science Board, and the second Science Board


 25   discussion was very important.  There was a topic




  1   that Dr. Woodcock herself discussed, and that was


  2   actually something similar to what we had the


  3   discussion on parametric tolerance interval test,


  4   because the current regulatory system and the


  5   current pharmacopeial system is such that actually


  6   does not promote continuous improvement, it


  7   actually penalizes people for doing more testing,


  8   and therefore it had to change.


  9             So, we had to bring the concept of


 10   research and moving away from the current mentality


 11   of 75 to 125 type thinking, the market standard


 12   type thinking, so we had to build that consensus,


 13   and we got strong endorsement from the FDA Science


 14   Board to move forward also on that aspect.


 15             The other presentation, which is very


 16   important to remember, is that of Dr. Ray Sherzer


 17   from GlaxoSmithKline speaking on behalf of CAMP,


 18   and the thing that he pointed out, that there are


 19   many barriers, we need a paradigm shift, and that


 20   paradigm shift is necessary because the barriers


 21   are cultural, organizational, historical.


 22             The challenges are not technical, the


 23   technical knowhow exists.  The scientists can do


 24   this, but the barriers are significant cultural


 25   barriers and organizational barriers, and we could




  1   relate to that, because we had the same barriers


  2   in-house at FDA.


  3             [Slide.]


  4             As we were building the PAT team process,


  5   and you will see a lot of the thought processes


  6   that Helen expressed in terms of the desired goal


  7   that OPS wants to move in, this becomes a model or


  8   the pilot project for a lot of the things we have


  9   done.


 10             So, we had to build a PAT team for


 11   reviewers and inspectors and compliance officers,


 12   because this was the engine for success.  We had to


 13   think very carefully about this because we have a


 14   long history of turf issues.  We don't talk to the


 15   field, the field doesn't talk to us type of


 16   mentality, or this is my issue, field keep away


 17   type of thing.


 18             [Slide.]


 19             So, we actually started a team building


 20   exercise, so starting with a definition of team, a


 21   team is a group of interdependent individuals with


 22   complementary skills who are organized and


 23   committed to achieving a common purpose, applying a


 24   common process, and sharing a common destiny.


 25             Now, I think we clearly have worked on No.




  1   1 and 2, we haven't really worked on No. 3 yet, but


  2   the importance of this is the quality of the


  3   results we expect from the regulatory assessment,


  4   review, or inspection really depend on the quality


  5   of relationship between the reviewer and


  6   inspectors, and the quality of the relationship


  7   defines quality of thinking, and the quality of


  8   thinking defines quality of action that leads back


  9   to the quality of results we expect.


 10             So, this is really a complex issue and


 11   that has to be dealt with very carefully.


 12             [Slide.]


 13             We started the PAT process with three


 14   organizations:  our colleagues in Office of


 15   Regulatory Affairs, which are the GMP inspectors,


 16   Center for Drugs, and Center for Veterinary


 17   Medicine.


 18             The Center for Biologics chose not to be


 19   part of this, and we will discuss that further this


 20   afternoon whether they wish to join us or not.


 21             So, we formed a PAT Steering Committee,


 22   again reflecting all the different organizations.


 23   We formed a PAT Review and Inspection Team, and we


 24   actually recruited a small group, Raj Uppoor, Chris


 25   Watts, Huiquan Wu, and Ali Afnan to come and join




  1   OPS, so we had a very successful recruitment


  2   process.  We actually got Ali to take half the


  3   salary to come to work for FDA, and he did.


  4             We actually put a PAT Training and


  5   Coordination Team, and the training was critical.


  6   One of the critical aspects of the PAT Subcommittee


  7   was developing a curriculum for training, and then


  8   we partnered with three schools: a School of


  9   Pharmacy, a School of Engineering, and a School of


 10   Chemistry to bring this process together, all three


 11   National Science Foundation Centers for Excellence,


 12   Center for Process Analytical Chemistry,


 13   Measurement Control Engineering Center at


 14   Tennessee, and Center for Pharmaceutical Processes


 15   at Purdue.


 16             So, we brought the groups together and the


 17   training occurred, but I do want to share with you


 18   the challenges are cultural.


 19             [Slide.]


 20             If you look at the first picture, if you


 21   can see, a perfect team, right, so we wanted to


 22   work together, so we did want to talk to each


 23   other, it is important, and that is the message I


 24   really want to hone in, because the challenges


 25   right now we are facing, especially in companies,




  1   is this challenge.


  2             We have been able to overcome that in a


  3   small way within the PAT team, but this has to


  4   occur broadly, as Helen pointed out, throughout the


  5   Agency.


  6             [Slide.]


  7             So, I think the challenges are great, and


  8   we have to build teams by dancing together, and we


  9   did dance together--that is Joe Famulare and Doug


 10   Ellsworth dancing, you will never seen them dance


 11   anywhere else--and working as a team on smaller


 12   projects and building a team.  You can see Chris


 13   Watts smiling.


 14             [Slide.]


 15             That led to a team process that paralleled


 16   the efforts that we put together to develop a


 17   guidance.  The guidance is different, it is a very


 18   different guidance, it is not a "how to" guidance,


 19   it is a guidance developed as a framework, and the


 20   guidance simply outlines a framework that reflects


 21   analytical chemistry, industrial pharmacy,


 22   pharmaceutical engineering principles, but in an


 23   integrated way.


 24             What it does is it changes quite a bit of


 25   things each discipline might think about.  The way




  1   I like to say that is if you change the way you


  2   look at a thing, the thing you are looking at


  3   changes, so when Tom and I were discussing, we are


  4   discussing as an analytical chemist and a


  5   industrial pharmacy type.


  6             When we brought engineers in, we got


  7   engineering aspect, so now PAT is somewhat


  8   different than any of the three views of that.


  9             DR. SINGPURWALLA:  It is called the


 10   Heisenberg principle.


 11             DR. HUSSAIN:  Yes.  So, this is a draft


 12   guidance which we are finalizing, and Chris will


 13   talk to you about that, but I do want to sort of


 14   share some other thoughts.


 15             [Slide.]


 16             We had very successful workshops.  The


 17   Arden House conferences this year and last year


 18   were very successful, but they were very emotional,


 19   especially the one last year was very emotional.


 20             The emotions came out first as R&D versus


 21   Manufacturing, because they didn't want to talk to


 22   each other, and then it come out between


 23   pharmacists and engineers, so the engineers came up


 24   to me saying these pharmacist types don't know what


 25   they are doing, but it was necessary because it




  1   forced soul-searching, it forced the thought


  2   processes that was needed, and many companies are


  3   going through that right now.


  4             So, the emotions gave into a lot of


  5   rational discussion at Arden House this year, IFPAC


  6   meeting, ISPE meeting, PDA meetings.  Now we have


  7   several proposals, in fact, I expect by the end of


  8   this summer or the end of this year, you will see


  9   two complete PAT lines, two different companies,


 10   from crystallization to endproduct, complete


 11   automated manufacturing, so that is how fast two


 12   companies have moved, and one we have approved, and


 13   Bryan will talk to you about that.


 14             The first training session is complete,


 15   certification process is ongoing.  We have an


 16   ongoing interagency agreement with National Science


 17   Foundation.  We would like to explore ways of


 18   expanding this, and one opportunity that has been


 19   created is a new initiative called Critical Path,


 20   and we will share that with you next time.


 21             The Critical Path Initiative focuses on


 22   the need for research in three areas:  to improve


 23   drug development itself.  One of those is


 24   industrialization, that is where PAT fits in, and


 25   we want to use that as a means to sort of highlight




  1   the need for public funding for research,


  2   especially academic research in this area, and hope


  3   to do so in the next several months and years.


  4             We had an ongoing CRADA with Pfizer on


  5   chemical imaging.  Things are looking good there,


  6   and we hope to bring some of the results back to


  7   you for some sharing of that with you.


  8             We have ongoing communication and


  9   cooperation with other regulatory agencies.  Now,


 10   our European colleagues have formed a PAT team very


 11   much like ours.  They are actually going to meet


 12   the end of this month, and they have invited us to


 13   participate.


 14             Health Canada has met with us and they are


 15   very eager to sort of join our training session


 16   next year, the next training session that we start.


 17             MHLW, the Japanese are looking at it very


 18   intently and things are happening on the


 19   harmonization front with our trying to harmonize.


 20             [Slide.]


 21             Now, standards development, it was very


 22   important that we have a venue to develop standards


 23   that bring in the multifaceted structure, engineers


 24   have to talk to pharmacists, have to talk to


 25   analytical chemists.




  1             The way we thought that will happen is


  2   through ASTM, because ASTM has a lot of knowhow


  3   already, so we formed a committee called E55,


  4   Pharmaceutical Applications of PAT.  Ali Afnan will


  5   talk to you about that.


  6             There is growing external collaboration


  7   and emerging support structure.  ISPE and PDA are


  8   interested in PAT and are actually developing


  9   programs to cover a lot of the training needs for


 10   the next several years, we have PAT Group in the


 11   AAPS, discussion group.


 12             We are looking at possible collaboration


 13   between AAPS and ISPE to bring the material science


 14   and the engineers together to really focus on


 15   processing, strong support from IFPAC and the


 16   formation of an association for manufacturers.  I


 17   think they are struggling with some identity


 18   crisis.  They call it IFPACma, so I suggested they


 19   should call it IFPATma.


 20             I think this association will be helpful


 21   because it will house all the manufacturers of the


 22   sensors, the software, and so forth, and give them


 23   a voice, a common voice to move forward.


 24             When you have an association especially


 25   with a nonprofit association, we can partner with




  1   them more easily. AICHE has an extensive


  2   discussion, and we are building on the vision 20/20


  3   of AICHE especially in processing to see how that


  4   can be leveraged.


  5             A growing number of academic programs that


  6   focus on PAT.  Several PAT companies and training


  7   opportunities have emerged.  Pharmacopeias are


  8   interested in PAT.  Hopefully, they resolve the


  9   acceptance criteria first.


 10             PAT is now a part of the 21st Century


 11   Initiative and FDA's Strategic Plan, so I think


 12   that small crystal is starting to crystallize the


 13   system.


 14             [Slide.]


 15             The next step is guidance finalization.


 16   We are moving towards a quality system for the PAT


 17   process.  FDA will participate in the ASTM.


 18             This afternoon, we will discuss


 19   application of PAT to the Office of Biotechnology


 20   Products.  I want to sort of make sure I say this


 21   in a way that emphasizes the structure.


 22             Expand the scope of the guidance to


 23   include Office of Biotechnology Products.  Since


 24   they were not part of the training and


 25   certification program, the guidance is not




  1   applicable to them.


  2             The guidance is a framework guidance.  It


  3   applies to any manufacturing, whether it's biotech,


  4   whether it's automobile, whether it's anything, the


  5   concepts apply to any manufacturing, so it will


  6   apply to Office of Biotechnology Products.


  7             The reason that office is not within the


  8   scope is they were not trained and certified on


  9   this aspect.  So, the question to you would be how


 10   would we develop a training program that will meet


 11   their needs, and as we go to the second training


 12   program, that will have a more biotech focus and


 13   then that becomes part of the PAT process.


 14             I will stop my presentation and invite


 15   Chris to continue.  I think in the next two to


 16   three years, we want a sunset PAT.  What I mean by


 17   "sunset PAT," is that becomes a regular part of our


 18   CMC and GMP program, so it will merge with the rest


 19   of the system.


 20             Is two to three years the right time?  I


 21   think we will see, but the intention is that this


 22   is no longer a unique program, it is part of the


 23   current system.


 24             With that, I will stop.  If you have any


 25   questions, I will be glad to answer, or we could




  1   answer after Chris and others have talked.


  2                     Finalizing PAT Guidance


  3                    Training and Certification


  4             DR. WATTS:  Thank you, Ajaz, and thank the


  5   committee for giving me just a few minutes of your


  6   time to go over what we have done in terms of


  7   training and certification and moving toward


  8   finalizing the draft guidance that we put out back


  9   in September of 03.


 10             [Slide.]


 11             I just want to take a step back really


 12   quickly and just summarize some of the discussions


 13   that took place at this committee and the PAT


 14   Subcommittee in terms of defining what PAT is, and


 15   that will really give some background on the intent


 16   of the training program and what the focus was for


 17   the training program.


 18             The definition that came from this and


 19   subsequently made its way into the guidance was PAT


 20   is a system for designing, analyzing, and


 21   controlling manufacturing through timely


 22   measurements of critical quality and performance


 23   attributes of raw and in-process materials and


 24   processes.


 25             So, it is not just focused on any one




  1   analytical technique, it is not focused on


  2   endproduct only, it is the entire manufacturing


  3   process.


  4             When you think about PAT, process


  5   analytical technology, that term "analytical" more


  6   should be thought of as analytical thinking, not


  7   just simply analytical chemistry, so we made a


  8   point of emphasizing that analytical, when you


  9   think about that term, you should include not only


 10   chemical, but also physical, microbiological,


 11   mathematical, and risk analysis, all those


 12   conducted in an integrated manner to come up with a


 13   framework for controlling the manufacturing


 14   process.


 15             [Slide.]


 16             So, with that definition, the unmistakable


 17   focus of PAT is to really understand the


 18   manufacturing process.  What we outlined was a


 19   process is considered well understood when, number


 20   one, all critical sources of variability are


 21   identified and explained; number two, the


 22   variability is managed by the process, and,


 23   finally, product quality attributes can be


 24   accurately and reliably predicted.


 25             So, with that focus on process




  1   understanding, it brings in the concept of really


  2   risk management, so we consider that the level of


  3   process understanding is inversely proportional to


  4   the risk of producing a poor quality product.


  5             So, a well understood process then offers


  6   less restrictive regulatory approaches to manage


  7   change to different approaches to validation.


  8             So, if you focus on process understanding,


  9   we can facilitate risk-managed regulatory decisions


 10   and innovation, not only within the Agency, but


 11   within the manufacturing arena and the


 12   pharmaceutical industry in general.


 13             [Slide.]


 14             So, having that background, I want to now


 15   talk about this framework that we developed for PAT


 16   that came out in the guidance, and it was a


 17   framework, as I just mentioned, for innovative


 18   pharmaceutical manufacturing and quality assurance.


 19             We really set forth some scientific


 20   principles, some basic principles and concepts, and


 21   described some PAT tools that would support


 22   innovation.


 23             In my opinion, one of the most important


 24   aspects was the regulatory strategy that would


 25   accommodate innovation, and that the primary focus




  1   there was on the PAT team approach again which Ajaz


  2   mentioned briefly, the team approach to review and


  3   inspection.


  4             Along those lines, we developed a joint


  5   training and certification program, so I want to


  6   talk to you now about that training and


  7   certification program.


  8             [Slide.]


  9             You have already seen a few slide from


 10   Ajaz on the team building aspect, really getting to


 11   know one another very well, and again that included


 12   people from the Center for Drugs, both reviewers


 13   and compliance officers, the field investigators


 14   from the Office of Regulatory Affairs, and, of


 15   course, the compliance officers and reviewers from


 16   the Center of Veterinary Medicine.


 17             During this training program, it was


 18   important that all 15 individuals who were part of


 19   that initial training program, we went through


 20   everything together, every didactic session we went


 21   as a team, every practicum we went as a team.


 22             The team building obviously, everyone was


 23   involved there, so there it would really break down


 24   the communication barriers, which is really going


 25   to be key to ensuring that science-based,




  1   risk-based or risk-managed approach to review and


  2   inspection.


  3             A brief outline of the training program


  4   that we had.  Two didactic sessions, both of those


  5   were conducted here at the FDA, and three practica,


  6   again, at the University of Washington, the Center


  7   for Process Analytical Chemistry; Purdue


  8   University, Center for Pharmaceutical Process


  9   Research, and the University of Tennessee, the


 10   Measurement and Control Engineering Center.


 11             [Slide.]


 12             In summary, the first didactic that we had


 13   was really just to provide a general overview of


 14   some of the pharmaceutical processes, the


 15   scientific basis for some of those processes, why


 16   they may be necessary, to really give the team a


 17   feel for what some of those unit operations


 18   specifically may be trying to do to the material


 19   and what are some approaches for trying to control


 20   that process.


 21             Of course, there was some extensive


 22   discussion on some of that process analytical


 23   techniques, multivariate analysis, an in-depth


 24   discussion on the background of where some of the


 25   multivariate analysis techniques came from,




  1   principal component analysis, partial e-squares,


  2   how those can be used in terms of developing a


  3   control system for the manufacturing processes, and


  4   then finally, a general introduction to true


  5   process control from a process control engineer.


  6             After that, we went to the University of


  7   Washington in Seattle, The Center for Process


  8   Analytical Chemistry, and the focus there was


  9   really on sensor technology and development.  I


 10   think CPAC did a wonderful job of tying that in,


 11   giving some other industrial examples, and tying


 12   that into how some of these sensors may be applied


 13   to the pharmaceutical industry.


 14             [Slide.]


 15             To maintain continuity with the practicum


 16   visits, we took some of those, the sensor


 17   technology, some of the sensors that were being


 18   utilized at CPAC, and put them in the use onto some


 19   pharmaceutical processes at Purdue University.


 20             There, we really focused on some of the


 21   experiments that we conducted were blending, for


 22   example, compression, granulation, traditional


 23   solids processes, how some techniques were emerging


 24   that may be able to allow us to control those


 25   processes on line, really understand the impact of




  1   those processes on the final product quality and


  2   how they relate, not just to consider them


  3   independently, but how they relate to the final


  4   product quality as a whole.


  5             After having done our experiments at the


  6   second practicum at Purdue, we then took some data


  7   on the granulation process.  Then, when we went to


  8   the Measurement and Control Engineering Center at


  9   the University of Tennessee, we actually analyzed


 10   that data.


 11             Paul Kemperlein, who is part of MCEC,


 12   really walked us through, you know, what are some


 13   of the techniques that you maybe use, what are some


 14   limitations of these multivariate techniques that


 15   you may be want to be keeping in mind when you are


 16   going through the review of these applications.


 17             [Slide.]


 18             Finally, the last didactic, we tried to


 19   tie everything together again.  We broke up into


 20   teams, developed some case studies, so that we


 21   could really apply what we had learned throughout


 22   the training program, and discussed those as teams,


 23   a true team approach, a reviewer, compliance


 24   officer and investigator, and really began to


 25   discuss what some of the relevant issues were in




  1   terms of managing the review and inspection


  2   processes.


  3             That really ended the initial training


  4   portion, but by no means did we think it is


  5   complete.  I think continuing education is going to


  6   be vital to the success of this team, which Ajaz


  7   mentioned is really going to drive the success of


  8   PAT within the Agency.


  9             Along those lines, we have monthly video


 10   conferences with the people that are here in


 11   Rockville and the investigators that are in the


 12   field, and we try to discuss some of the relevant


 13   issues that are coming out, for example, some


 14   recent publications or some inspections, review


 15   issues that may have surfaced, and discussed those


 16   as a team, not individually as reviewers or not


 17   inspection issues individually as inspectors, but


 18   as a team.


 19             We also have developed a seminar series to


 20   discuss some publications that may be relevant to


 21   what we are trying to do within the PAT initiative,


 22   and, of course, we are using the Intranet to


 23   communicate some of these publications and discuss


 24   those on line, really, an easy way of communicating


 25   with the entire team.




  1             [Slide.]


  2             In summary, we have, in terms of the


  3   training and certification, we have completed the


  4   initial training program.  We are now in the


  5   process of conducting some lessons learned in terms


  6   of what we have accomplished with this, maybe some


  7   additional aspects that need to be considered, and


  8   some of those will be discussed with this committee


  9   this afternoon in terms of expanding the scope of


 10   PAT to include biotech products.


 11             Again, continuing education and


 12   involvement in the next training, I think is going


 13   to be critical for this group, so that we maintain


 14   links, not only with the team that we currently


 15   have, but the team that we intend to build.


 16             We can take some of the experience of


 17   those reviewers and investigators who have


 18   processed and will be processing some applications


 19   and who have gone on inspections and really share


 20   those with the new group that is coming in and the


 21   group that we currently have, so that we can


 22   understand maybe what is the best approach for us


 23   to go in terms of taking a team to do an


 24   inspection.


 25             Maybe we don't need to have all three




  1   people, maybe one or two should be sufficient, and


  2   we can do discussions over the telephone or


  3   videoing to handle some issue.


  4             Of course, we have involved the entire


  5   team in finalizing the guidance.  In my opinion, I


  6   think it was very important to get a real feel for


  7   how the reviewers felt about the guidance, how the


  8   compliance officers and how the investigators felt


  9   about the policy that was emerging in the guidance,


 10   really how that framework was going to be


 11   implemented because they are going to be the ones


 12   who are really driving things.


 13             They are going to be the ones who are


 14   enforcing the policy, not really enforcing the


 15   policy, but making sure that the process works as


 16   it should, so that it is a least burdensome


 17   approach to the industry.


 18             Within the Office of Testing and Research,


 19   you heard Helen mention Dr. Khan is coming on


 20   board, I think it is going to be important to


 21   maintain a link to the Office of Testing and


 22   Research, so that we can support policy development


 23   and future training if we develop some in-house


 24   expertise and what are some critical issues that we


 25   may want to be able to focus on in terms of review




  1   and inspection and some of the technologies that


  2   may be developed, if we can develop some of that


  3   expertise in-house, we can not only bring some of


  4   the training in-house, but also have some consults,


  5   we have expertise within the Agency that we can


  6   consult on a given basis.


  7             [Slide.]


  8             So, building on a little bit of the


  9   guidance finalization, we involved the entire team


 10   in the development of the guidance, and, of course,


 11   they are going to be involved in finalizing the


 12   guidance.


 13             The guidance was issued in September of


 14   03, and the public comment period extended through


 15   November 4th, and those comments are available on


 16   the docket.  You can see all, I think there were


 17   some two dozen companies or individuals that


 18   submitted comments to the guidance, and we are in


 19   the process of going through those and discussing


 20   those and addressing each one of those.


 21             We have included the entire team and we


 22   have broken the teams down into reviewers again,


 23   compliance officers, and investigators, and have


 24   those address each of those and see which comments


 25   they may think are most relevant and convey that




  1   back to the policy team, so that we can move


  2   forward in finalizing the guidance.


  3             With that, I am going to conclude this


  4   portion right here.  Again, I think we may have


  5   time for some questions afterwards, and I want to


  6   turn it over to my colleague, Ali Afnan, who will


  7   discuss the standards development process for PAT.


  8                      Standards Development


  9             DR. AFNAN:  Thank you very much for giving


 10   me the opportunity to be here.


 11             [Slide.]


 12             I am going to be very quick.  The outline


 13   of the talk is why we went with ASTM, what is ASTM,


 14   what is the history of the committee, where are we


 15   going with it, and I will give you some background


 16   also as to how, what Chris has just said, links


 17   into this process.


 18             [Slide.]


 19             Having focused on the processing, going


 20   away from product testing, which Chris very


 21   beautifully put out as PAT being process


 22   understanding, we had to come up with new standards


 23   and new ways of assessing whether a process was


 24   right or wrong.


 25             If the process was working well, then, the




  1   product would be right, so for that reason, we


  2   began to look at alternatives to the current


  3   specifications we were working with because


  4   effectively, we needed standards, not


  5   specifications.


  6             We needed a process which included all the


  7   interested parties and allowed them to come in for


  8   a balanced discussion, definition of balanced


  9   discussion being that we would each have one vote,


 10   it would have a due process, and, of course, there


 11   was the NTTAA Act, the National Technology Transfer


 12   Act, which mandates federal departments and


 13   agencies to use voluntary consensus standards in


 14   place of government standards wherever possible.


 15             So, having looked at all of those, we


 16   decided to look at ASTM, which had already been in


 17   dialog with our other departments in the agency.


 18             [Slide.]


 19             So, ASTM, which now they call themselves


 20   ASTM International, is an ANSI-accredited standards


 21   development organization with more than 100 years


 22   of experience in standard development.


 23             They actually generate standards, best


 24   practices, and guides, three different things, but


 25   they are all done through a peer review process. 




  1   Their offices are in West Conshohocken, and they


  2   meet regularly.  There is a committee which goes


  3   around to various places.  This year it is in Salt


  4   Lake City, and next year it is somewhere in Europe.


  5             [Slide.]


  6             The history of developing the committee


  7   was that through the winter and spring of 2003, FDA


  8   met with ASTM re: development of a new committee


  9   for Process Analytical Technology.


 10             In October of 2003, there was a meeting at


 11   ASTM, and then in December, the first


 12   organizational meeting was held at which interested


 13   parties from academia and industry were present.


 14             In January, the nomination and election of


 15   committee officers took place.  Again, if you are


 16   interested in the procedures and the processes of


 17   elections or how ASTM functions, the best place to


 18   look at is ASTM.org, World Wide Web.


 19             In February of this year, we had the first


 20   meeting of ASTM E55 Committee, and the next one is


 21   in Salt Lake City, 18th through 20th of May.


 22             [Slide.]


 23             What is the scope of E55?  E55 pretty much


 24   reflects the FDA PAT draft guidance, but the scope


 25   of the committee is that the scope of the committee




  1   shall be development of standardized nomenclature


  2   and definitions of terms, recommended practices,


  3   guides, test methods, specifications, and


  4   performance standards for pharmaceutical


  5   application of process analytical technology.


  6             The committee will encourage research in


  7   this field and sponsor symposia, workshops and


  8   publications to facilitate the development of such


  9   standards.  The committee will promote liaison with


 10   other ASTM committees and other organizations with


 11   mutual interests.


 12             What was quite interesting was it took


 13   about an afternoon to come up with that, and,


 14   really, we thank the industry for taking a very


 15   active role in coming up with that scope.


 16             [Slide.]


 17             Currently, E55 has three subcommittees.


 18   One is E55.01, which is PAT Systems Management;


 19   E55.02, which is Systems Implementation and


 20   Practice.  The Executive Subcommittee is 90, and


 21   then there is a third one, which is E55.91


 22   Terminology.


 23             [Slide.]


 24             The Chair and the elected officers, which


 25   was by ballot effectively, of E55, the Chairman is




  1   Don Marlowe from the Office of the Commissioner.


  2   The Vice Chair is Ray Scherzer from GSK.  The


  3   Membership Secretary is James Drennen from Duquesne


  4   University, and the Recording Secretary is Gawayne


  5   Mahboubian-Jones from Optimal Industrial


  6   Automation, Ltd., a system integration company.


  7             [Slide.]


  8             The Subcommittee officers.  E55.01's chair


  9   is Ken Leiper, Vice Chair is Gerry, the Secretary


 10   is Chris Watts.  E55.02 Chair is Ferdinando Aspesi


 11   from Aventis.  The Vice Chair, from AstraZeneca, is


 12   Bob Chisholm.  I am the Secretary.


 13             E55.91, which is the Terminology


 14   Subcommittee, has Larry Hecker, Abbott, as Chair,


 15   and Jim Fox, of GSK, as its Secretary.


 16             There are also 8 members at large, who


 17   serve on the E55 Main Executive Committee, and they


 18   are appointed from industry and academia.


 19             Thank you.


 20                     Rapid Microbial Methods


 21             DR. RILEY:  What I would like to do this


 22   morning is give you a brief update on the status of


 23   rapid microbiology methods as part of the PAT


 24   initiative.


 25             [Slide.]




  1             As you may know, rapid microbiology


  2   methods were not originally part of the PAT


  3   initiative.  We were sort of looking at rapid micro


  4   methods in a parallel track with the development of


  5   the PAT initiative, but finally, someone recognized


  6   it would make sense to have rapid micro methods as


  7   part of PAT, so at the October 2002 PAT


  8   Subcommittee meeting, there was an extensive


  9   breakout session dealing with rapid microbiological


 10   methods.


 11             A number of speakers discussed the


 12   importance of rapid microbiology methods, how they


 13   could fit into PAT and also the best way to look at


 14   rapid microbiological methods for the


 15   pharmaceutical industry.


 16             [Slide.]


 17             From that point on, we worked to try to


 18   integrate rapid microbiological methods into the


 19   PAT initiative because PAT had sort of a headstart


 20   on us.  So, the first thing we did was looking at a


 21   training session for rapid micro.  To do that, in


 22   July of 2003, here in Rockville, we had a training


 23   session.


 24             We invited people from CDER, ORA, CBER,


 25   and CVM to attend.  As an agenda, we had an




  1   overview of rapid microbiological method


  2   technologies, a very extensive overview.  We had


  3   two rapid micro method vendors come in and talk


  4   about their products and how they can be used.


  5             We also had a company come in and talk


  6   about their experiences of validating a rapid


  7   microbiological method for pharmaceutical use.


  8             [Slide.]


  9             Since the team approach is very important


 10   for PAT, one of the things we had to do was to form


 11   a rapid micro method team for PAT.  That team


 12   consists of Bob Coleman, expert drug investigator


 13   from ORA; Dennis Guilfoyle, a pharmaceutical


 14   microbiologist from the North East Regional


 15   Laboratory at FDA, Brenda Uratani, a microbiologist


 16   from the Office of Compliance, CDER, and myself.


 17             [Slide.]


 18             As we were doing the training and setting


 19   up the team, we were also in contact with a large


 20   global pharmaceutical manufacturer who was


 21   interested in using a rapid microbiology method for


 22   their pharmaceutical manufacturing process.


 23             We had a number of meetings with them to


 24   discuss their use of these rapid micro methods, how


 25   they would validate them, how they would submit the




  1   information to the Agency, that sort of thing, and


  2   these meetings culminated with a formal


  3   presubmission meeting with the applicant in 2003,


  4   where they discussed what they would submit and how


  5   they would submit it.


  6             Because what they wanted to do was to use


  7   some different rapid micro methods for release


  8   testing of a variety of non-sterile drug products,


  9   they wanted to use these at multiple manufacturing


 10   sites, it was decided that a comparability protocol


 11   would probably be the best way for them to submit


 12   this information to begin with.


 13             A comparability protocol is simply a


 14   written formal experimental protocol where, in this


 15   case, what they are demonstrating is that their


 16   rapid method is equivalent to or superior to the


 17   traditional method they have been using, and it


 18   talks also about the experiments they will do and


 19   also the acceptance criteria that they would want


 20   to use to demonstrate that equivalence.


 21             So, what they did after this meeting was


 22   they submitted two comparability protocols, one for


 23   product release testing for several non-sterile


 24   drug products, and also testing for pharmaceutical


 25   grade waters.




  1             After the approval of the comparability


  2   protocol for product release testing, they then


  3   submitted a changes being affected supplement to


  4   implement that rapid micro method for one of their


  5   non-sterile drug products.


  6             [Slide.]


  7             It was decided as part of this application


  8   process that an inspection would be done related to


  9   the rapid micro method implementation, and because


 10   of that, the rapid micro method team had several


 11   meetings, one in September of 2003, where we mainly


 12   discussed the comparability protocols that were


 13   submitted by the company, and then finally, in


 14   early February of 2004, we talked about the actual


 15   inspection itself, what we would do, how we would


 16   do it, that sort of thing.


 17             The inspection took place in late February


 18   of 2004.  It was led by again Bob Coleman from the


 19   Office of Regulatory Affairs, and Bob's experience


 20   and his leadership in this process was very, very


 21   helpful to us especially on the inspection process.


 22   It made it go very smoothly.


 23             We looked at the rapid micro method


 24   itself, how it was validated.  We looked at just


 25   the general microbiological laboratory aspect of




  1   the pharmaceutical manufacturing facility, and also


  2   looked at some of the GMPs related to the


  3   manufacturing of the product that they would be


  4   using the rapid micro method test for.


  5             The inspection found no significant


  6   problems.  There was no 43 issue as a result of


  7   that inspection, and we thought everything went


  8   well both from our standpoint, as well as the


  9   firm's standpoint.


 10             [Slide.]


 11             What is the future of rapid microbiology


 12   methods in the pharmaceutical industry?  I think


 13   the ultimate goal, the ideal would be real-time


 14   testing to provide immediate feedback.  I think


 15   that would be very, very helpful.


 16              Where are we today?  The  traditional


 17   micro methods require several days to several weeks


 18   to get results.  The current available rapid micro


 19   methods that are available today, and can be used


 20   today, significantly shorten that time to result.


 21             It can be as little as a day or maybe a


 22   little bit more than a day, and some of the rapid


 23   methods can give you results in as little as a


 24   couple of hours.


 25             We think even though it is not real-time




  1   testing, it still provides much better control,


  2   much better understanding of the manufacturing


  3   process from a microbiological standpoint and


  4   hopefully, can help detect and enable you to


  5   correct a potential problem before it becomes a


  6   real and serious problem as far as microbiological


  7   quality of the drug product is concerned.


  8             We are hoping that our experiences that we


  9   have had so far with our rapid micro method


 10   submission and inspection and approval process will


 11   encourage others in industry to also use this PAT


 12   regulatory pathway to look at other rapid micro


 13   methods and use them to improve their manufacturing


 14   process and understanding.


 15             I thank you for your attention this


 16   morning and I guess we will take questions of any


 17   presentations of this session.


 18            Committee Discussions and Recommendations


 19             DR. MEYER:  One question for Ajaz and I


 20   guess one for Chris.


 21             As the U.S. develops this PAT concept and


 22   begins to apply it, it seems like it is better to


 23   harmonize as things are being developed than after


 24   they are set in stone.


 25             Is there an effort with the Japanese, the




  1   Europeans, the Canadians to harmonize on the front


  2   end?


  3             DR. HUSSAIN:  Yes, in terms of I think


  4   there is quite a significant dialog and discussion,


  5   and I think the framework provides a way forward


  6   because as a framework, it does not get in how to,


  7   and harmonizing how-to guidance is a difficult


  8   challenge, so this is the time to do this.


  9             That is the reason we felt ASTM also


 10   provides a way forward because the devices, the


 11   Center for Devices, for example, utilize the ASTM


 12   standards, and these are international standards,


 13   so many of the members on the ASTM committees are


 14   international members right now, Europe and U.S.


 15   right now, and we are encouraging people from Japan


 16   to join in.


 17             So, that would be a way forward, so you


 18   are absolutely correct.  I mean we are trying to do


 19   that as you move along, and the progress has been


 20   significant on that.  That is what I tried to say


 21   is we are harmonizing without trying to harmonize.


 22             DR. MEYER:  My question to Chris, if I


 23   understood you correctly, there is about a


 24   15-member team, a variety of disciplines, that were


 25   sent through this fairly intensive training




  1   program?


  2             DR. WATTS:  Correct, yes.


  3             DR. MEYER:  Will that be all there is, or


  4   how is this going to grow to be 150 people or will


  5   it?


  6             DR. WATTS:  Well, as Ajaz mentioned, I


  7   think within a few years, two to three years, he


  8   envisions it being a regular part of the operation


  9   within the CMC review and GMP inspection when it


 10   comes to this team approach to PAT.


 11             We have every intention of expanding the


 12   training program to include more members within


 13   CDER, the Office of Pharmaceutical Science, Office


 14   of New Drug Chemistry, Office of Compliance, but I


 15   think the immediate need may be to expand the scope


 16   to include the Office of Biotechnology Products,


 17   which will be included in the discussion this


 18   afternoon.


 19             Based on a lot of the comments that we got


 20   from the guidance that we issued in September,


 21   there were a significant number of comments


 22   suggesting that we do expand the scope to include


 23   OBP, and as far as an immediate need, I think that


 24   may be more urgent in terms of expanding the team


 25   concept.




  1             DR. COONEY:  Another question on the


  2   education side, actually, two questions.  Could you


  3   comment a bit on what do you see as the important


  4   metrics that you use in measuring the success of


  5   the educational program and then could you also


  6   elaborate a bit on what do you see as the major


  7   challenges in continuing to evolve and develop the


  8   educational program?


  9             DR. WATTS:  Actually, I think one of the


 10   most important aspects was just the team approach.


 11   The technical aspects will be actually rather


 12   simple to address when it comes to terms of getting


 13   some expertise either within academic environment


 14   or within industry that have given technical


 15   expertise that can convey that to the team.


 16             Given the team approach, rather than