DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE
Advisors and Consultants Staff Conference Room
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.
SPECIAL GOVERNMENT EMPLOYEES
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.
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
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
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.
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
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
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.
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
22 Thank you.
23 DR. KIBBE: Thank you. I am Art Kibbe. I
24 am Chairman of the Pharmaceutical Science's
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
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
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
pleased to have both of them here working with us.
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.
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.
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.
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
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
development, manufacturing, and quality assurance
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.
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.
22 Basically, the goals are for OPS programs
23 and projects to support the achievement of the
24 following attributes of drug products:
The drug quality and performance is
1 achieved and assured through design of effective
2 and efficient development and manufacturing
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.
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.
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.
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
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.
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.
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.
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
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
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
important aspects of the initiative.
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,
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
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
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
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
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
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
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.
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
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
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
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
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.
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
more efficient and effective manner.
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
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.
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
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.
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
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
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.
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
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.
6 The advantages for industry is hopefully,
7 that we will have fewer, more efficient,
8 science-based inspections, faster, more consistent
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.
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
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.
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
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
24 This is another thing that we have not
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.
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
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.
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
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
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
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.
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
24 Also, we will be adding Dr. Mansor Khan
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.
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
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
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
committee, and we want to talk about topical
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.
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
topics that we discussed.
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.
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
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
studies that may help streamline the dose finding
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
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
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.
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.
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
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.
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
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.
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
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
23 There seemed to be consensus that
24 nonclinical information, such as data from primate
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.
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
state-of-the-art, what can FDA use as basis of
1 review for new incoming NDAs.
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
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.
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.
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
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
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
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
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
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
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
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.
5 Moving Forward -- An Approach for Resolution
6 DR. O'NEILL: Good morning.
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.
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
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.
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
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
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.
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
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
folks on the working group.
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.
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
appropriate statistical procedures.
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
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.
24 The next steps are to ask you folks to
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
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
in that zone, it is not acceptable, so it's a
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
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
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
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
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.
DR. KAROL: Could you tell me how
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
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
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
rather than less. That is another
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
second stage, so you have to meet
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,
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
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
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
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
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
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,
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
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
12 I think that is the sense of the
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
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
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.
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
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
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
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
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
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
2 DR. KIBBE: I will give you all 15 minutes
3 and then we will have Dr. Hussain.
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.
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.
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
20 What we are doing with respect to
21 standards development. Ali Afnan will talk about
23 A topic that we have discussed twice with
24 you, but we thought we would sort of bring some
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?
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
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.
23 The aspect I think which was important is
24 this was a presentation that Tom and I did together
FIP meeting. Tom had left FDA and was
1 the USP at that time. The title was Advanced
2 Quality Control of Pharmaceuticals: In-line Process
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.
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
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.
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
subcommittee, and that is the reason I brought
1 Bryan Riley to come back and share with you that
2 discussion again.
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
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
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
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.
24 The subcommittee moved so rapidly we did
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
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
14 So, these working groups provided us
15 information, feedback to sort of help create a
16 framework to write this guidance.
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
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
barriers and organizational barriers, and we could
1 relate to that, because we had the same barriers
2 in-house at FDA.
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
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.
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.
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.
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
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
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.
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
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
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.
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
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.
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
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
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
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.
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
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
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
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
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
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.
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
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
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
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.
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.
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
23 In my opinion, one of the most important
24 aspects was the regulatory strategy that would
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
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.
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
be key to ensuring that science-based,
1 risk-based or risk-managed approach to review and
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.
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
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.
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
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.
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
discuss what some of the relevant issues were in
1 terms of managing the review and inspection
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
with the entire team.
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
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
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.
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
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
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.
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.
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.
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
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.
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
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.
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.
23 What is the scope of E55? E55 pretty much
24 reflects the FDA PAT draft guidance, but the scope
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.
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
24 The Chair and the elected officers, which
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.
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
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
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.
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
24 We invited people from CDER, ORA, CBER,
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.
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.
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
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
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.
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
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.
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.
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.
Is there an effort with the Japanese, the
1 Europeans, the Canadians to harmonize on the front
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
sent through this fairly intensive training
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
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
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
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