FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

MANUFACTURING SUBCOMMITTEE

OF THE

ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

8:30 a.m.

Wednesday, May 21, 2003

Ballroom Salons A-D

Gaithersburg Marriott - Washingtonian Center

9751 Washingtonian Boulevard

Gaithersburg, Maryland 20878

ATTENDEES

ACPS MEMBERS:

PATRICK P. DeLUCA, PH.D.

Professor, Faculty of Pharmaceutical Science

401 College of Pharmacy

University of Kentucky

907 Rose Street

Lexington, Kentucky 40536-0082

ROBERT GARY HOLLENBECK, PH.D.

Professor of Pharmaceutical Science

University of Maryland School of Pharmacy

20 North Pine Street

Baltimore, Maryland 21201

KAREN M. TEMPLETON-SOMERS, Acting Executive Secretary

Advisors and Consultants Staff (HFD-21)

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, Maryland 20857

AD HOC MEMBERS (Special Government Employee Consultants):

JUDY P. BOEHLERT, PH.D.

President, Boehlert Associates, Inc.

102 Oak Avenue

Park Ridge, New Jersey 07656-1325

DANIEL H. GOLD, PH.D.

12 Route 17 North, Suite 308

Paramus, New Jersey 07652

THOMAS P. LAYLOFF, JR., PH.D.

Principal Program Associate

Center for Pharmaceutical Management

Management Sciences for Health

5 Thomas Court

Granite City, Illinois 62040-5273

GARNET PECK, PH.D.

Industrial and Physical Pharmacy

Purdue University, 575 Stadium G-22C

West Lafayette, Indiana 47907

ATTENDEES (Continued)

AD HOC MEMBERS (Special Government Employee Consultants):

(Continued)

JOSEPH PHILLIPS

230 Hillcrest Avenue

Blackwood, New Jersey 08012

G.K. RAJU, PH.D.

Executive Director, MIT/PHARMI

MIT Program on the Pharmaceutical Industry

Room 56-653

Massachusetts Institute of Technology

77 Massachusetts Avenue

Cambridge, Massachusetts

RICHARD SERAFIN

240 Aldrin Drive

Ambler, Pennsylvania 19002

NOZER SINGPURWALLA, PH.D.

Director

Institute for Reliability and Risk Analysis

Distinguished Research Professor

Professor of Statistics

George Washington University

2201 G Street, N.W., Room 315

Washington, D.C. 20052

GUESTS AND GUEST SPEAKERS:

EFRAIM SHEK, PH.D., Acting Industry Representative

Divisional Vice President

Pharmaceutical and Analytical Research and Development

Abbott Laboratories

Department 04R-1, Building NCA4-4

1401 Sheridan Road

North Chicago, Illinois 60064-1803

KENNETH LAVIN, M.Sc.

Director, Regulatory Compliance

TEVA Pharmaceuticals USA

1090 Horsham Road

P.O. Box 1090

North Wales, Pennsylvania 19545-1090

ATTENDEES (Continued)

GUESTS AND GUEST SPEAKERS: (Continued)

GERRY MIGLIACCIO

Pfizer, Inc.

235 East 42nd Street

New York, New York 10017

FOOD AND DRUG ADMINISTRATION STAFF:

JOSEPH FAMULARE

DAVID HOROWITZ

AJAZ HUSSAIN, PH.D.

HELEN WINKLE

ALSO PRESENT:

COLIN R. GARDNER, PH.D.

Transform Pharmaceuticals Inc.

C O N T E N T S

AGENDA ITEM PAGE

CONFLICT OF INTEREST STATEMENT

by Dr. Karen Templeton-Somers 8

INTRODUCTION

by Ms. Helen Winkle 10

PHARMACEUTICAL cGMPs FOR THE 21st CENTURY:

A RISK-BASED APPROACH

FDA PERSPECTIVE

by Mr. David Horowitz 19

by Ms. Helen Winkle 44

ACADEMIC PERSPECTIVE

by Dr. Gokeju K. Raju 76

OPEN PUBLIC HEARING PRESENTATION

by Dr. Colin Gardner 128

GPhA PERSPECTIVE

by Mr. Kenneth Lavin 148

PhRMA PERSPECTIVE

by Mr. Gerry Migliaccio 164

DEVELOPMENT OF SUBCOMMITTEE WORK PLAN

by Dr. Ajaz Hussain 186

P R O C E E D I N G S

(8:30 a.m.)

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

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

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

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

DR. SHEK: Efraim Shek from Abbott Laboratories.

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

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

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

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

DR. DeLUCA: Pat DeLuca, Professor of Pharmaceutical Sciences at the
University of Kentucky.

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

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

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

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

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

(Laughter.)

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

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

DR. BOEHLERT: Thank you.

Our next order of business is Karen Templeton-Somers will read the
conflict of interest statement.

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

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

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

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

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

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

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

With respect to FDA\'s invited guests, Ken Lavin has no financial
interest or professional relationship with any pharmaceutical company.
Gerry Migliaccio is employed full-time by Pfizer, Incorporated, and is a
member of PhRMA GMP Steering Committee. Glenn Wright reports he is
employed full-time by Eli Lilly & Company.

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

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

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

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

DR. BOEHLERT: Thank you, Karen.

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

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

(Laughter.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

MR. HOROWITZ: Please.

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

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

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

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

DR. SINGPURWALLA: That\'s just a comment.

MR. HOROWITZ: I appreciate it.

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

(Laughter.)

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

DR. SINGPURWALLA: Thank you.

DR. BOEHLERT: Dan.

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

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

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

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

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

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

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

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

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

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

DR. GOLD: Yes, I realize that.

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

DR. GOLD: Thank you.

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

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

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

DR. BOEHLERT: Gary?

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

MR. HOROWITZ: Right.

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

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

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

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

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

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

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

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

MR. HOROWITZ: Correct.

DR. LAYLOFF: Actually we led everybody else.

MR. HOROWITZ: Absolutely.

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

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

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

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

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

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

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

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

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

DR. BOEHLERT: Wait a minute.

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

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

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

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

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

DR. BOEHLERT: Any other discussion?

(No response.)

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

Helen has been standing in the wings.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

(Laughter.)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. BOEHLERT: Any questions or comments? Dan?

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

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

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

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

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

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

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

DR. BOEHLERT: Nozer?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

DR. BOEHLERT: Efraim.

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

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

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

DR. BOEHLERT: Gary?

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

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

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

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

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

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

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

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

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

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

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

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

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

(Laughter.)

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

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

(Laughter.)

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

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

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

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

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

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

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

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

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

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

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

So in many ways, when FDA figures out or has a better understanding of
how to better focus its inspectional resources, that information will
automatically be very useful to industry. First of all, they like to
know what we\'re going to be looking at so they can get there and fix it
before we ever find it. And second of all, I think it will be useful for
them to focus their limited quality control resources on what we jointly
can determine matters most.

DR. BOEHLERT: Any follow up?

DR. SINGPURWALLA: The only comment I\'d like to make is that there may
be some common ground, but there is also opportunity for an adversarial
situation evolving because industry\'s attitude is to maximize utility.
Your particular attitude is to maximize safety. So the two are kind of,
by definition, adversarial unless industry wants to change its complete
form of existence.

MR. HOROWITZ: Well, I agree with your basic point that there\'s a
natural tension ‑‑ and there should be, frankly ‑‑ between the regulator
and the regulated. But at the same time, it\'s in industry\'s interest
to avoid problems with the FDA for a variety of economic and more
public-spirited reasons. It\'s my view that when we are transparent
about what we believe that matters most, that industry, assuming
there\'s a sound scientific basis for those conclusions, will also
benefit and be able to focus their limited quality resources on those
activities, and in the end, they\'ll be better able to control their
quality and improve the efficiency of their operation and ultimately be
able to innovate more effectively.

DR. BOEHLERT: I think we have time for two more comments. Ajaz, then
Efraim.

DR. HUSSAIN: Well, I think this is a very important point. In my
presentation this afternoon, I want to build on that. That is, I think
we can create a win-win opportunity here, and science is what brings the
win-win. And David alluded to this already. If you understand your
processes and can justify that you have that level of understanding,
then that becomes low risk. So there is an incentive for doing good
science and understanding your processes. That I think would really
create a win-win. For companies who do not, then our attention gets
focused on them.

DR. SHEK: If I just may add some comments especially with regard to the
quality. Yes, I think industry is a business, running as a business, but
quality in the pharmaceutical business is extremely important and it\'s
just good business. So this aspect is there. And it\'s true. The whole
system is a check and balance system, and that\'s going back to human
nature.

But maybe one thing to think about while we look at new ‑‑ and there are
really fresh wins here ‑‑ and trying to change the approach is to look
not only at the stick, but have some carrots because there you can
achieve much more if you have some kind of specific benefits where both
parties can realize that there is a win-win situation there. I think
there is one initiative to have a development report there. If that can
be as an example situated as a carrot instead of as a stick, I think we
can achieve much more then.

DR. BOEHLERT: Unless you have one burning, brief comment, it\'s time for
a break.

DR. DeLUCA: I just had one on the subject.

DR. BOEHLERT: Okay.

DR. DeLUCA: I would just inject a little humor before I ask this
question along these lines. My tenure in academe is longer than it was
in industry, but I\'ve served on a number of USP and FDA committees. I
guess a lot of times things come out when we talk about regulations.
Colleagues in industry will say, we can\'t live with that. I usually
interject, well, it seems like the patient can\'t live without the
regulation.

A question I had was with the slide, \"Changes Without Prior Approval.\"
I guess this is something that this subcommittee is going to get
involved with, these types of issues in much more detail. But I guess I
just wondered what was the thought to allow post-approval manufacturing
changes without FDA review and approval prior to implementation. Can
anyone articulate on what types of manufacturing changes?

DR. HUSSAIN: Well, I think you will have several presentations tomorrow
and this afternoon also on that.

But if we wish to have a continuous improvement model, innovation and
change is necessary. And if change requires a prior approval supplement
and its associated long review times and the type of development
information that needs to be submitted, then that becomes a hurdle for
change or innovation and improvement. So I think we would like to create
a flexible change model that is based on science, scientific
understanding of the change, and thereby sort of reduce the prior
approval supplement process for that.

MR. FAMULARE: It\'s a carrot.

DR. HUSSAIN: It\'s a carrot.

DR. BOEHLERT: It\'s time for a break. I\'d like to thank all the
committee members for very fruitful discussions this morning. There\'s
food available here for the committee members. Please help yourselves,
and we will begin promptly at 10:30. Thank you.

(Recess.)

DR. BOEHLERT: I think we have most of our members back again. I\'d like
to try to keep us on time, if we can, if at all possible.

Our next speaker is G.K. Raju, and I\'ve asked him to just introduce
himself. He missed the introductions this morning.

DR. RAJU: Thanks, Judy. My name is G.K. Raju, as you can see here. I\'m
the Executive Director of MIT\'s Pharmaceutical Manufacturing
Initiative.

I was asked to give an academic perspective on the cGMPs. I\'m going to
give a personal perspective. It will be just my opinion, and because of
the academic bent to this perspective, I\'m not going to call it cGMPs.
I\'m going to call it manufacturing science, the means to cGMPs in the
21st century. Although I\'m going to call it cGMPs, I\'m not going to
call \"c\" cGMPs, but GMPs because I\'m going to challenge the word
\"c\" in the cGMPs, and I\'m going to say it\'s not current good
manufacturing practice but future, great manufacturing practice that I
really want to talk about.

(Laughter.)

DR. RAJU: Let\'s see if I can begin to shed some light on this.

This is an extension of a talk I gave on manufacturing science at the
PQRI meeting that Ajaz asked me to present on, and I\'m going to try to
repeat a lot of that material and extend it to see if I can build a
connectivity to our discussions from earlier this morning.

It sounds like an academic perspective. I\'m going to start with a
definition of some of the terminology. So let\'s see if I might start
there. I\'m not going to define cGMPs. I\'m going to define
manufacturing science because I think that\'s going to be the paradigm
in which to decide whether we\'re good, current, or great.

When you\'re looking for a definition and you can\'t find one, you
sometimes end up looking in the dictionary and you end up looking in a
library. Somewhere out there somebody tried to do that before and
documented it.

The first shot at trying to find a definition goes back in time to the
very word \"manufacturing\" which, like many things in the world and
many words in the world, is derived from Latin and comes from manus,
which is hand, and factus, which is made, meaning made by hand. And if
we were going to talk about great manufacturing practice for the 21st
century, it sounded like I shouldn\'t go too far with that definition.
It was a good place to start. We did do a lot of things by hand, but we
can do a lot of other things by hand instead of pharmaceutical
manufacturing.

So there was an opportunity to look for another definition, and a second
one is the one below that says, manufacturing is the transformation of
materials and information into goods, which are materials and
information, for the satisfaction and maybe even delight of human needs.
I like this definition a lot. It includes material and information,
includes a transformation which is value addition, but connects to why
we are doing all of this, which is to satisfy and delight human beings
by increasing the quality and quantity of human life. So that then is
the definition I\'ll choose from the slide.

There was another word in this phrase, \"manufacturing science,\" and I
had to figure out the definition of science. So once again, I went off
to the library. In this case I did find a lot of definitions and again
ended up with the luxury of choosing the ones that I might use for this
context.

Science can be viewed in many different ways, and here are some possible
ways to describe it and define it. \"A body of knowledge, body of facts
or information, body of laws or principles, body of truths, verities or
realities.\" Good stuff. \"Skill, expertise, mastery, know-how.\"
\"Organized knowledge.\" \"A means to solve problems.\" I would have
loved that to be a means to capture opportunities because I don\'t
believe there is anything such as a problem. But let\'s go with the
definition from The Synonym Finder for now.

That then gave us some flexibility to decide which one to choose among
them, and since this was the cGMP initiative, I thought I might choose
the first one, and of course, the other ones below must apply.

We then have a definition of the word \"manufacturing\" and a definition
of the word \"science\" and we\'ve now got to figure out how to combine
them into a phrase we want to start talking about, called
\"manufacturing science.\"

When I first went to the library and looked for manufacturing science,
the MIT library, there was no definition, but here on the next slide are
the beginnings, I hope, of one version and one interpretation of a
definition that we might choose to use. \"A body of knowledge, laws,
principles\" ‑‑ that\'s from the science points ‑‑ \"involved in the
transformation of materials and information into goods for the
satisfaction of human needs.\" That then is a definition.

A definition is a great place for academics, but doesn\'t always end up
with something operational for people in the industry on the shop floor
to use. We\'ve got to start talking about building some connectivity
from that definition into something that\'s tangible that we can change
and enhance and measure performance around.

So let\'s let go and start describing the dimensions of manufacturing
science so that we can connect it to some bigger system called
manufacturing system, so we can figure out how we want it to be.

The dimensions of manufacturing science should now say, if that\'s the
definition, what are its dimensions. One of the things I figured out
very early on is that it\'s good to presume that we live in a Newtonian
world where our two dimensions are space and time. I haven\'t been able
to figure out anything that Einstein has said really. I like the Star
Trek, the Next Generation in terms of space and time in the next
frontier, but for now, if we\'re talking about pharmaceutical
manufacturing going beyond made by hand, I think it\'s okay to restrict
ourselves to a space and dimension that are seemingly distinct. So
that\'s the definition. Let\'s try to put some pictures around the space
and time dimension.

Let\'s talk about extent of manufacturing science along the space
dimension. You can then translate that into different levels that
describe some set of discrete, not always easy to separate levels of
manufacturing science in terms of this thing called knowledge, and there
are different levels of knowledge.

Along the space dimension then, you can argue that you can start talking
about different kinds of knowledge.

Descriptive knowledge. What did you do? Knowledge that says, I opened
the top of the blender. I put in the excipients. I put in the active.
Then I closed the top of the blender. Then I did this. This was my final
reading on my certificate of analysis. And when the FDA comes in, they
say, what did you do? You say, I lifted the top of my blender. I put in
the active ingredient. I put in the excipient and then I closed it and
then I mixed it for 15 minutes. And here it is. I met specification.
That is descriptive knowledge. That is meant to ensure that you meet
safety and efficacy, which is did you meet specifications and describe
what you did as part of doing that.

The descriptions of the how are about how you did different parts of
your process. It\'s about connecting not just that blender but
connecting it to all the unit operations before and after, which is the
process knowledge, which brings the measurement and each of these steps
together into a connectivity of how. How did you do this? I granulated.
I blended. I dried. I compressed tableted capsules. That is your process
flow diagram knowledge that in many cases is not part of your common
knowledge that\'s shared across your organization, and that\'s the next
level of knowledge that brings in the space and time dimension to your
\"what\" knowledge.

In many ways, the focus of the cGMPs is about saying that you can do
that, while the focus of the bottom level knowledge is to say that
you\'re safe and efficacious and you satisfy the ultimate customer.
Since the FDA cannot consume and test all of our products, they have to
come down and look at our paper trail around our processes. That\'s the
level of knowledge that they look at to figure out if we have the level
of knowledge that demonstrates safety and efficacy, which is the
customer of our product, while in many ways we have a customer for our
information and our paper product as well.

We then, over the life cycle of knowledge and space and time dimensions
of knowledge, have the ability to either have known why we did things
the way they are, which is why do we do this and this. We could do that
in process development. You can learn that from the data during
manufacturing, and that\'s the causal knowledge.

You can then figure out if you can get general classes of mechanisms,
mechanistic knowledge. This is a first order reaction. This is a second
order reaction. Here are the basic pieces of the models that I can build
to get a mechanism that can begin to predict because a correlative
knowledge in no way can predict. It can only interpolate that.

In the end, it\'s about going back to the basic first principles, and
the basic first principles of saying this is my state of manufacturing
science. This is my knowledge, and here this knowledge presumes that
you\'ve climbed the pyramid of knowledge, and that then is the space
dimension of manufacturing science. So that\'s the space dimension.

What is the other dimension I should be showing on my next slide? The
one that we believe based on Isaac Newton is the time dimension that
says we now have to decide where we want to be, where we can be, where
we should be, where we could be on the space dimension over the course
of the life cycle of each of our products, each of our processes, each
of our organizations.

If you choose this to be the time when you actually submit your NDA and
you first go into commercial manufacturing, ideally you could say I\'m
going to do all my learning and going up the pyramid of knowledge just
before and after I go to the market because I have these large scale
trials that I\'m going to learn from a lot of data, a lot of
experiences, and now climb the pyramid of knowledge. And that\'s my time
profile along the space and time dimension of manufacturing science, and
that\'s the learning by doing approach.

The good news there is you\'re learning about the product that actually
goes into somebody\'s body. The good news also is that you\'re learning
while you\'re actually making something and getting some money for it.

The other approach and obviously complementary approach is to do most of
your learning before time, before you go to market, and you start at a
much higher point. Maybe you start at level 5 which is the learning
before doing.

Now, I want to make a clarification here. This does not mean that this
company or this product does all that learning before time. In many
cases, in most industries, academia, government, the industry in a
social structure has put in place a set of principles that the industry
can leverage to start at a very high point even as they start.

As you go by some of the comments that were brought up today, if society
and academia haven\'t laid that foundation, it puts an overwhelming
burden for the company for one product to suddenly climb this pyramid
ahead or to do that in the case of this, when the basic principles of
manufacturing science for pharmaceutical manufacturing have not been put
in place.

Just for sake of completeness, that\'s the learning by doing. This is
the learning before doing, which is often the lab scale and the pilot
scale. But there are two other learnings before that. There\'s the
learning through simulation and computers, which is even before that,
and there\'s a learning by thinking and planning. So you can learn
inside here by thinking and planning. You can learn in a computer. You
can learn in your pilot and lab scale, or you can learn in your
commercial environment. Each one is more and more expensive. Each one is
closer and closer to \"right first time,\" and each one is more and more
expensive as you go forward in time.

I\'m going to start with just these two, the pilot scale, which you
actually have to do a lot of design work, if you can. That\'s the
academic piece of laying the foundation.

I want to emphasis this is a personal opinion slide. After having had a
chance over the last 15 years to study pharmaceutical manufacturing in
quite a deep way with a large number of organizations, it is my opinion
that while there are differences in levels of manufacturing science in
space and time across products and across companies and structures of
the industry, it is very clear in my opinion that there is a big
difference between where this manufacturing science is and where it can
be, should be, and could be. And when I was at the PQRI meeting, I used
this slide to say that the regulator, the FDA, the regulated, the
industry, and academia all put together have a learning disability. And
we need to find out how we can do more investments into pharmaceutical
sciences ahead of time.

I\'m not sure if this was said in my introduction. I had the great, good
fortune of getting a Ph.D. in chemical engineering from MIT, and MIT
claims, at least, that they invented chemical engineering many years
ago. If that is true ‑‑ and even if it isn\'t true ‑‑ I could tell you
that in all of my curriculum I didn\'t learn anything about solids
processing. Chemical engineering has gone into the liquids and the gases
and the biotechs. There is nobody who works on pharmaceutical
engineering or pharmaceutical sciences. If you want them to do it, they
will throw you out. It is not one of their top priorities.

If you look at pharmacy schools, their focus has been more and more on
the clinical side and more and more of the industrial pharmacy pieces
are being lost, just when I\'m saying that we have a learning
disability. And many of these pharmacy schools do not train people to
run plants at a large scale and a pilot scale, and as a result academia
has very much mimicked the industry and the regulators\' bigger
structure of working together to move to this higher plane.

So there\'s reason for us to be here. There\'s a reason for having these
academics and industry and regulators all in this room together because
it is our purpose in life then to see and understand why we are not
there, figure out if we should be there, and honestly within ourselves
see if we can assist each other in making this leap in space and time
upwards. The reasons can be business. It could be compliance. It could
be cost. It could be cycle times. But in the end it\'s simply because
it\'s the right thing to do.

Those then are the different dimensions in space and time for
manufacturing science. In the end I\'m talking about manufacturing
science. Let\'s just now connect that back to a manufacturing system,
not because we want to forget the science, but we want to connect that
science into something that we can start looking around and tailoring.

A manufacturing system ‑‑ and there is a definition here and there are
many definitions of manufacturing system ‑‑ is a set of processes and
systems bound by a common material and information flow. Notice, for the
first time, when I put in manufacturing system rather than just science,
there\'s a description of a process, and that process brings in a set of
people that are bound by this same information and material flow. When I
talked about manufacturing, I just drew a box around it. Now when I\'m
talking about a manufacturing system, I\'m putting more description
around the details of the box, around people and the system of space and
time, the way they\'re connected to help us go from a set of inputs to a
set of outputs. That then is a manufacturing system.

And if you look deeper at most of the manufacturing systems,
particularly on the drug product formulation/fill finish side, this is a
process flow diagram of what many of these manufacturing systems look
like.

So if this was the bigger manufacturing system and we want to figure out
how we are doing, let\'s draw a box in space and time ‑‑ like I said,
just like manufacturing science has a space and time dimension, so does
the system ‑‑ and ask how are we doing with this manufacturing system.
And we can measure how we\'re doing in terms of quality, time, cost, or
safety.

Let\'s take a look at one of these process flow diagrams and ask what
the manufacturing system looks like. The manufacturing system ‑‑ in this
case their drug product, and it\'s shown in boxes all the drug substance
in API side which is at least as important, if not more, but more
difficult to show in a public forum like this. Here is a set of unit
operations, one of the terminologies I learned in chemical engineering.
Weighing, dry mix, wet granulation, a set of steps that I don\'t want to
describe in further detail, drying, sieving, blending, and
encapsulation.

If you look at this bigger system of making something, you will find
that we have a lot of sequential unit operations, very little
measurement of performance along the way, as a result, little or no
feedback control along the way, and a huge burden of testing in this
pharmaceutical system at the beginning and end of this pharmaceutical
manufacturing system.

If you then look at the tests at the back end of this process and you
look at your C.F.R. 210 and 211, you will find that these tests map
identically to those. We test exactly, to a large extent, the minimum
that we need to test at the latest possible point in that process.
Performance is made here and performance is tested here. If this is the
set of causes and this is the set of effects, they are very, very, very
far away in space and time, and that is okay if you are on level 4 and
level 5 of the manufacturing science pyramid. That is not okay if
you\'re in the level 1 and level 2 of the pyramid because then you have
not designed the quality in and the testing is just for business
reasons. You can even drop the test, but instead you are trying to, even
though you don\'t really want to, test in quality.

This, particularly on the drug product side, is what a process flow
diagram looks like. We have to figure out how we can make it look like
this or even take out the tests by doing a lot of this level 4 and level
5 stuff ahead of time and figure out how we can go from level 2 to level
3 to level 4 to level 5 after, which is the learning and doing paradigm.
So how do we go from here to there?

One of the benefits of being at MIT is the Sloan Foundation, which funds
a lot of work at the MIT Program on the Pharmaceutical Industry, has a
number of industry centers where they look at textiles, semiconductors,
and look at their evolution over time. And I\'ve looked at the software
industry and a couple of other industries and tried to map their
evolution over time relative to a process flow diagram.

I\'ve tried to capture those five levels of manufacturing science along
these five pictures of a process that reflects that level of
manufacturing science. Nobody exists in business here unless you\'re
already at level 5 and you don\'t have to test. So let\'s not talk too
much about level 1.

Level 2 is very much about a process that tests at the beginning and the
end and very little in between. And if your level of variability
justified that, that would be just fine, but in many cases this can be
also mapped down to a level inherent internal variability or a sigma
level. And this in ascending scale of sigma levels is in descending
scales of variability or increasing levels of process understanding or
increasing levels of manufacturing science.

What we\'d like to do is to figure out what our process flow diagram
should look like, measure what the critical variables are, but you\'ve
got to measure a lot more before you figure out what\'s critical, then
measure what\'s critical, analyze, understand, correlate causality,
mechanisms, maybe close the control loop. And now we have a much more
automated process, much more well-understood process. Now that we have
it better understood, we don\'t necessarily have to test quality in. We
might choose to do it for business reasons or liability reasons, but one
day we may not.

The bottom line is manufacturing science described in those five levels
of manufacturing knowledge has five levels of pictures in terms of what
your process flow diagram could look like along these five levels.

And product by product, product class by product, processes by
processes, our goal is to climb this pyramid either before doing or
after doing, and hopefully both, because you can\'t do everything. You
can\'t finish thinking before you do any doing, and you can\'t do all
your doing without any thinking. Right? We can\'t separate thinking and
doing to the extent that we have.

That is, we want to now climb that pyramid of manufacturing science and
that\'s going to be reflected in our manufacturing system in the picture
that we paint, and let\'s look at that manufacturing system now to
figure out how we can go from here to there.

If you believe the personal opinion that we are here, then we can now
continue the rest of my slides to figure out how we can go there. If you
don\'t, then Judy is going to get you during the discussion session and
you can ask.

How do we get there? This is multi years of opinion about where we
stand. Why and what are the implications now of this manufacturing
science and manufacturing system and its implications?

What are the implications then of manufacturing science? Let\'s start
with the FDA initiative, which is one of the reasons why we\'re here. We
should be all talking about our own initiative rather than the FDA\'s
initiative, but today we\'re talking about the FDA initiative which is
the pharmaceutical cGMPs for the 21st century, a risk-based initiative.

So why was I talking about manufacturing science in the context of
today\'s meeting which was about the FDA\'s cGMPs for the 21st century
initiative? Because the first part of that initiative that Lester
Crawford and Janet Woodcock and Mark McClellan and Ajaz Hussain and
Helen Winkle list as the components of that initiative, the first thing
they say ‑‑ maybe not the first thing they say. Sometimes the first
thing they say is risk-based. But one of the four things they say is
science-based. The other things they say are risk-based, modern quality
management techniques, and harmonization. And this is what the FDA calls
the four pillars or the four pieces of their 21st century cGMP
initiative.

But among them, I choose to only talk about this. Why is that relevant
for the other four and why is that relevant to the initiative itself?
Let\'s look at the science-based aspect of it, given this foundation.

First, if you agree that we\'re at the level 2 of our knowledge across
the industry and our processes look like this, then that is going to
show up in terms of large inventory levels; incomplete, delayed
investigations because cause and effect are far apart; a low quality of
life because we haven\'t measured and automated; and a disconnectivity
between the making and the testing. Do we see that? If we see that,
we\'ve now to figure out what we might do about that.

One thing we might do about that is to see how we might leverage the
FDA\'s PAT initiative, which by the way, I call the FDA PAT initiative,
based on the web site of the FDA, to simply be this: simply an effort to
facilitate introduction of new technologies to the manufacturing sector
of the pharmaceutical industry. It\'s not about NIR. It\'s not about the
technologies. It\'s simply about having a mechanism of communication
between the regulator and the regulated, and that is most of its
potential benefit and most of its potential benefit can be described in
terms of the consequences of us working together.

Why am I excited about that PAT initiative? It\'s because if you look at
the cause of our performance, the process step itself, and the
measurement of that performance, which is the actual test in the QC/QA
lab, what we do in between is interrupt the process, secure a sample,
hold a sample, document a sample, transfer a sample, batch a sample,
prepare the test, then the actual test, test data collection,
documentation, results, decision. Red are the human manual operations
given by human beings and trees that are cut into paper. Those are the
variable expensive operations. Those make it very difficult, even
despite the test that\'s far away, to have a high enough signal-to-noise
ratio to connect cause and effect that we need to do to climb the
pyramid from level 2 to level 3 to level 4 to level 5. And we need to do
that both in learning by doing and learning before doing.

What I like about this PAT initiative is it allows industry and the
regulator to start talking about how we might bring in on-line
technologies, the key word really being \"on-line-able\" rather than
whether it\'s LIF or NIR or pattern recognition. It\'s not about the
chemistry or physics about the test. It\'s about the paper and human
being of the test.

And the fact that we make most of our drug products in solids and test
in liquids creates all of this red stuff. An ability to be able to test
in solids is the on-line-able aspect that begins to connect cause and
effect that lays the foundation, if we haven\'t already been there, to
go from level 3 to level 4 to level 5. If you\'re already at level 5,
chances are you already did that in development, and if you did so, you
would see that in your inventory levels. The question is do you see
that.

It\'s not about the technology. Most of this has been developed in other
parts of the planet, other parts of this planet, and you can look at PAT
technologies that can measure different aspects of this process, and you
have many different ways of doing it. In this case I show about LIF
technology that we discussed we\'ve developed at MIT, but there are many
other technologies that can be used to measure things that are
inherently on-line-able connecting cause and effect. Not everything, but
a lot more things than we\'ve used so far and a lot more things that can
give us a lot more value.

But it\'s not about measurement either. It\'s about using the
measurements to figure out what measurement is important to figure out
how you can analyze those important measurements to understand your
processes better so that you can now talk about designing quality in,
which is the purpose of existence really, if you\'re doing
pharmaceutical manufacturing, and was supposedly the purpose of the cGMP
in 1978. Hopefully, it was about moving us up the pyramid. But where we
ended up, the current state, is all of us looking very similar to each
other.

In many ways I want to say that there shouldn\'t be too much of this
\"c\" in cGMP. We want to all be different and at different levels of
the pyramid and somewhere in the structure of academia, regulator, and
regulated, we haven\'t had the right benefits and penalties and rewards
for climbing that pyramid. And that\'s why all the stakeholders, or some
of them, are here, to help us together as a society lay in a good
cost-benefit tradeoff and a structure for it.

That was the reason why I talked about the science-based aspect in
manufacturing science, but it connects to where we are. It connects back
to the very purposes of cGMP.

But there were three other components listed in this initiative. Does it
connect that? How can it not?

Let\'s start by agreeing that we make two products. A physical product
for a patient for whom we greatly transform the quality and quantity of
human life. Taking a tablet is better than sitting in a hospital for two
months. That is an increase in the quality of life. Taking a tablet
beats dying for most. That\'s an increase in the quantity of life.

But we also, as part of 1978 cGMPs, have a responsibility for level 2
which has a reasonable level of understanding about how we went about
doing that because the FDA, despite all the things that they don\'t have
the ability to do, don\'t also have the ability to take all our tablets
and consume them to see if they work fine.

So they have to look at our paper product and our information to figure
out how well we are. Are we closer to level 2, which is very much that
quality systems framework. It\'s very much about how do I look at the
level 2 to figure out that you can do level 1 well.

Manufacturing science is about moving up this pyramid so that you can
separate the safety and efficacy issues from the cGMP issues. Moving up
this pyramid, as long as we are here in this pyramid, we ‑‑ I\'m
absolutely sure, 99.999 percent sure, that we make a safe and
efficacious product. I do not believe this is a level 1 issue. We\'re
talking about a level 2 issue because when you go back to the cGMPs of
1978, when we get approved with an NDA, we have a responsibility to have
something already put in place on level 2.

And that is where it is not so clear whether the warning letters are
talking about level 2 or level 1. In my opinion, I think we have a solid
foundation across the industry in terms of safety and efficacy. I think
that\'s a good thing for the FDA and academia and I think for industry.

The question then is about how we\'re going to do level 2. And level 2,
once it\'s done, now actually begins to lay the foundation for us to
climb the pyramid, which is really about understanding our processes not
because the FDA says we should, but because we think we should or we
know we should or because we could.

Really, this is about climbing the level of the pyramid so that we can
make the FDA irrelevant. Just like the EPA doesn\'t have to show up in a
plant too often, one day the FDA won\'t have to show up at our plants.
And the only thing we can do to control it, the reward structure, is to
climb this pyramid so that first, once we presume safety and efficacy,
we want to presume good manufacturing practices, and the way to do that
is to get to great manufacturing practices.

So how can manufacturing science not be about that risk? And if you look
at each of those levels and their primary focus, the focus at the bottom
is about conformance, conformance to product and process requirements,
which is the basic safety and efficacy argument.

The next level up is the focus on prevention and how you get there,
which is failure, defects, complaints, and recalls, very much connected
to the CA/PA systems and the quality systems. In many ways, when you
have an effective process, that lays the foundation for an efficient
process. You want to do the right things before you lay a foundation to
do the right things well. You won\'t do them simultaneously, but you
must lay a pyramid of effectiveness before you climb the pyramid of
efficiency, otherwise you will collapse. That is, if you are here and
you cut costs, the pyramid collapses. You want to lay the foundation of
these two and then you have a highly profitable reward structure in
terms of efficiency, cycle times, and costs.

This is about risk. Climbing up this pyramid, every part of this pyramid
is a lower risk than the one below. This is the manufacturing science
argument, but it is no different from the lower risk argument from a
manufacturing point of view.

I would take this one argument further to say while we start with a
customer and work at the risks and try to look at the bioequivalence and
the equivalence between our products, our clinical trials, and our
product changes, there is so much of a lack of precision and accuracy in
those connectivities from in vitro to in vivo, from bioequivalence to
what is not equivalence, that we can only go so far with that minimal
level 2 approach that centers around risk.

It\'s appropriate for the FDA to be calling it the risk-based approach,
but if you really look at it, it\'s more appropriate for the industry
and academia to be calling it the science-based approach because it\'s
so difficult to connect from the product down into your process that you
shouldn\'t necessarily have to start there to improve your process. Look
at your process. Climb the pyramid. That\'s only going to make you
stronger for all the risk issues coming on from the outside. In many
ways, there should be an inside-out approach to risk management rather
than just an outside-in approach, a process for its own sake approach,
while in parallel to a product and its connectivity back to the patient
approach because those are somewhat sticky data and very low
signal-to-noise ratios. Those are signal-to-noise ratios of process
performance that are basically appropriate for measuring level 1 and
level 2, not appropriate for really being able to look at deeper issues
of process understanding.

But really, this is the ability for you to automate. This is the ability
for you to have a higher quality of life. This is the ability to create
resources so you can put it into prevention. And this really is the
ability to ultimately, long term always guarantee that you meet
specification.

The way to meet specifically is not look at what you did and whether you
meet specification, but to focus on the capability to meet
specification. So the higher and higher you are up the pyramid, the
higher and higher is that capability, and the higher and higher is the
ability to make the FDA irrelevant. Just like you want to bring your
quality system into your process, in many ways you want to being some of
the thought process of the FDA into your process so you don\'t need to
have them disconnected to inspect you.

There is no difference from this side. It\'s just a matter of where they
meet. In terms of the inside-out science-based approach and the
outside-in risk-based approach, they are different sides of the same
coin. This is the coin we have in our control, and I believe this is the
coin that we should focus on within academia while we can focus on the
outside-in as well.

What does this have to do with quality management techniques?
Everything. If you look at quality management techniques along this
manufacturing science pyramid and ask what is the focus of quality
management, you can go down to the focus at the bottom level on
conformance, prevention, improved performance, superior value, and
\"right first time.\" And what really is that? It\'s about effectiveness
and efficiency, performance excellence, and \"right first time.\" It\'s
about effectiveness in quality control systems. It\'s about
effectiveness in quality assurance systems, which lay the foundation for
the effective and efficient quality management systems, performance
excellence, and doing things \"right first time\" even beyond just
financial performance.

So in many ways this is modern quality management system and techniques.
This is what Juran taught us and Deming taught us. That is, this is not
about quality control. It\'s about connecting the quality control deep
down into designing quality into your system.

Manufacturing science and modern quality systems. No difference. A
difference in terminology and focus where you start, but very much
integrated into the whole overall system.

You can talk about quality in terms of where you measure it and what is
the time associated with addressing the cause for not being right and
where you measure right. You can measure right outside in society by
looking at whether you have a warning letter or consent decree, and
that\'s really far away between cause and effect, very, very far away,
and really very expensive to start measuring your quality system there.
This better not be your quality system. Manufacturing science says this
better not be your quality system either.

Begin by laying your quality system to be some combination of this and
this, which is your learning before doing and the level 3 of learning by
doing. The manufacturing science is the inside-out approach to be able
to enable this transformation to prevent you from going there.

I would argue that in a regulated industry, coming from here backwards
is a very, very difficult thing to do. Although seemingly academic and
esoteric, I believe that this initiative outside is a much higher
probability of success initiative than one that focuses on incremental
changes around there. It\'s about a bigger structure of manufacturing
science in space and time.

What does this have to do with harmonization? I do not know very much
about harmonization. I\'m not sure how many people do. I certainly
don\'t. But the bottom line says with all the new countries coming into
EU, you might have different governments and different customers, and
you now have to figure out how to harmonize around them. We just heard
how difficult that is and why we might need to postpone that for later.

An inside-out approach says you become independent of that government,
that customer section. It\'s about doing things right. Once you do
things right, you have now built a capability to harmonize, a capability
to handle risk, and a capability to have designed the quality in \"right
first time.\" An inside approach makes now a common language between the
FDA and the other agencies, we hope. Although I don\'t know much about
harmonization, I believe that the foundations of manufacturing science
very much lay the foundations for this harmonization which is very
difficult to do with a government issue rather than connecting it back
to process understanding.

We want to learn and move from a less learning before doing and even
less learning by doing approach to a more learning before doing and more
learning by doing approach. That is, during process development we want
to be able to fail and explore the different boundaries of our processes
instead of simply doing them similar to the way we did before and then
having those few batches thrown out and then doing the same thing at the
end, very much safe and efficacious. Everything in this is safe and
efficacious. But we have not laid the foundation for us to ultimately
hit the target. This is what a learning curve should look like, which is
a learning curve of that desired state, which is the learning curve of
the current state.

So I\'m hoping that all of us sitting together can then begin a
conversation ‑‑ I would say continue a conversation ‑‑ that can enable
this structural learning that can overcome this learning disability that
I talked about.

That then I believe is the way that manufacturing science connects to
the reason why we\'re here. But it\'s bigger than the FDA initiative.
The FDA, I said, after level 2 should be irrelevant.

So the question is what is this bigger thing that we\'re trying to do
that goes beyond level 2. And if you look at the pharmaceutical industry
itself and look at the fact that all of us in our companies do research
and development, manufacturing and marketing, and if you try to simplify
this in some ways ‑‑ in fact, it really is oversimplified in this
industry ‑‑ the R&D is the thinking organization. Manufacturing is the
doing organization, and marketing is the talking organization. And we
want to bring more talking and more thinking into manufacturing, and
together as a structure of academia, industry, and regulated, we better
create that structure.

And the fact that we haven\'t created that structure today puts the vice
president of manufacturing in a very difficult position. To me the hero
is the vice president of manufacturing. When he gets his appointment
letter, it says, welcome to the management team. You are now vice
president of manufacturing of Merck or Pfizer or Glaxo.

But really, what\'s in the invisible ink in the appendix of their
appointment letter and all the messages that that poor guy hears is, you
are not as important as R&D and marketing. You are a cost. And really,
at level 2 and level 1, you shouldn\'t be talking about costs. The guy
before him says, the head of R&D says, don\'t be on a critical path. The
guy after him says, just don\'t stock out. And the guy outside, the FDA
says, now, you told me you\'re going to do it this way. Now, you better
do it the same way for the next 12 years.

Clear definitions of failure, dysfunctional, almost incomplete, may be
missing definitions of success. And if you have only a definition of
failure and no definition of success, what will your risk-reward
tradeoff be? If the only thing you can do is fail, what is the only
thing you will do? And if the only thing you can do is fail, how much
risk will you take? Little or no, and that\'s not a good thing for
manufacturing science. That\'s not good for the vice president of
manufacturing. It\'s not good for the company. That\'s not good for
society.

So it\'s about those four pieces of the FDA\'s cGMP initiative. It\'s
about putting pharmaceutical manufacturing right to its rightful place
in the overall organization and the overall academic and social
structure. Not everybody is going to make it up that pyramid. So
finally, just like big, small, and medium pharmaceutical companies
compete by their ability to research and market, they are now, I hope,
at the end of all of this, two years and beyond, going to be able to
compete and be different in how they do manufacturing.

That is the business proposition that must exist for us to capture this,
enable this and encourage them. And that\'s the point that Efraim made
about putting the rewards in place for us to enable climbing up this
pyramid. That is about process understanding. That is about decreased
variability, and of course, that is about lower costs. But we\'re not
going to get to that lower costs unless we get to this level of the
pyramid, and we have got to help each other climb that level of the
pyramid.

That is also about a change in the industry structure in terms of what
the FDA should do and what it is able to do, and now if we climb that
pyramid, the FDA does not need to come into our plants as often as they
do because you have now climbed the pyramid and communicated to them.
And that\'s the foundation for asking for a reward tradeoff from them,
and the inside-out approach says, let\'s focus on what we can do in
terms of climbing the pyramid and describing the data and knowledge and
framework to do that, and then let\'s go to the FDA and make a deal for
saying that they\'re not going to come inside our plants once we climb
above level 2.

That then is manufacturing science. I talked to you about the definition
of manufacturing science. I then talked to you about the dimensions of
this manufacturing science. I talked about where the manufacturing
system is today and where it could be tomorrow. I talked about a path
from here today and talked about the huge implications of being able to,
together, go from here to there in terms of science, in terms of risk,
in terms of modern quality management, maybe even harmonization, but
really about business and really about doing the right thing.

I would, again, make the last point that one day I hope it will be the
science-based initiative for the 21st century rather than risk-based,
and that should be what everybody else does in academia and industry,
not necessarily what the FDA does because their focus is to ensure
safety and efficacy.

I am ready to take some questions.

DR. BOEHLERT: We have time for questions because we only have one
speaker in the next session. So fire away.

DR. SINGPURWALLA: I come from a very different culture than you come
from. So a lot of my questions will reflect that particular side of the
culture.

You raised in my mind a very important notion that perhaps is very
useful for this particular group, and that has to do with the five
levels of ‑‑ I believe they\'re due to Crosby.

DR. RAJU: Sorry?

DR. SINGPURWALLA: The five levels that you mentioned.

DR. RAJU: Different people have different kinds of knowledges. Crosby
has done a lot of the quality management, together with Juran.

DR. SINGPURWALLA: Now, I had the pleasure of working Walt Humphrey at
the Software Engineering Institute where what they did is they took a
software house and placed it in one of these five levels that you
mentioned somewhere along the line. The motivation for that was that the
Department of Defense would give software development contracts based on
the level at which the particular organization belonged. So there was a
motivation for these organizations to get themselves rated.

The process of rating involved a long series of questions. It was
completely ad hoc. Then at the end of that process, a particular
organization ‑‑ just pick a name ‑‑ software house was placed in
category 1, 2, 3, 4, or 5. Nobody achieved category 5. Maybe just one
organization achieved. Most of them were at category 2.

Now, the complaint I heard from the other side is that any process that
places an organization in one of these categories with any sense of
definitiveness should be flawed. In other words, they could only place
them in these categories with a certain probability, and calculating
that particular probability was not an easy task.

So the first part that comes to my mind is could a similar system be
developed by the FDA. The software engineering system was called the
\"capability maturity model.\" And I\'m just wondering or at least
throwing open the idea that one may consider some kind of a parallel
scheme, recognizing that these schemes have a lot of obstacles and
objections associated with them. So that\'s the thought occurred to me.

Now, the second thought that occurred to me comes from my academic
cultural background. You constantly used the word cause and effect. Of
course, that\'s a very deep philosophical question which plagued Newton
and others, and it\'s a very difficult thing to essentially come up with
a precise cause and effect relationship.

And the other point is you called science- based manufacturing and you
contrasted it with risk-based manufacturing or you wanted the word
\"risk-based\" to be removed and it be called science-based
manufacturing. Now, my thought goes back what is the scientific method,
and basically it boils down to this, that if you cannot quantify, you
cannot talk about it, and if you cannot quantify, you cannot use the
logical method. So quantification is absolutely a fundamental step to be
able to invoke the scientific method. A lot of what you said is not
quantifiable. So I would challenge that it be called scientific.

Now, recognize I come from a different culture. So I want to stop at
that.

DR. RAJU: Sure. Let me try to take all the three points in sequence.

Just to kind of connect back to the comments, going back 10 years now, a
little bit later than 1988, the 1980s now, Carnegie Mellon University
developed the CMM model which is for software, which is the capability
maturity model, which was referred to here. Dr. Humphrey and a whole
bunch of people have developed a framework of rating software companies.
It started off with a bunch of failures in the defense industry, the
fact that they had to allocate contracts to different people to put
software into something that takes off, and how would you base your
decision about who you\'re going to do it with. That resulted in
Carnegie Mellon, together with the Department of Defense I believe at
that time and a whole bunch of software companies that resulted from it
‑‑ and I think benefitted greatly from it ‑‑ in rating things in terms
of level 1, level 2, and level 3. And there are many books around
written on the capability maturity model, and that\'s now been expanded
into a people maturity model and other dimensions.

I fundamentally believe that that was a very successful approach. Today
there are 20 or 30 software companies at level 5 just in India just in a
couple of cities. When you\'re at a distance far away and you want to
get a contract from a big person who doesn\'t have the ability to
inspect, you have to lay in a foundation of describing your level of
knowledge. And a company that\'s very small and doesn\'t have to be
inspected has now created that foundation to be able to rate its ability
to make software.

I believe the general principles of that are quite applicable in the
case of pharmaceuticals. I would actually argue that in the case of
software, it\'s inherently at least as difficult to measure as
pharmaceuticals. I think that pharmaceuticals are at least as inherently
capable of being measured ‑‑ this is my opinion ‑‑ in terms of ability
to measure because we\'re talking about defined physics and chemistry.
Macro scale doesn\'t necessarily mean the case. Human beings interacting
with it and many of those pictures that you saw connect back to the
software capability model as well. So that\'s the first framework.

I think a lot of it applies and I believe strongly in it. I\'m not so
sure that the FDA should be the one that drives the intellectual content
of that quantification and levels. Similar to Carnegie Mellon, I think
somebody similar to that and a neutral party has to define some of the
pieces around it. I think the process capability measurements that come
from the whole TQM society nicely fit into quantifying different levels,
and that\'s a nice thought process in terms of CPKs and CP to measure
capabilities for many different aspects of effectiveness and efficiency.

So a lot of foundation of quantifiability is already done. There are
parallels in other industries that we could grab, but I\'m not sure that
the regulator should do that. I think industry and academia should
develop the foundation just like the past. The FDA should probably
connect back with the Department of Justice to connect with some
learnings across it and then be the ultimate decider of whether to use
it or not, of course. Of course, there are many other extensions of it.

So let me go to the second question. I agree. There is no such thing as
a cause. There only different levels of causes. Why am I tall? What is
the cause? Because my dad was tall? He wasn\'t. So I\'ve got to go down
to different levels of causes, and you want to be able to ask the first,
second, or third question. Usually in this whole total quality
management thought process you say, let\'s ask why six times, and by the
time you get to the fifth or sixth time, you\'ve gotten close to a
cause. But there is no such thing.

If you go back and ask a question, what is the cause of Brownian motion,
you might say just molecules that vibrate. But sometime deep down
inside, if you go further, you might be able to find a cause. So at
every point, there\'s a level of granularity of cause and effect based
on the purpose of that problem solving process. The cause at each level
of the pyramid is a different level of thinking.

The third point about quantifiable. I feel one of the difficulties about
why they used this whole capability maturity model in software was
because it was so difficult to define those processes. So it began to
define the processes and do the quantifiability. It\'s actually quite
difficult to quantify, in some aspects, software. I think many of those
are applicable here. I think that whole measurement aspect of
performance beautifully maps onto the PAT initiative which is at level 2
and level 3 which is about measuring relevant process and product
performance for the sake of process understanding. It may be connected
to safety and efficacy, but it\'s more level 3, level 4, level 5
measurement for the sake of process understanding.

So that would be my three or four thoughts on that.

DR. BOEHLERT: Efraim, did you have a comment?

DR. SHEK: Yes. G.K., I\'d like to refer to the term of the science, and
let me start with a question. Why isn\'t MIT spending time understanding
the engineering of powders and mixing and granulation and so on?

The reason I\'m asking the question is because I am somehow concerned
that we are going to miss the target here. So when we use PAT, basically
what you have shown we do a lot of measurements. And that\'s right.
It\'s the first step. I would assume we need that understanding. What I
didn\'t hear is where is the next step we are going to understand in
other processes. Because a new dimension there ‑‑ and I think it\'s
important. Time is a composite of many impacts. It\'s not just the
seconds, the hours. Things are changing. You have a scale-up, you change
equipment you are using, changes in the drug substance quality. There
are changes in the excipients, and that happens at a time. So time is
not just one measurement.

We can do all the measurement we want. If we don\'t still understand, we
don\'t have the knowledge base ‑‑ and that\'s why I\'m referring to MIT
and other people in academia. Something has to be done to understand
more the principles and knowing on a small scale how it\'s going to
behave in a large scale because that\'s really the big timing impact. I
would like to see something is happening there.

DR. RAJU: Sure. Let me sort of answer both those comments, although not
questions, in some personal way at least.

Why do universities fund something? Is it because somebody pays for it?
Usually they fund a set of important problems, a set of important
applications, among the different things that they want to do. If you
look at where they get their money from, they get the money from
industry or they get the money from government. Those are the two big
sources. There could be other ways. There could be foundations.

Go back into industry and you ask the CEO of manufacturing to put some
money, where would he put the money? Talk about Novartis coming down
next to MIT, putting all their money in MIT to be next to MIT. It\'s
about new drugs. That\'s the CEO\'s tradeoff of where to put his money.

I\'ve tried to do this personally, apply for funding for pharmaceutical
manufacturing from the National Institute Standards or some part of the
government. Where do they put their money? They put money on
bioinformatics or genomics. Those are the better tradeoffs for them.
Those are the better tradeoffs for the pharmaceutical company. There\'s
a bigger social structure that says, that is where the biggest bang for
the buck is, given the time frame that I have of a few years.

The consequence of that, yes, it may be justified for this
pharmaceutical manufacturing and the science around it to be a lower
priority than genomics and bioinformatics and for it to be a lower
priority than R&D and marketing. So that takes care of the relative
priorities. But despite its seemingly lower priority, not having done
something about it for a long enough time creates a lack of missing
knowledge that everybody deals the consequences with.

Now let\'s connect to the next point that you made. If you want to now
generate this knowledge, your costs, to a large extent, come from the
material and the scale of your operations. If knowledge is about
generating information per unit of material, then the way to do that is
at the small scale.

And so it is exactly your point. The way to get that knowledge is to go
back to the small scale where you can get a lot more information per
unit of material. The way you do that is by choosing the right
measurements that gives you the right data that you analyze and then you
understand it and you create the knowledge. And so I like the
measurement piece.

However, there\'s a whole other piece that says, we don\'t want to take
all of these steps and go to the small scale and start understanding and
measuring. We\'re just not going to do drug product manufacturing like
this anymore, which is a whole new set of making drug products,
different kinds of drug delivery technologies. So you either lay the
foundation or you simply make it unnecessary to do things. Now if you
focus on drug delivery technologies, a lot of research and funding has
been put there. It\'s higher on the priority list.

So there\'s a reinforcing dysfunctionality, but there\'s a reason for
that. It\'s the reason that it lives in a bigger society where many of
us sitting around the table, even if we weren\'t in manufacturing, would
have made the same decisions.

I think a nice outcome of all of this is for the FDA, now as a
regulatory industry very much focused on the pharmaceutical industry and
not necessarily on long-term bioinformatics and human genomics yet, to
make the case for a special focus ‑‑ either the FDA or the government
and academia ‑‑ to this because it\'s the right thing to do anyway, and
for the FDA to say we have been working with this. We think there needs
to be a structural connection back with the government. Even though this
is a lower priority than genomics, this is still a higher priority than
not doing it.

And I think the FDA and two or three leading universities have laid the
foundation to do that. I will maybe let Ajaz comment on that further.
I\'m familiar with most of them, but probably Ajaz is itching to say
something there.

DR. HUSSAIN: No. I\'ll pick it up later on.

DR. RAJU: Okay.

DR. BOEHLERT: Tom?

DR. LAYLOFF: I was going to comment a little bit about the manufacture
of dosage forms because from the outset it\'s trivial because you know
all the components that you\'re putting in very accurately and you can
calculate out the average properties of the final forms, but in solids
the behavior of heterogeneous solid mixtures is very difficult, I think,
from an engineering point of view, and solutions and gases are very
easy. So they are trivial to deal with. But at the outset, the
formulation is trivial, but the process is very poorly defined because
of the heterogeneity of the system. So it\'s very difficult. I\'m not
sure it\'s soluble. I think you\'re stuck with PAT of defining endpoints
rather than understanding what\'s actually happening.

DR. RAJU: So you believe that we\'re stuck with that at the beginning
and the end and we can\'t do anything in between.

DR. LAYLOFF: I think you can define endpoints in the heterogeneous
system, but as far as understanding how it gets there, I\'m not sure you
can do that.

DR. BOEHLERT: Other questions, comments? Pat?

DR. DeLUCA: Were you going to comment on that?

DR. RAJU: It\'s an opinion that might be valid if you\'ve already
defined and understood your process. But I think if you haven\'t, then
having the cause and effect so different from each other makes a huge
price to pay for society. The FDA has to go in everywhere. The industry
has to be so manual. Automation becomes nonexistent. We end up becoming
documenters instead of learners, and we don\'t evolve to the higher
quality of life in making. The question is, is it unsatisfactory? We
agree. Is it a difficult problem? We agree, otherwise it would have been
done. Should it be attacked now and addressed? I think so and that\'s
why we\'re here I think.

DR. HUSSAIN: Just to add to what Tom mentioned, I think it\'s doable,
but I think he\'s also right that the pragmatic solution is endpoint at
this time. And the primary reason for that is the task to get to what we
would like to is humongous and the source of that challenge comes from
our materials not being characterized and understood from a physical
sense to a large degree. But I think getting an endpoint is a means to
managing variability, and I think it would be a leg up, a significant
step in the right direction than what we do as use time as a control
right now.

DR. RAJU: The key is it\'s got to be voluntary because it\'s safe and
efficacious in level 2, and companies can choose whether to climb the
pyramid. That\'s fine. Whether it\'s difficult or not is their own
decision. However, there is a bigger structural foundation that\'s
missing that\'s not about the company\'s decision, about the fact that
maybe we all have to put a structure together to lay the foundation for
them to make that decision easier.

DR. LAYLOFF: Then also I would say that controlling a process is
different from understanding it. You don\'t have to understand
everything to control it repeatedly. Automation is repeatably doing
things. You don\'t have to understand each step.

DR. RAJU: There are different levels of understanding, and at level 3
and level 4, when you can get a set of correlations that have some
meaning, you can begin to lay the foundation for an automatic control
around certain boundaries, but you\'ll have instability outside those
boundaries if you don\'t know the first principles.

DR. LAYLOFF: And there may be some time when we will learn how tall you
are, but we can measure it very easily.

(Laughter.)

DR. DeLUCA: I really enjoyed the presentation. I think it was well done.
You put a lot of time in on it.

Before I make a comment, I recall back in the 1970s FDA had a symposium
on total product quality management. I participated in that, and
there\'s a pink document, monograph that was actually published. I think
probably a couple of printings went into that. But my part in it was to
look at the case studies with regard to self-inspection, self-evaluation
in the industry. So I had contacts in the industry ‑‑ this is after I
went to academe ‑‑ and was able to do this.

One of the things I emphasized I guess in my talk ‑‑ it was a little bit
spiritual too ‑‑ was doing things right the first time, which you have
emphasized here.

As you move up that pyramid ‑‑ and you positioned just nicely where FDA
was at the second level, and I think that\'s where we stop is at that
second level. But there\'s a deterrent from going further up that
pyramid, and the one is that before the product is introduced now, I
think there\'s the mentality of high throughput screening and wanting to
get there as quickly as possible. So many times it\'s getting the
product and if it\'s working, not really going into why and getting up
that pyramid.

The other one is afterwards there\'s a deterrent of don\'t change
anything. This is the way it is, especially with generics and that. When
you come out with something, you don\'t want to change it because
that\'s the way it was, and so you don\'t make it better. I think
there\'s a hesitancy to really stress the process, take the time to have
a failure. Like I always say, in baseball, if you\'ve got a base runner
and he tried 10 times to steal bases and he stole them 10 times, well,
it doesn\'t mean hasn\'t tried hard enough. He should have tried 100.
It\'s better to maybe get caught a few times to show that you really
tried.

As an example, I\'m involved with a process. There\'s a product on the
market. It\'s freeze-dried. It\'s been on the market for about 20 years,
and it\'s like a five-day cycle. Well, the company wants to put a
generic out, and they came to me because I\'ve done some experimentation
with freeze-drying. I looked at it and I said, well, this cycle should
not be five days and there are ways to make it shorter by stressing the
product.

I like your slide you use with the target there. The idea was to try to
fail, so you stress the process knowing that you\'re going to fail
sometimes, but then you can hit that bull\'s eye.

But the point here is that there\'s a deterrent because the company is
saying, this is the process and we don\'t want to change it because then
how will you file for an abbreviated NDA.

Or to be able to add, let\'s say, a mass transfer accelerator to the
product to shorten the drying cycle. Now, the mass transfer accelerator
is going to be removed from the product when you\'re finished, but it
means adding something, a volatile substance, to be able to dry faster.
And that\'s a no-no. Now, I think here in the United States probably the
FDA would accept something like that, but whether the European market
would accept it ‑‑ they\'d come right back and say, well, the Germans
wouldn\'t accept this.

So these are, I think, deterrents that we face. It\'s real life. So I
commend you. I think that\'s great. I like the idea of moving up that
pyramid, but it seems like there\'s a lot of deterrence. I think the
climate is such that there\'s deterrence for this.

DR. RAJU: Patrick, it sounded like there were two classes of deterrence.
The first one is the learning before doing where you\'re trying to make
a business tradeoff of don\'t be on the critical path. Why should I take
a risk that might slow me down? And there are two pieces to that.

I\'m not sure what the FDA has to do with that or can really help with
that. However, they do have a role in educating themselves earlier in
the process about possible technologies and increasing the probability
of a new technology being accepted and not being on the critical path.
So that would be one way the FDA has a role.

But really this is a bigger issue about what is the relative importance
of products versus processes. As you say, the business decision usually
prevents too much of learning before doing. Over the last 10 years,
I\'ve seen a trend that seems to be headed even more in that direction.
If you look at the head of manufacturing, he actually is trying to
figure out the perceptions of making changes and the learning by doing.
But the learning before doing piece, especially on the drug product
side, has largely been kind of in the pharmaceutical sciences group
within the R&D groups. Since the process is so much lower down on the
totem pole, relative to the product in those organizations, every year
over the last 10 years that group is getting smaller and smaller and
smaller. So it\'s getting even more true from a science side, and
that\'s going to further complicate situations in terms of the learning
before doing.

That kind of a business paradigm ‑‑ maybe moving pharmaceutical sciences
into manufacturing would be one business organizational issue, but
there\'s a tradeoff of product versus process. There\'s an education
process from the FDA saying we are going to help you earlier on increase
the probability of the success, and then there\'s another kind of
technology and thought process that says, actually process innovation is
going to get you there faster rather than slower. So there\'s a nice
paradigm there that might help.

On the learning by doing paradigm, I think it\'s very much about
building in a framework that says you can makes changes and here\'s how
you can make. It\'s about taking the SUPAC kind of a document, which is
a level 1 to level 2 kind of document, and having an equivalent for
level 2 and level 3 and building in more information and structure into
it and having a communication, just like you did on PAT, about process
understanding and evolution up that pyramid. And that needs I think
perception or real communication and maybe a guidance document and maybe
some basic rethinking of the word \"c\" in cGMP on the second piece.
Both of them I think need some help.

DR. BOEHLERT: I think I\'d like to cut the discussion at this point in
time because we have one more speaker before lunch. Thank you, G.K.

DR. RAJU: Thanks.

DR. BOEHLERT: The speaker is Colin Gardner. This is now the open public
hearing part of the agenda.

DR. GARDNER: Thank you very much to the organizers for giving me some
time to present this morning. In the interest of full disclosure, I have
to tell you who I am and what I represent. My name is Colin Gardner.
I\'m currently the chief scientific officer at Transform
Pharmaceuticals. It\'s a high throughput technology company in
Lexington, Massachusetts focused on finding new methods to look at the
form and formulations of compounds.

Formerly I was the Vice President of Global Pharmaceutics R&D at Merck,
and I was there for 19 years.

So what I\'m going to present today are my own thoughts, just like G.K.
I\'m not representing Transform necessarily or Merck. But we also have
another thing in common. We both have got a heritage from MIT chemical
engineering. So maybe what we\'ve got to say is very similar.

The reason I\'m here today actually is because Ajaz asked me to come
down here. I was the former representative on the PQRI product
development group. During the discussions of that group, the subject of
SUPAC came up on a number of occasions, and I coined the phrase,
\"create your own SUPAC,\" because I felt the SUPAC that was defined
back in the early \'90s really was a very, very narrow document and
really bore no resemblance to what was really done in developing a
product. So we came up with that concept, but it didn\'t catch on very
well I think.

So I made a presentation probably six years ago at a workshop, and I\'ve
pulled a few slides from that to use as a description of where I think
we may be going.

So let\'s look at the facts then. Drugs are really materials and I think
we tend to forget that. The rest of the world thinks about materials,
but we tend to think of them only as organic drugs.

Pharmaceutical production processes are a series of unit operations, as
G.K. just told us, and these operations are governed by exactly the same
chemical engineering principles as any other operation in the
manufacturing industry, whether it\'s in the chemical industry or the
software industry or whatever. The problem is that we really need to
treat them that way, and I don\'t think we\'ve done that in the past.

So if we look at a historical time line here of things that have changed
at the FDA and relationships with industry over the last
decade-and-a-half, first of all, we had preapproval inspections. Then we
had the SUPAC document. Then we had the site-specific stability issue
that came and went. We had PQRI and now we\'ve got comparability
protocols. G.K. has already touched on issues associated with a number
of those. So I\'ll just concentrate on SUPAC and comparability protocols
because I think they\'re related.

So if you go back to the early \'90s, in pharmaceutical research there
was a publication on where SUPAC was coming from. It said for years the
agency has had difficulty developing a regulatory policy based on solid
pharmaceutical principles for scaling up solid oral dosage form batches.
And we\'ve heard several people say that it\'s very difficult to do
because you\'re dealing with solids and powders. You\'re not dealing
with liquids. And that\'s certainly true.

The published scientific literature does not presently provide a
sufficiently rich source of data to enable such regulatory policy
formation.

They went on to say, additionally, the process should be controlled by
employment of a validation protocol which defines the critical
parameters and also establishes acceptance criteria for the granulation
or blend which may include sieve analysis, flow, density, uniformity,
compressibility, and moisture. These, I think, are what someone referred
to as controlling the process, but this isn\'t understanding the process
because all these are just phenomenological measurements. They\'re not
fundamental process parameters that can be used to model and predict
process parameters as the conditions change. And the conditions do
change. The excipients change over time or your drug product changes a
little bit over time, and it can dramatically affect your process. If
you don\'t understand your process and the key critical parameters that
control it, you will never be able to react to those changes.

So let\'s look at the SUPAC guidelines. This is just pulling one section
of it. For composition, if changes are defined as minor or major,
they\'re purely arbitrary. So you can change 5 percent in a filler and
you don\'t have to do anything. If there\'s a change of more than 20
percent in the particle size, you have to change something. If there\'s
a 20 percent change in the volume of the granulating fluid, you have to
change something.

Where are the data to support these changes? And would you really expect
them to be valid or to be the same for every single process or every
single formulation? And I think the answer is a resounding no.

So here\'s another quote. \"It\'s been decades since the chemical
engineering discipline made the transition from a highly descriptive
framework of distinct unit operations and processes to a generalized
body knowledge based on interlocking fundamentals, transport phenomena,
thermodynamics, kinetics, and chemistry. These fundamentals have been
quantitatively developed so as to create powerful predictive tools that
permit us to apply know-how acquired in one context to any other, as
well as to deal with the broadest range of natural phenomena.\" And that
is what we have to do when we design a pharmaceutical process. This came
from Carlos Rosas who was formerly head of chemical engineering R&D and
then manufacturing at Merck.

So a different look at SUPAC, and I\'m going to talk here about the
pharmaceutical product processing because, as we\'ve already heard, when
you\'re talking about the API processing, 95 percent of the time you\'re
in solution. And we know how to control solutions and we can monitor
solutions. But two parts of the API production which are usually not in
the liquid state are the final crystallization step and the control of
particle size, and these are the things that process chemists least like
to do. They love to design a process that\'s very efficient, that
produces very few intermediates and also has very few impurities, but
they don\'t really like to work on these last few parts.

But what we have to do is completely characterize the API to select
appropriate manufacturing processes based on what that API is and the
particular form we\'ve chosen to develop, characterize each unit
operation, and then establish scale-up, tech transfer and validation
criteria.

Unfortunately, the way in which a lot of the industry works is not by
doing that at their small scale, as G.K. said, but by very quickly
getting into manufacturing, making the clinical batches in
manufacturing, making all the phase III clinical supplies there,
tweaking the process, filing that process, and then the FDA comes in and
says, where did you make your phase III clinical supplies? Made them in
manufacturing. Where are you going to make your final product?
Manufacturing. Click. So we don\'t really need to worry. It\'s the same
place. It\'s the same process.

But do people really understand that process and what happens if
something subsequently changes? And the answer is no because they
didn\'t do the fundamentals.

So these activities would alleviate many of the production problems that
were evident in the industry, and we\'ve seen many, many companies get
into significant trouble because they had GMP issues on scale-up.

And this isn\'t even envisioned in the current generalized SUPAC
guidelines. So that\'s why I believe we should create our own SUPAC.

So let me just compare that with comparability protocols. The FDA
guidelines came out, I think, in February, and it\'s really similar in
concept to \"create your own SUPAC.\" But it will really only be
successful if pharmaceutical processes are adequately developed and the
influence of fundamental process parameters are understood and then used
to define the protocols for scale-up, for technology transfer, and raw
material formulation, and process changes because all of these will
occur at some time in the lifetime of the product.

So I just wanted to concentrate on a couple of areas here. There\'s a
whole range of things that you do at various stages from candidate
selection through form selection, composition and process, process
development, scale-up, tech transfer, and then post-approval changes.
And you really can\'t separate these three because form selection, the
composition and process that you use to develop that form, and the
process development will all be intimately tied together. So you don\'t
just select the form and then select a composition. Someone said it was
a very simple job to fix the composition. It\'s really not. It\'s very
intimately tied into the process.

So I\'m going to give you an example of form selection and I\'m going to
give you some examples that we had from Merck. These aren\'t outstanding
examples. They\'re fairly simple examples of how you can control your
process.

So I hate to make Abbott the poster child here, but they were the only
ones, unfortunately, that were caught in the marketplace. I think almost
every pharmaceutical company, when you ask them, will tell you that
they\'ve had a new polymorph appear at some point in their history of
development of a particular compound. Abbott was in the unfortunate
situation that it not only appeared after they were on the market, but
it appeared in a product that was very, very highly visible because it
was an HIV protease inhibitor for AIDS.

They developed a compound in 1992, launched a capsule in 1996, and in
1988 they started failing dissolution specs, and it was virtually tied
down that this was a new polymorph with lower solubility. The product
was then promptly pulled from the market in that form and they put in a
massive effort to reformulate that, and it was back on the market again
in its form two in 1999.

So one could ask yourself ‑‑ and many of us have asked this question ‑‑
how could we not find one of these polymorphs during development?

So nowadays there are high throughput technologies, and I\'m speaking
for Transform, but there are many other companies and within large
companies and also other companies that are doing this today, that are
using parallel processing of thousands of crystallizations to be able to
find conditions to explore that entire space in terms of forms, salt
forms, hydrates, polymorphs. Then you get a very comprehensive discovery
of solid forms which then gives you more informed and better choices,
which then eventually can lead to better products.

So we selected ritonavir, and we said, okay, what would we have done
with ritonavir if we had that compound. So here\'s the time line. Abbott
started with form one. Later they found form two. We took this material
and we put it through a high throughput screen with 2,000
crystallization experiments using 2 grams of compound, 32 different
combinations of solvents, and we found five forms. We found the two
original forms and three other forms. These are less thermodynamically
stable so that this is still the most thermodynamically stable form, and
so it\'s the right one to have on the market. But this took only six
weeks to find. And this publication, by the way, is in Proceedings of
the National Academy of Science this year. So it shows you that by being
able to use these kinds of techniques, you can learn. You can explore
the whole space with a very small amount of time, and this took six
weeks.

Let me talk about processes now. This is where I disagree with the idea
that you can control a process without understanding it.

If you explore your process at a small scale, you can find out where the
process is unstable and where the process is stable. Then you can set,
as a result of that, some parameters which will allow you to track the
drift of that process, and so you know where it\'s going before it falls
off the edge of the cliff onto the unstable region.

So let me give you one example. Someone spoke earlier about a
lyophilization process. The idea here was by putting a residual gas
analyzer onto the end of a lyo chamber, you can monitor this in
development and you can determine your conditions. Then you can use
those same parameters then in manufacturing. Then you can put a residual
gas analyzer on there. The ability to do this ‑‑ the manufacturing
division ‑‑ and I\'m talking here about the head of manufacturing had to
decide to do this. And this was no simple choice because know, when the
FDA comes in, they\'re going to see this information. And this is not a
filed specification. This is a process control. So the fear is that the
FDA will see a change in this process control, and they\'ll say, what\'s
going on here?

So it really means that in development you have to understand the
process. You have to understand the range that produces a satisfactory
product and you set those ranges so that in manufacturing, you can
control it within those ranges. You monitor for trends, and when it
starts to trend out of the normal range, then you know something is
happening. You challenge your process, find out what\'s wrong with it,
and get it back under control. And I\'ll come back to that point later
because I think it\'s important.

The second one. Very often in the industry in the past ‑‑ and I know
this is changing, but people would simply take their powders. They would
dry mix them and then they would add granulating fluid, and then they
would mix for a certain time. And so the NDA would read, mix for 10
minutes plus or minus 2 minutes or something like that.

But in fact, a very simple thing you can do is to do granulation
endpoints. So you can measure the power in the mixer and you can
normalize that as a function of the amount of water, and you can do this
at different scales. So here\'s comparing a 65 liter with a 10 liter,
and you can see that basically these two curves totally overlap. Then
you can go to the next scale and you can compare a 65 to a 250 liter,
and again they overlap. So now you control to that endpoint. You don\'t
control by time. You don\'t control by volume of granulating fluid. You
control to get to the same conditions that produces the same product.

A third example is a controlled-release formulation. And this is a
pretty complex formulation. It consists of the drug dispersed in a water
soluble polymer, which is then overcoated and then the tablet coating is
drilled by a laser to produce many, many holes in the surface. When this
goes into an aqueous environment, the water will penetrate through the
film, cause the polymer to swell, and basically you get spaghetti
noodles extruded from this, carrying the drug with it.

So if you\'re going to develop a process like this, you better
understand all the critical parameters. So what happens if you change
either the polymer or the neutralizing agent that\'s in here to control
the conditions of swelling? You modify the amounts of each of those and
you look at how it affects the drug release. So now you know even if you
change within plus or minus 10 percent, you\'re not going to change the
overall performance of the tablet.

Likewise, in terms of the laser drilling process, you can change the
pulse width and the power at constant energy, and you get essentially
the same release rate. So now you can control the drilling process by
the energy per hole as a process control.

Likewise, you can compare the hole size with the release rate and now
you have the same curve regardless of the coat thickness that you have
on the tablet.

And finally, you can look at the effect of the number of holes, at any
one size of hole that\'s been drilled, and you can see that if you have
only 20 holes in the tablet, you get this release rate, and this
increases as a function of the number of holes.

If you want a robust process, then you better be up here because if you
missed a couple of holes down here, you would change the delivery rate
quite considerably. If you\'re up here and you miss a couple of holes,
it doesn\'t make any difference.

Likewise, if you fix the number of holes and you now look at the hole
size, the same applies. If you\'re down at this low end, if the laser
starts to change in its energy as a function of time, then you\'re going
to start changing the hole size and you could change the release rate.
If you\'re up here, then you could have much larger variability of the
laser power and it still will give you the same product.

So I hope that I\'ve shown you that, in fact, processes can be
controlled. They can be understood and controlled. And this is a very
good reason why we need to do this.

So what really has to happen? Well, I think pharmaceutical companies
have to change. They have to understand and control the raw materials
and that\'s the API and the excipients. Just think about it. The APIs we
really do try to understand. Excipients are the byproducts of materials
that are used in the oil drilling industry. We don\'t have nearly the
amount of control that we have over the API.

We need to develop and understand the fundamentals of each unit
operation in the process, and then we have to track key critical
parameters, including in-process controls. Now, I like the PAT because
it means that now we should be thinking about what things we can measure
on-line so that we have instantaneous feedback on what the process is
doing. And we do that during development. And then we use these
parameters to characterize the process entirely. We use a subset of
those to do our scale-up, our technology transfer into marketing and the
validation of the process on the commercial scale.

And then we define a smaller subset as regulatory specifications. These
are the ones that we\'re going to file and the FDA will have the right
to examine.

But we also define a larger subset of these parameters that we can use
for trend analysis so that we can monitor the drifts in the process
before they\'re disastrous.

This all makes really good business sense since it reduces batch
failures and it simplifies the changes and the inspections that we\'re
bound to have.

So staying with the pharmaceutical companies then in a regulatory
submission, whether it be an NDA, an sNDA, or an ANDA, we would include
a well-constructed formulation and process development report. And I
know we put in reports that this has really got to be well-constructed
with all the information.

Just imagine if you are an FDA reviewer sitting in Washington. You may
have a background in analytical chemistry or you may have been involved
in drug delivery and your Ph.D. in pharmaceutical sciences, but you have
no experience of processes. And all you get is what the company sends
you as the NDA without any background on the processes that the company
has developed over six years. How is that person going to really
understand what\'s happening in that process? So they\'re going to be
very afraid to make a change or make a decision unless they have a box
to check, and that\'s the last thing we really want is a box to check.

So we would like to be able to have a process development report that
shows the rationale for the choice of the materials and the processes
and the critical parameters to control that process.

Then the company would use this document as the basis of the regulatory
specifications and for review at the FDA central office. And I like the
idea of the central office and the field inspectors being tied together.
They understand this process, both of them, so that the validation and
the change control protocols that are reviewed at the PAI would also
come from the same document.

And it would also be the document that would be used in the negotiations
of the regulatory pathway for subsequent changes either in composition,
because we would have covered that in the process, or in the site. We
went through site stability a few years ago and there was some people at
the FDA that said if you change the ZIP code, you\'ve changed the
process. You had to do stability again when, in fact, what really
happened was that the processes were poorly controlled, poorly defined,
and when they went to a different environment and the humidity was
different or the equipment was different, it didn\'t work. So
understanding your process and being able to do this would get around
that whole problem.

Well, what has to happen at the regulatory agencies? We have to move
beyond stability as an indicator of process reliability, site transfer,
composition and process changes. Of course, stability is important but
it\'s only one of a series of parameters that are important.

We have to apply chemical and material science and engineering
principles to evaluation of new products and to post-approval changes.

We have to treat trend parameters differently from regulatory
specifications. So if the inspector goes in and sees these are drifting,
it doesn\'t mean that the process has failed. It means it\'s slightly
drifting, but it\'s still well within control and you\'re going to be
able to get it back in control.

And somehow the FDA has to provide incentives to encourage companies who
develop and run robust manufacturing processes, either by reduction in
prior approval requirements or faster or less frequent GMP inspections
and lots of other things I\'m sure that people could think about, so
that there\'s a reward for people who do this well.

And that\'s the end of my presentation. I thank you for listening to me.

DR. BOEHLERT: We have time for a few questions for Colin.

DR. HUSSAIN: Colin, thanks for that presentation.

This was a discussion I think that occurred in early parts of the PQRI.
I don\'t think we had formed the PQRI yet. So it was Larry Augsburger,
myself, and Colin sort of discussing this, but it never went anywhere in
PQRI because I think it was too much out-of-a-box thinking at that time
and probably still is.

But I think \"make your own SUPAC\" or \"create your own SUPAC\" makes
logical sense in the way I think we have to do business. I think the
comparability protocol just is a reflection of this but not to the
extent I think I\'d like to see that happen because I think if you
really have process understanding and knowledge and you can predict,
then I think you can have so many rewards coming from that. That\'s the
reason I wanted you to listen to this presentation.

DR. BOEHLERT: Tom?

DR. LAYLOFF: I agree with Ajaz. I think defining the robustness around
the various control points is really critical. Essentially you build
your own SUPAC because you define the robustness around each control
point. That\'s what should be what\'s in development and it should be
there. I think building your own SUPAC is the only way to go.

DR. BOEHLERT: Gary.

DR. HOLLENBECK: Colin, that was really good.

The question I would ask you is, if I recall things right, I think this
philosophy was espoused in SUPAC. Certainly there was language in there
that encouraged people to establish validated ranges and there were
rewards for doing that and for working within your validated ranges. And
to the extent that my memory is correct there, I guess that wasn\'t
enough, was it? That wasn\'t incentive enough for the industry to really
pick up on that. Is that correct?

DR. GARDNER: I think that\'s probably true.

DR. HUSSAIN: And I\'ll add SUPAC \'95 allowed only one change. And how
do you manage a change in a multifactorial system when you\'re just
allowed to do one change? What did that mean?

DR. BOEHLERT: Other questions or comments?

(No response.)

DR. BOEHLERT: If not, I\'d like to thank the speakers and the committee
members for this morning\'s discussion. It was a very good discussion.

We will reconvene promptly at 1:30.

(Whereupon, at 12:10 p.m., the subcommittee was recessed, to reconvene
at 1:30 p.m., this same day.)

AFTERNOON SESSION

(1:30 p.m.)

DR. BOEHLERT: I\'d like to welcome you all back to the afternoon
session. We have two presenters right after lunch. First is Kenneth
Lavin.

MR. LAVIN: Good afternoon. On behalf of the GPhA, I\'d like to thank you
for allowing me to speak with you regarding this initiative. We believe
that this program is an important step in clarifying the pharmaceutical
industry\'s requirements for providing safe, effective, as well as
affordable pharmaceutical products to the American public.

At the recent workshop, we heard several broad ideas and concepts put
forward to improve the quality systems within industry, as well as
within the FDA. While GPhA supports any program that will improve our
ability to deliver high quality pharmaceutical products, we believe that
much work needs to be done in the area of providing guidance and
training on the various programs and ideas expressed at this workshop.

While it\'s intuitive that implementing a risk-based approach to quality
systems is appropriate, what was apparent was the lack of understanding
as to what this will entail when the day is done. That is, even the
definition as to what is risk and how to mitigate risk and the
codification of such a program could not be agreed upon. What we have
not heard is exactly how this will be implemented and what the
ramification of this approach will entail especially when it comes to
enforcement. The GPhA is requesting that as the details of this program
get fleshed out, the FDA, in conjunction with the different industry
coalitions, continue a dialogue on this topic to ultimately develop the
appropriate guidance and education forums prior to its implementation.

In addition to further defining the risk-based approach to current good
manufacturing practices, we believe that certain of the topics or ideas
presented at the forum need further definition and appropriate guidance
put into place. Among these are changes to approved applications, the
CMC review, and the inspections.

One of the items of discussion revolved around changes to approved
applications and approval of applications with interim specifications.
Along with the adoption of this approach would be the necessity for
firms to file some kind of development report. GPhA would support such a
measure if there were some definite guidelines published on what is
necessary to be included with these reports, how the information in the
reports would be used, an assurance that there would be no negative
impact on the review of these reports, and an expectation that the
filing of these reports would improve the approval times of later
supplements. Again, we would urge the agency to prepare guidance
documents on this topic, outlining the requirement of the program with a
clear understanding of the goals that are to be achieved.

With the current resource constraints placed on the FDA, we believe that
a review of the preapproval inspection program be performed. Utilizing
some of the principles of a risk-based approach, we do not believe that
the preapproval inspections are necessary for most of the applications
that are being filed. We do agree that some inspections may be necessary
for novel compounds or formulations or for products utilizing new
technologies. Further, while the presence of chemistry reviewers on the
inspection teams may be beneficial in the long term by providing an
excellent training forum, we question whether their time spent out of
the office will cause delays in the approvals in the short term.

A large portion of the discussion centered on communication issues. A
483 dispute resolution system consistent across all districts should be
implemented. We believe that additional information sharing issues
should also be addressed. Internal policies of the FDA should be made
public. Written requests for information, for example, control
documents, are not responded to in a timely manner. Further, information
contained in these requests, once deemed releasable, should be made
available to the public as soon as the determination is made. Publishing
this information on the Internet would be a viable approach.

A process for requesting and holding pre-ANDA meetings should be
proceduralized and not be perceived as an unusual request. We believe
that the best approach to timely approval of applications and providing
the FDA with all of the information they deem necessary would be
enhanced by more open and forthright communication.

By providing the industry with these guidance documents and procedures,
we believe that the goal of protecting the American public and providing
safe, pure, and effective products is assured. Industry cooperation and
input into these guidance documents is paramount to the success of this
program. Inspection and review based on these documents will provide
consistent compliance and provide our industry with the needed
information to consistently supply pharmaceutical products in an
economical and timely fashion.

Finally, the GPhA looks forward to continued dialogue on the subject and
supports the FDA in this endeavor. We stand ready to provide the needed
input into this program and are willing to serve on any committee or
task force empaneled.

DR. BOEHLERT: Questions for Ken? Tom?

DR. LAYLOFF: Yes, I have a couple of questions. One of them is on the
definition. Helen this morning put up a definition of risk management
was to ensure that systematic risk management approaches are applied to
allocating resources, selecting sites for inspection, and determining
the scope of GMP programs for human and veterinary drugs, which is an
FDA vision for their risk management. Do you think that\'s unclear?

MR. LAVIN: Well, it\'s unclear when it comes to enforcement. Does a
particular investigator\'s observation warrant continued review of a
firm? How serious an observation does it have to be in order to ‑‑

DR. LAYLOFF: That\'s a 483 dispute resolution issue.

MR. LAVIN: Yes, but we\'re talking about the enforcement side of it.

DR. LAYLOFF: This was on the risk management from the FDA perspective.

MR. LAVIN: I think the details of this program really need to be fleshed
out a little bit better than it has been to date. We\'re just cautioning
the FDA to take their time to develop the program before proceeding.

DR. LAYLOFF: Another question I had was you noted that they should
publish the control docs. Does that mean when a control doc is made
public to one, it should be made public to all at the same time?

MR. LAVIN: That\'s correct.

DR. LAYLOFF: So as soon as it\'s released to one, it should be public on
the web site for all.

MR. LAVIN: That\'s correct.

DR. LAYLOFF: Thank you.

DR. BOEHLERT: Dan?

DR. GOLD: Mr. Lavin, I\'m a bit confused. On your slide on preapproval
inspection, it says, no longer universally necessary. I thought
preapproval inspections from the outset were not mandatory if the firm
were following essentially the same type of technology and it was within
the two-year time frame. Is that not the case any longer?

MR. LAVIN: From my experience, at least in my district, they were
managed pretty well. What I am hearing is there are certain firms that
are routinely getting preapproval inspections for similar products,
similar profiles, and the like. It\'s not a consistent approach.

DR. GOLD: So it\'s the consistency of ‑‑

MR. LAVIN: Well, that\'s what we\'re asking for. Obviously, if there are
new products or novel technologies, then it would trigger an inspection,
but to repeatedly have an inspection, regardless of the class of
products that you may have been cleared on before, really needs to be
evaluated.

DR. GOLD: Have those firms approached the agency and asked why the
policy that\'s been stated, that\'s in writing, is not being followed?

MR. LAVIN: I\'m not aware of that.

DR. GOLD: But the word \"universally\" then in your slide is perhaps
misleading because you said your firm has not been subject to repeated
inspections on PAIs.

MR. LAVIN: Recently. But we\'ve had preapproval inspections. Part of the
preapproval inspection program was with the top 200 drugs. If one of
your products fell in that, that triggered a preapproval inspection
regardless if it was a simple single ingredient solid dosage form. If it
was on that list, you\'d get it again. So there\'s really a haphazard ‑‑
no, not haphazard ‑‑ maybe not a well-defined system because if you
choose the top 200 products simply to trigger a preapproval inspection,
there\'s no assessment of that.

DR. GOLD: Joe, do you have any comment on this reported inconsistency of
this program?

MR. FAMULARE: I was hoping you meant Joe Phillips.

(Laughter.)

DR. GOLD: No, no. He\'s no longer the official spokesperson.

MR. FAMULARE: We have, in our compliance program, set criteria for
conducting preapproval inspections and some of those are set in terms
of, as you said, the top 200, new chemical entities, et cetera. Once we
go through that list, then it\'s pretty much at the option of the
preapproval manager, or it may never even reach the preapproval manager.

One of the first steps that we\'ve taken, in terms of cutting down the
frequency of preapproval inspections, you might call a back door
approach, but it was enhancing our GMP inspection program through the
systems-based inspection approach. Many GMP inspections that are
conducted are for the reason that we\'re not able to keep up on a
two-year basis on the GMP compliance status and we keep doing these
short preapproval inspections because we haven\'t been there, and we
don\'t do systematic coverage of the firm.

Under the new compliance program that issued February of 2001, if we
cover the minimum number of systems, we will mark all the profile
classes so that individual inspections against a particular profile
class should no longer come up. So we see the need to even further
tailor preapproval inspections, but they\'re not universally done.
They\'re selected, and probably for every one you see done, there are
many, many, many that we just make the decision on a daily basis not to
do based on other information we have.

DR. GOLD: Thank you.

MR. PHILLIPS: Could I comment on that?

Just to support what Joe is saying, I myself come from a long career
with FDA and was rather closely involved with the PAI program. I\'ve
been out of the agency for two years. But exactly what Joe is saying was
the case then and I suspect it is now.

Preapprovals were not mandatory 100 percent of the time. In many of the
districts, the preapproval managers opted not to do a preapproval if
there was sufficient case history there of a firm consistently meeting
its commitments and complying with GMPs. So I think that is the
situation. I used to see many of the decisions for making PAIs and those
for not making them, and they were rather consistent across the country.

DR. BOEHLERT: G.K.?

DR. RAJU: I just wanted to make sure I\'ve compartmentalized. It\'s
clear that the FDA can improve on a lot of fronts, particularly on the
investigation front, and that\'s the history, if you go back many years,
on the many things they can improve.

But in terms of your feedback and your opinion, I wanted to see if we
could separate that from the actual GMP initiative itself. Do you
believe that in terms of being clear and in terms of positioning the
future, they have not been? Because if you look at the PAT Subcommittee
or the PAT effort before and what I\'ve heard in six months from the
FDA, in my opinion they have been the faster ever in terms of the PAT
Subcommittee, in terms of being clear about the principles. I was very
skeptical in the beginning, but I thought they were surprisingly fast
and surprisingly open-minded. So is your view more about the practices
of the past or is it about the cGMP initiative itself?

MR. LAVIN: Well, just to step back a little bit with the PAT initiative,
while I think the endpoint is something that is pretty well defined ‑‑ I
mean, having the desire to have firms implement this to enhance their
quality systems, I think that goal is pretty well fleshed out. But
we\'re still having these little sub-arguments about, okay, once you
start capturing this information using the PAT, what are you going to do
with it? So while, yes, maybe in PAT the goal is defined, the
incremental steps of the program and what to do with that information
has not been fleshed out.

What the worst thing in the world would be, I think, for a firm would be
to implement some PAT technology and then find themselves holding a bag
of information that they can\'t do anything with. Now, we\'ve heard talk
about the safe harbor portion of the program and the like, but those
things really need to be put down on paper. Much like we have
inconsistencies from district to district relative to a 483 item, in one
district a PAT ‑‑ dealing with the information may go pretty well. In
another one you might as well shut your product down and move somewhere
else.

We\'re really stressing the need for guidance in these things. Tell us
what you want. Tell us how to deal with these things, who to talk to,
how to resolve these issues. Once we get down and have the rules on
paper, I think the game will be played a little more easily.

DR. GOLD: I have one additional question, Mr. Lavin. How in your opinion
are the procedures for the pre-ANDA meeting ‑‑ and you talk about
proceduralize the pre-ANDA meeting. How are they different currently
from the pre-ANDA meetings that occur?

MR. LAVIN: Well, currently there is no procedure for having a pre-ANDA
meeting.

DR. GOLD: So you mean at times you\'re not called in for a pre-ANDA
meeting?

MR. LAVIN: Oh, I would say ‑‑ 100 percent is a pretty high number, but
99.99 percent of the time there is no pre-ANDA meeting. It\'s you file
the application and you deal with the reviewer comments.

There are situations where one would be helpful where a firm has some
questions about some technology or some of the requirements of the FDA.
We\'ll file an application knowing there will be questions. If we could
sit down or ask for a meeting and get one to talk with especially OGD,
that would be helpful. And currently there is no procedure for doing
that. You can ask for a meeting but it won\'t necessarily be granted.

DR. GOLD: How do you see that a pre-ANDA meeting would help the generic
industry?

MR. LAVIN: Well, as I said, there are applications that will go in where
we know there will be a question either from a bio reviewer or a CMC
reviewer would have. If we could sit down and talk about it, how it
should be filed, how it should be highlighted in the file, how it should
be presented to address this problem instead of waiting for the first
review letter which inevitably will be a major deficiency.

DR. GOLD: There\'s no one here from the agency who could speak for the
generic division, is there?

MS. WINKLE: I can but we\'re in the process of looking at the various
processes in OGD and in the process of starting to meet with industry,
not an individual basis but a broader basis, to talk about some of the
areas in the process where we could make improvements, and that\'s
certainly something that we could consider. I don\'t know that we could
do it in every case, but there are certainly cases where I think there
are significant questions that could be answered and save both sides
problems. So I appreciate it.

MR. LAVIN: Right. If there were just a procedure for allowing them to
happen instead of \"you want to come down and do what\" type of reaction
would be beneficial for both sides.

DR. BOEHLERT: Ajaz?

DR. HUSSAIN: I just want to share my perspective. From a PAT
perspective, I think Ken mentioned that we still have a discussion, what
do we do with data and so forth. I think from my perspective that\'s an
issue that I think companies will have to grapple with. If you have
volumes of data and you don\'t know what to do with it, then I would say
you haven\'t understood the process that you\'re trying to do. So I
don\'t think we can help in that regard.

MR. LAVIN: Well, that\'s not necessarily true. You\'re testing every
single tablet maybe for content uniformity, whereas the current test is
you test 10 tablets and the spec is 85 to 115. You\'re testing every
tablet now. What is the acceptance criteria? You\'re going to get a
tablet maybe that\'s 84 percent. How is the investigator in the field
going to come out and say, here\'s evidence right here that your product
is not uniform. So from an enforcement standpoint, while a firm may be
well justified with the way they handled that particular data point,
there\'s still that second guessing coming on.

So without guidance on this, a firm is putting themselves at risk.
They\'re going to have to have data that they\'re going to have to
answer to.

DR. HUSSAIN: I think the way we approach the guidance it will have that,
but the guidance is not going to solve any problems in terms of giving
you a cookbook. It\'s not going to be a cookbook guidance.

MR. LAVIN: No, no, no.

DR. HUSSAIN: It\'s going to be a guidance which simply defines the
general principles of saying we\'ll use sound statistical principles to
evaluate that. You have a new method. You have to have acceptance
criteria that is consistent with the method. That\'s about it.

MR. LAVIN: It\'s still open to interpretation.

MR. FAMULARE: The GMPs require that it be scientifically sound and
statistically valid. So to use a measuring stick ‑‑ and we were talking
about measuring sticks this morning ‑‑ against what you do for 10
tablets versus the whole batch would not be valid.

MR. LAVIN: I agree with you. I agree with you entirely. Now, you\'re
going to have every investigator in every district thinking the same way
or you\'re simply going to get that opinion document ‑‑

MR. FAMULARE: The other approach we\'ve taken in terms of the PAT realm,
realizing these nuances, as has been mentioned many times by Ajaz, is
the dedicated team, a small group of people to start this process. So
that was one of the first issues addressed head on. Not only the
investigators, the reviewers, they\'re all in that same boat.

MR. LAVIN: We certainly understand that. What we\'re asking for is have
the details fleshed out in a guidance before we launch into this.

MR. FAMULARE: But again, to the point Ajaz made, a guidance can take us
so far and then we have to apply science and reason to get to the
answer. That\'s the process that we\'re working on.

MR. LAVIN: I agree.

DR. LAYLOFF: I was going to say you could write up your own criteria. I
mean, you could say if you analyze 10 tablets, you fall in this range.
If you analyze 100 percent of them, you go with a standard deviation of
6 percent, and that\'s it. You meet the USP criteria in the broadest
sense, but not in the very narrow definition.

DR. BOEHLERT: Joe?

MR. PHILLIPS: Sure. I just want to give my perspective from the
10,000-foot level of the overall initiative. Just back up a little bit.
I\'ve been out of the agency two years. I\'ve worked with the industry.
I\'m not with an association.

But I think this is a very, very bold step for the agency to take. They
took a system, which in my opinion wasn\'t broken but certainly can be
improved. They looked at themselves internally. They listened to the
industry, to academia, to associations, and they identified a number of
initiatives, all of which in my opinion are very substantive.

There\'s a lot of work to be done on all of those initiatives by FDA.
There\'s a lot of work to be done on all of those initiatives by
academia, by industry, consultants, associations. So now is the time for
us outside of FDA to step up to the plate and give them support on this
new initiative.

When I first saw the initiative in August, I asked myself is this
rhetoric or is this going to happen. The February progress report came
up and there was a lot of progress made. If nothing else happens than
the Part 11 changes, it\'s substantive to the industry.

So I just commend the agency and I encourage you to keep going forth. I
heard you ask for any other initiatives. If we have them, we should be
coming up with them for the agency.

DR. BOEHLERT: Any other comments?

(No response.)

DR. BOEHLERT: Ken, thank you.

MR. LAVIN: Thank you.

DR. BOEHLERT: Our next speaker is Gerry Migliaccio.

MR. MIGLIACCIO: Good afternoon. I am Gerry Migliaccio. I am the Vice
President of Global Quality Operations for Pfizer, and I am here
representing a PhRMA perspective.

The way I\'d like to do that ‑‑ you\'ve heard a lot about the FDA PQRI
workshop that occurred a couple of weeks ago, and what I\'m going to try
to do for you is in 15 minutes distill down two-and-a-half days of very
exciting discussion. What I hope to represent is what the industry input
was to FDA at this workshop. Joe, you stole my first slide in what you
just said. So thank you.

(Laughter.)

MR. MIGLIACCIO: The PhRMA perspective on the quality initiative is that
there has been significant progress to date. We have been advocating
science-based guidance and regulation. We\'ve been advocating a lot of
things. When your first announcement came out, we had the same
impression that Joe did. It was sweeping. It was ambitious, but when we
saw the status reports, we were very impressed.

More importantly, we were impressed at the organization and the
commitment to the workshop in April. There were 500 people at this
workshop. I think there were well over 100 FDA representatives, the rest
industry and consultants, but there was a significant commitment to the
process.

The industry is very supportive of this initiative and we are trying to
contribute in any way we can. We think it is a once-in-a-lifetime chance
for all of us to move the state of the regulatory processes around,
pharmaceutical manufacturing up to the state of available technology.
We\'re in violent agreement on many issues, conceptual agreement on
others, and somewhat disagreement on very few issues, and I think those
will resolve themselves.

We definitely considered the workshop a success. I personally thought
that the views were expressed openly and we got a lot of good value out
of those three days.

So let\'s talk about what that workshop was about. There were four
individual workshops. The first was risk-based GMPs; the second,
integrated quality systems approach; the third, changes without prior
approval; and the fourth, manufacturing science. A day at the beginning
with academia, FDA, and industry giving introductory talks on these four
subjects, a day of intensive workshops, and then a half-day of
summarizing the workshops.

Significant overlap in the discussions and the findings from all four
workshops. That was not unexpected. In the planning of the workshop
moderators, it became very clear that there was going to be overlap, and
that\'s the good thing. There is no way you can divorce the whole
concept of risk and risk-based from any of the other subjects. Quite
honestly, as G.K. has said, there\'s no way you can divorce the concept
of science from all of them. Therefore, there was significant overlap
and a lot of commonality in the discussions.

But now it\'s time to operationalize those concepts. I\'m the first
manufacturing quality person here, practicing one. So we want to
operationalize, and it\'s time to move on to that.

G.K. uses pyramids. I\'m a practicing quality guy. I can\'t use
pyramids. I have to use curves, things like that, because pyramids imply
that you get to the top of the mountain and you\'re king. That\'s not a
politically correct thing to do in industry.

What I\'m going to try to do is paint this manufacturing science and
risk model which really came out of this three-day workshop. Let\'s
first look at manufacturing science. It\'s a continuum. There are three
key elements to manufacturing science. Product and process knowledge is
the first. What do you know about your process? Technology is the
second. What manufacturing technology are you using and what process
control technology are you using? And finally, the third is the
underlying quality systems infrastructure. How good are the quality
systems at the manufacturing site?

As you go up the manufacturing science curve contributing from all three
of those elements, you gain a higher knowledge and better control over
your processes. More importantly, you have a greater ability to predict
what will happen when you make a change to those processes. And that\'s
what\'s key here. If I have a change or a deviation, an event, can I
predict what will happen? Will it impact the fitness for use of the
product?

So we are struggling with what do we mean by fitness for use. Well, we
mean at the base level safety, efficacy. Others will add convenience to
use and availability. So let\'s use that as a definition now.

Will a change impact fitness for use? The higher you are on the
manufacturing science curve, the greater the ability to predict that.

So then you overlay the risk curve. The risk of a change, an event, a
deviation impacting fitness for use goes down as you go up the
manufacturing science curve. But it is important to note that it does
plateau. Technology for technology\'s sake is not always the answer.
There is not a gain. For certain products and processes, for certain
unit operations, there is no further gain in risk reduction by investing
in more technology. That\'s just an important point to realize.

Now, in the end what we\'re looking at is trying to take this
manufacturing science and risk model and overlay a flexible or tiered
regulatory process. I\'m not proposing that there are only three. I will
go with G.K. and say maybe there are five. But a tiered regulatory
process model which goes along with this, which provides the flexibility
for a firm who has demonstrated that they know what the impact of a
change or a deviation will be on their product, to innovate in a more
timely manner, to demonstrate to themselves scientifically that they
know what the impact of the change is, that they know that there is no
impact on fitness for use, and to make that change, to innovate in a
much more timely manner without significant regulatory hurdles is really
what it all distills down to from the three days of workshop. A PhRMA
group sat around a room and drew this out in about three hours. This is
really what it means to us.

So what are the prerequisites for this model? The first is culture
change. And I\'ll go through each of these individually. The second is
knowledge sharing, and you heard this from David this morning. We can\'t
be in more violent agreement that we have to share knowledge, but it\'s
the right knowledge ‑‑ not more knowledge, the right knowledge. Risk
management principles. You\'ve heard this from everyone, and finally the
whole concept of an integrated quality system. These are the
prerequisites to achieving the ultimate goal of a good manufacturing
science and risk model.

Let\'s talk about culture change. Every workshop, all four, the first
thing on the slide, trust, both ways, not just industry being able to
trust FDA, but FDA being able to trust industry. The trust to be able to
share knowledge and have that knowledge used in an appropriate fashion.

Open communications. More than once we heard in a workshop somebody from
industry say, well, we can\'t approach the FDA. We can\'t get a hearing
on this, and to have the FDAers say, well, our doors are open. The
communication just wasn\'t there on how to get that into the right
communication link.

Helen mentioned this this morning. We have to move from \"change is
bad\" to \"change is good.\" Change is bad. You\'ve heard a couple of
people talk about this. When you develop a product and you put it on the
market, one of the worst things you can do is then try to change it
because the regulatory hurdles just keep spiraling upward.

Most of us will readily undertake a process change for an API because
those process changes for APIs have real gain in safety, environmental
control issues. They\'re beneficial, and we try to continually improve
those processes.

On the drug product side, there are very few that have those safety and
environmental impacts, and you have to make the decision whether you\'re
willing to go through the regulatory hurdle to make a change that would
improve the process. So that is a difficult decision.

We really want to move to \"change is good.\" We want everybody to say
that change means innovation and change is good.

I\'ve said it before, but fitness for use by the patient has to be the
key driver for both FDA and for industry. I acknowledge that we still
have to work on what we mean by fitness for use, but I think
fundamentally we\'re talking about safety and efficacy to the patient
and availability.

Knowledge sharing. A lot of discussion at the workshop about knowledge
sharing, and probably the fundamental concept that we really need to get
our arms around here. What does FDA need to be able to ascertain the
level of understanding that we have about our formulation, our process,
and the potential impact of changes on fitness for use? So in the end
what that means is what does FDA need to assess risk. That\'s what
we\'re really getting at. What is it that they need?

We have a large database. We share a portion of that with the FDA.
Currently we\'re probably not sharing the right portion of that. We have
to decide what is the right portion. Again, I have to stress it\'s not
more. It\'s the right knowledge.

The key concern of industry is how is that information going to be
handled? Is it going to delay the review and approval process of an NDA
because we are sharing a different knowledge base? Or is it going to be
used in a very scientific sense to help support and facilitate the
review and approval of the NDA?

What kind of knowledge are we talking about? Development pharmaceutics
clearly. Critical-to-quality attributes and parameters. Have we
identified them? Do we know what they are? And more importantly, do we
know what the impact of variation of those are on fitness for use? And
as G.K. mentioned, process capability. If we can provide at an original
NDA or in a supplement to an NDA after we have more commercial
experience this kind of knowledge, we believe this should allow the
agency to look at this product or process and say it is low risk, it is
moderate risk, and therefore the regulatory processes associated with it
will be less burdensome.

Risk management principles, the area that needs, as we\'ve already said,
the most development, but risk assessment. What\'s the process going to
be? When I talk about risk, I\'m talking a very narrow scope of risk.
I\'m saying what is the risk that a change to my manufacturing process
or a deviation that occurs during manufacturing will have an impact on
fitness for use. That\'s a very narrow scope. We\'ve talked about risks
associated with inspections and what level of inspection should a firm
have. That\'s a different level of risk. But we need a risk assessment
process.

And we need to agree on risk mitigation strategies. You saw the
manufacturing science curve and the associated risk curve. Now, I may
have a very complex product which you would put at a high risk
initially, but if I use certain technologies, certainly process
analytical technologies, to monitor, provide continuous feedback, I
should come down the risk curve. I should come down that risk curve. And
that is certainly what we are striving for, and I think that\'s one of
the things that the agency and the industry are in violent agreement on.
It\'s just a matter of how do we demonstrate to each other where we are
on that risk curve.

And then risk classification. How do you classify a ‑‑ and I don\'t
think it\'s a firm. I don\'t think you can classify a firm. You might be
able to classify the underlying quality infrastructure at a firm, but
it\'s a product or a process and it\'s a manufacturing site, but I
don\'t think you can classify a firm unless a firm is one site with one
product. Because people ask me where is Pfizer on that manufacturing
science curve, and I will tell you we\'re every place on that curve,
depending on the product. Depending on the product, we are everywhere on
that curve, and I think any other company would say the same thing.

So the definition of risk is still a work in process, as you heard from
David, but we have to remember that risk does change through the product
life cycle. The more knowledge you have, as you gain experience in
commercial manufacturing, the more technology you apply to that
manufacturing process, you can mitigate risk, you can change the risk
factor. So because at the time of NDA approval we assign a certain risk
to a product, it doesn\'t mean that that carries that risk for the rest
of its life. It will change.

The integrated quality system. Now, here\'s where I lumped in a lot of
very good input from the workshop, and I think it really does come into
the whole concept of an integrated quality system within the agency
starting with science- and risk-based GMP guidance documents. I think
PAT is the model. Aseptic is right on the doorstep as well. I think
these are becoming now the model of how to do it and how to get it out.

Knowledge transfer between the center and field is critical. I think the
pharmaceutical inspectorate will facilitate that. If we\'re going to
share knowledge with the center, it also has to get out to the field or
we haven\'t accomplished much because you\'ll have the inconsistencies
that were talked about in the last presentation.

This whole concept of specification life cycle. You heard interim
specifications in the last presentation. I\'ve gone away from that
concept just to a concept of specification life cycle because if you are
monitoring process capability, then as you go along and you learn more
and more about your process capability, you really should reevaluate
your specifications, and that\'s really what we\'re about with the
specification life cycle which really was born out of the original idea
of an interim specification.

And then flexible regulatory change management process. First of all, it
starts with the original knowledge base that we transfer to the FDA, and
it should lead to more changes that do not require prior approval. What
we\'re saying here is that we have demonstrated to ourselves and to the
agency that we understand this process and we understand the impact of
changes on this process. Therefore, you can use the \"make your own
SUPAC\" terminology if you\'d like, but I\'ve put the boundaries around
what change I can implement because I\'ve already demonstrated that I
understand what the impact of changes like that will be. So that\'s
really what we\'re getting at there.

Now, I have a few bullets here on inspections based on risk assessment.
Before I get into my slide, I would like to address some of the comments
from this morning on 483s from kind of the real world of having to deal
with 483s.

More than 10 years ago now, when most of your inspections were what
we\'ll call general GMP inspections and you received a 483, you had the
ability to evaluate, decide did we actually explain this properly,
should we go back to the district and discuss this further, should we
appeal, whatever. That\'s 15 years ago when you had the luxury of time
to do that because, first of all, the time it took to get from a 483 to
a regulatory letter at the time was significant. So you had the time to
have a discussion with the district and try to put more scientific
rationale behind your argument of we\'re doing it this way because it
makes scientific sense and we think it\'s a valid way to do it. So you
could take that time.

With the implementation of the preapproval program, most of the
inspections we get now, as David said, are preapproval, which means
there\'s a new product waiting to be approved. And if you look at
G.K.\'s slide about manufacturing ‑‑ you know, make sure the product is
available, don\'t be on the critical path, that\'s very valid. That\'s a
business reality.

So I have made decisions to implement policy or practice on a global
basis based on a 483 because if I don\'t, the product won\'t be
approved. Why? Because right now there is no dispute resolution process.
Right now there is no ability to get a timely resolution of an issue
like that, and right now it takes a very short period of time to go from
the 483 to the warning letter.

Now, I say all that and now I will add we are very supportive of the
dispute resolution process that is in development. We are very
supportive of the fact that the center is reviewing all warning letters
now because we do believe that will lead to consistency and
predictability. We\'re so supportive of this initiative because the FDA
understands what the issues are and are addressing them one by one.

So that\'s why the industry has reacted to 483s and will continue to
react to 483s in the context of preapproval inspections where a new
product approval is hanging out there and if the district says that\'s
what they expect, then that\'s probably what we\'re going to do until
there is an effective dispute resolution process to enter into, and
we\'re hoping that\'s right around the corner.

So I just wanted to add that to this morning\'s discussion on 483s.

We do believe that inspections should be based on a risk assessment, and
I think that\'s uniform. What is the firm\'s and the site\'s prior
compliance record? The product type and the process complexity, the
level of risk associated with it. The facilities and the technology
used. Are we talking about aseptic? Are we talking about direct
compression, solid orals? What are we talking about?

We think that there should be more of a focus on what I consider the
more value-added systems inspections. Why do I say the more value-added?
They give the agency one of the elements on that manufacturing science
curve. What is the underlying quality systems infrastructure at the
site? That contributes to their ability to understand the risk, the
level of science we\'re at, the risk associated with our operations. We
think the focus should be on those types of inspections versus the
preapproval, which has turned into more of a documentation review and
doesn\'t say much about the underlying infrastructure unless they turn
the preapproval into a systems inspection as well.

So the next steps. I can never leave one of these talks without saying
what I think we ought to be doing, and so what I\'m going to do is point
out a few focused workshops that I think we should be having. By we, I
mean FDA, academia, and industry, and I would hope that this
subcommittee would be driving the impetus to get to these workshops.

The first clearly is what is the knowledge base that needs to be
transferred and how will it be handled in the regulatory process. So
going back to one of my first slides, what does the FDA need to assess
risk and how will that information be handled to facilitate the process,
not to delay the process?

As David said, we need to define what we mean by risk, what risk
assessment process will we adopt, and what are the risk mitigation
strategies. What do we believe will effectively mitigate risk?

We need to continue the focused workshops related to science-based GMP
guidance. Process analytical technology again is on the doorstep.
You\'re going to hear about aseptic tomorrow. OOS is another one, a
draft guidance that\'s been sitting there, which we really would like to
see come out. It\'s very critical during inspections, and having a
finalized guidance that we all agree upon is critical.

Certainly cleaning validation is another area. This is an area where the
technology now has far outstripped fitness for use. You can see down to
levels that mean nothing to the fitness for use of the product, and
it\'s critical now that we get some guidance around what is really
important in the cleaning validation area.

Finally, this concept of developing a proposed guidance for
specification life cycles I think is a workshop that should be held.
This is very much a new product focused workshop with the continuation,
the life cycle concept built into it.

Finally, the tiers that I showed earlier. What are the change management
requirements for a given product based on where you are on the risk
curve? What should they be? They obviously will vary from prior approval
to CBE to annual report. Some had suggested at the workshop a changes
already effected supplement which would be a more timely supplement than
an annual report but have the same effect of essentially it was already
implemented because you had demonstrated that it would not impact
fitness for use. But that certainly is another workshop that we\'re
recommending.

So that\'s the end. I\'ve tried to, like I said, put two-and-a-half days
into a very brief presentation. Questions?

DR. BOEHLERT: Nozer.

DR. SINGPURWALLA: Well, I have two questions. I\'ll start with the first
one which is a comment. Your picture on manufacturing science and risk
model I claim is misleading, and I\'ll tell you why. If I were to look
at that picture, the sense I get from it is less effort is the breakeven
point between your manufacturing science curve and the risk curve. I
grant you that these curves are subjectively drawn, but one could get
the general impression that really to reduce risk, you really don\'t
have to put in much effort because the tradeoff with manufacturing
science would come in the way.

MR. MIGLIACCIO: Yes, and I acknowledge that. The terms \"impact\" and
\"effort\" were put there. You could have put investment.

DR. SINGPURWALLA: You could have drawn a different curve and shown that
you really need to put a lot of effort to get rid of risk.

MR. MIGLIACCIO: Most of the risk is reduced with very little effort, if
you look at the curve.

DR. SINGPURWALLA: That\'s the impression that the curve gives.

MR. MIGLIACCIO: And I believe that you can get a significant reduction
in effort with a reasonably significant capital investment. Let\'s say
if want to talk about PAT. There is some significant capital investment,
but that will lead to such an increased knowledge of your process that
you will bring your risk down significantly. So you can talk about
effort, investment, whatever. It\'s at the other end of the curve that
we were trying to make the point that you can continue to make a lot
effort after a certain point, and it\'s not going to reduce your risk
any more. That\'s really what we were trying to draw.

DR. SINGPURWALLA: Let me just reemphasize the point that these curves
may be realistic, but to a skeptic like myself they may not be and you
may be asked to explain.

There are two points. One of your slides says, \"definition of risk,
still a work in progress.\" From my perspective, risk has been defined,
maybe not defined in your particular context, but there is a general
definition of risk and any tampering with the existing definition will
essentially cause you to introduce a new definition. And where does that
process stop?

MR. MIGLIACCIO: I ‑‑

DR. SINGPURWALLA: Let me make my third point and then you can answer.

The third point is on your last slide, you said inspections should be
based on prior compliance record, product type, and process complexity
risk. I grant you that, but there is a danger. Suppose you have an
organization that has an excellent compliance record when it comes to
uncomplex processes, but when it comes to complex processes, it may not
have. So there could be a negative correlation between those two. We
want to be sure that ‑‑

MR. MIGLIACCIO: No, no. In that you misunderstood what I said. The need
for inspections should be based on risk. If a facility which has never
made a product of that complexity is about to introduce a product of
that complexity, regardless of prior compliance risk ‑‑ and I think the
speaker before me said the same thing ‑‑ new technologies obviously are
going to beg inspections. Moving from what you\'ve done for 20 years to
a totally new paradigm in manufacturing, obviously we would expect that
the FDA would be coming in. That\'s not the issue at all.

But let me go back to the risk. I think what we\'re trying to grapple
with ‑‑ and maybe David will support me on this one ‑‑ is what does risk
mean or risk-based mean in the context of this quality initiative. When
this started, Janet Woodcock gave three separate different definitions
of risk, not so much definitions of risk, but the type of risk we were
talking about. And that\'s really what we\'re saying. What risk are we
talking about here? I talked about a very narrow focus of risk, and that
is the risk of something, a change impacting fitness for use of the
product. That\'s what we\'re trying to grapple with here.

David?

MR. HOROWITZ: Yes. I think this actually might be one of those issues in
which we\'re in violent agreement.

But I think risk is actually very easy to define, and the generic
definitions that I talked about, the key elements being the severity and
the probability of harm or exposure to a particular defined hazard.
Those are concepts that run throughout the different disciplines that
have applied risk in various contexts.

But the real challenge is applying those more general concepts to drug
quality and to drug regulatory quality oversight. And that is something
of a challenge because we can define the harm that we\'re after in many
different ways, and the way that we define that harm will ultimately
determine how we quantify and thereby assess, prioritize, and manage
risk.

DR. SINGPURWALLA: Can I react to that please?

DR. BOEHLERT: By all means.

DR. SINGPURWALLA: There\'s only one definition of risk: expected loss.
How do you calculate expected loss? Two ingredients: probability
multiplied by utility.

MR. HOROWITZ: Yes, but the challenge is loss of what.

DR. SINGPURWALLA: Whatever it is that you\'re looking at.

MR. HOROWITZ: But that\'s the challenge.

(Laughter.)

MR. MIGLIACCIO: That\'s what we\'re trying to get around.

DR. SINGPURWALLA: But that is different from defining risk. What we are
discussing here is how to apply well-known, existing technologies to a
particular application. I took a taxi this morning to come here, and I
wish I had taken the Metro because the taxi driver was driving rather
aggressively. I made a decision. It was a risky decision, and it\'s a
question of an application.

I think what this committee should be looking at more carefully is not
how to define risk but more so how to apply the existing definitions and
the existing notions. The most difficult job in doing risk analysis is
calculating the correct probabilities. That takes a lot of effort.
Calculating utilities. That takes a lot of effort. The principles are
all well established, and this group, including myself, is not going to
change those principles because they have been around for 250 years.
That\'s the only point I\'m trying to make.

DR. BOEHLERT: Other comments, questions? Yes, Ajaz.

DR. HUSSAIN: I think the fundamental issue is fitness for use, the
definition of that. I\'ll sort of share my perspective on that. The way
we have practiced, specifications are fitness for use. The scientific
process of establishing controls and specification is intended to define
that use of a product which essentially defines its intended use. So
from that definition, quality essentially is at one level ability to
meet your specifications, and those specifications have to be meaningful
and science-based and so forth.

In modern terms, quality is also defined as customer satisfaction. In
that regard, I think in pharmaceuticals that has always been a
challenge. In a clinical setting, you really don\'t have the tools
necessary to define whether the product really worked or not.

So it really boils down to your specifications, quality. Therefore, risk
is not able to meet those specifications. So that\'s the current model.
So how do we move from that model to something better would be one of
the topics for discussion.

DR. BOEHLERT: One last comment and then we\'ll move on to the next
presentation.

DR. HOLLENBECK: I\'ll save it.

DR. BOEHLERT: Okay. We\'re going to have plenty of time for discussion.

I think Ajaz is on next, and he\'s going to tell us what this is all
about. Right?

DR. HUSSAIN: My goal here is to actually share some thoughts with you to
essentially have you discuss and identify topics and their
prioritization for several meetings that you will engage with us.

Both Helen and David have outlined the goals and objectives and the
activities under this initiative. One of the tasks that we were asked to
do was to essentially define the vision for the future because all these
goals and objectives are fine, but we do need to know where we are going
so all these activities lead in a meaningful way to this desired state
or vision. So I\'d like to share with you the desired state or the
vision for the future, and we believe this has become a shared vision
for the future. And I\'ll pose that question to you, if you agree or
not.

Next, I think we would like to identify and prioritize topics for
discussion. As Gerry said, we want to move towards creating a system
that really starts working now. We\'d like to hear your recommendations
on a format and background information FDA should prepare for discussion
of identified topics. So this is the task for you this afternoon, the
discussion this afternoon.

We have kept sufficient time for this discussion, and based on what I
have seen this morning, the time may not be sufficient.

(Laughter.)

DR. HUSSAIN: But you may surprise me.

So this is what will happen this afternoon.

Tomorrow what we would like to do is update you on current activities,
the PAT initiative and how that fits into the drug quality system for
the 21st century initiative. We\'ll share with you comparability
protocol as a tool for continuous improvement. I think this goes hand in
hand with what Colin presented this morning. I would like your
discussion on the comparability protocol and what opportunities still
remain to be realized. Is this approach on target or should we be
thinking more in line with what Colin Gardner suggested this morning?
And you\'ll hear Dennis Bensley, who will summarize this comparability
protocol for you, tomorrow.

We also wanted to share with you a perspective on risk analysis. Our
risk expert will not be here tomorrow, but we hope to get his comments
in today. He has already seen the presentation. This is a presentation
from a CVM person which was presented at the workshop also, essentially
bringing in concepts such as failure mode/effect analysis and so forth
and just get the thought process on risk system models and so forth
started because I think that one of the first topics for discussion in
the discussion with this committee is likely to be the definition of
quality, risk, and getting a handle on these definitions and sort of
defining the concept. So at one of the next meetings, we\'ll focus on
that.

So committee discussions on the relationship between process
understanding, change management, and risk to quality would be the
discussion tomorrow after you get a chance to hear these presentations
and approaches.

In your program, the discussion is occurring on the program after the
aseptic manufacturing update presentation. We\'d like to move that
discussion up front so that we can focus our discussion immediately
following these presentations. So we just want to change or tweak
tomorrow\'s program in such a way that we end the meeting with the
aseptic update because this committee has not discussed aseptic before.
We had discussed that at the main advisory committee. So it\'s simply an
update so you are aware of what\'s happening.

So that\'s the rest of the program for today and tomorrow.

Listening to the presentations this morning and what we have announced
on the web site, there are five key elements that form the goals and
objectives of the entire initiative. You will notice that I\'m not
calling this a GMP initiative. It is no longer a GMP initiative. It is a
drug quality system for the 21st century initiative because it covers
review, inspection, compliance, all aspects of the quality system. And
it has to. Just imagine now when you set your specifications, when you
approve that, and then when you\'re not able to meet those
specifications, the question always can come back to were the
specifications set right. So you cannot have a quality system that does
not include CMC review, compliance, and inspection all together. So
that\'s the reason we are calling it a drug quality system for the 21st
century initiative.

Just to sort of reiterate and summarize, the objectives are: to bring
risk management; quality systems thinking; recognize and encourage
scientific advancement and innovation; bring the continuous improvement
process in; review and inspection programs are coordinated, synergistic,
and consistent; effective and efficient utilization of FDA and I added
industry resources. So those are the broad goals and objectives of this
initiative.

But we can do that by changing or modifying current systems, but if you
just do that on that basis and not think about the future, then I think
we might miss something. So therefore, what I would like to do is to
begin with the end in mind, and the end is not two years from now. The
end is maybe 2020, at least the end of my career. No.

(Laughter.)

DR. HUSSAIN: So how do we begin here? I would like to start with the
desired state for pharmaceutical manufacturing and associated regulatory
processes in the 21st century. We announced this as part of the progress
report that was issued in February. In fact, our Commissioner had ask us
to define a vision for the future, and this was part of that exercise.

So as we move forward with this initiative, it is essential to define
what we wish to achieve. So what should the desired state of
pharmaceutical manufacturing and associated regulatory policies be in
the 21st century? We think this is important because we need to have a
shared vision to guide future evolution of this initiative. I\'m a bit
scared right now in the sense that we are in violent agreement with
industry on some aspects, as Gerry put it. That\'s good. I think that\'s
wonderful.

We would like to enroll all stakeholders in this journey to better serve
the patients. Keep in mind we are here to serve the patients, and
that\'s the whole objective. The patient is paramount.

But also, always linking back to the academic community where I came
from, I think there is a strong need to highlight for the academic and
research community the scientific needs in pharmaceutical engineering.
The pharmaceutical profession, pharmaceutical engineering, industrial
pharmacy are very small disciplines when you compare it to, say, the
American Chemical Society or American Institute of Chemical Engineers.
This is a very small fraction of those big organizations, and unless the
agency or the regulatory authorities recognize the science, science will
not grow in this discipline. So that has always been my concern. So I do
want to highlight the need for academic and research community and what
they should be focused on.

But David actually has summarized this. I\'ll repeat this. Whatever
approach we use, it must strengthen the public health protection
achieved by FDA\'s regulation of drug product manufacturing. The
approach should not interfere with strong enforcement of existing
regulatory requirements, be risk-based and be science-based. I did not
change the sequence after G.K.\'s presentation. The reason for the
sequence of science coming last is because I want to build on that
further.

Gerry in his talk talked about trust. Now, trust is a difficult concept
in a regulated industry, but I think there\'s a win-win here, and the
win-win comes from science. The open hands is a symbol for trust. It is.

(Laughter.)

DR. HUSSAIN: I have chosen those very carefully.

Science provides a win-win approach, and the reason for this was, when I
joined the agency about eight years ago, I saw such a big gap between
the science out there and science practiced within the agency. I knew
just filling that gap was a win-win because I knew many companies had
good scientific basis for doing their development and so forth, but
never shared it with the agency. There was a trust issue. There was an
issue of many different reasons.

So the win comes from just recognizing that pharmaceutical manufacturing
is evolving from an art form to one that is now science- and
engineering-based. It doesn\'t mean that we have solved all the
problems. There\'s much more science to be done, but even just
recognizing 30 years of science brings us a win.

Effectively using this knowledge in regulatory decisions in establishing
specifications and evaluating manufacturing processes can substantially
improve the efficiency of both manufacturing and regulatory processes.
So we\'re looking at a win-win on both sides, and the focus is
knowledge. This goes back to Gerry\'s presentation. What is the
knowledge? What is the right knowledge? Not volumes of data, not volumes
of submissions.

The initiative is designed to do just that through an integrated systems
approach to product quality regulation founded on sound science and
engineering principles for assessing and mitigating risk of poor product
and process quality in the context of intended use of pharmaceutical
products. Intended use, mitigation strategies sort of create the
balance, brings a pragmatic perspective. I think I agree with Gerry. You
can keep increasing the level of redundancy and so forth, but you reach
a limit, so you really need to have the right balance. And what is the
right balance is the search that I think we will ask you to help us.

So the desired state is product quality and performance achieved and
assured by design of effective and efficient manufacturing processes.
Does that mean we don\'t have effective and efficient manufacturing
processes today? We\'re not saying that. What we are saying is many
products are effective and efficient today, some are not, but we don\'t
have a means of judging which is which. We put everything in one basket
and we regulate as if everything was the same. There\'s no difference in
quality. So if you start distinguishing and letting science win, then
there\'s a win that comes through.

I think what we don\'t do well is the second bullet. Product
specifications based on a mechanistic understanding of how formulation
and process factors impact product performance. The way we set
specifications in absence of development data is to some degree
guesswork. If these are your three batches that you tested in the
clinic, this was your dissolution, this was the slowest dissolution,
that\'s your specification. That\'s how we set specifications. And we do
not bring into discussion and in our analysis what is the basis for that
specification and how does that relate to process, how does that relate
to safety and efficacy. Often we go back to the historical. We needed a
dissolution test, so we have a dissolution test. Whether the dissolution
is rate-limiting or not, those questions sometimes don\'t come into
discussion. So moving towards a mechanistic understanding of how or when
specifications are set is important, and that cannot happen without
sharing knowledge about your process understanding. And if you don\'t
set your specification right, you essentially are throwing this over
from R&D to manufacturing, and the manufacturing cannot manufacture it.

Continuous real-time assurance of quality. I think this brings in focus
not only that we can be more efficient. This goes to the slide G.K.
showed in terms of how much time is lost between the process and
actually the analysis and all the time in between is not truly value
added. Plus, doing a simple experiment takes much longer now than it
should. So continuous real-time assurance of quality also brings in more
efficiency in your R&D itself.

That\'s from a manufacturing perspective, but to make that happen from a
regulatory sense, our regulatory policies should be tailored to
recognize the level of scientific knowledge ‑‑ again, underscore
knowledge ‑‑ supporting product application, process validation, and
process capability. Today often I get involved in discussions saying
that this is a validated process, but the product is not capable. So
what does that dichotomy tell me? If process validation doesn\'t lead to
a capable process, what was the value of that validation? That becomes
the question.

Risk-based regulatory scrutiny that relates to the level of scientific
understanding of how formulation and manufacturing process factors
affect quality and performance. I underscored \"level of scientific
understanding.\" So what is the right, appropriate level for that
particular product and so forth. But this provides a win. You let
science win with that bullet right there. Now, if you provide incentive
for companies to do the right science and share the right science, then
there is progress. I first then focus on companies that do not.

The capability of process control strategies to prevent or mitigate risk
of producing a poor quality product. This is also important because
today when we look at complexity, we would say aseptic manufacturing is
a complex, high-risk process. So it is high-risk. That is a starting
point for discussion. Then the question becomes how well understood is
that process, how well controlled is that process, and so forth. So
control strategies to mitigate or prevent risk need to be recognized
too. Again, I think I\'m reflecting what Gerry also said, the same
thing. How do you manage your risk today?

We believe that since we articulated the desired state, not just dreamed
it up ‑‑ this evolved from lots of discussion. Under the ACPS PAT
Subcommittee, the Science Board discussion led to a common understanding
of what the shared vision was. We have presented it at several public
workshops and meeting. We believe it now represents a shared vision of
the pharmaceutical community. It\'s not just what we are saying. I think
this is what academia is saying. It\'s what industry is saying.

But I stopped there and posed this question to you. We believe these
statements have become a shared vision for the future. Does the
committee agree? I\'d like to get your feedback on that.

Topics and setting priorities for discussion at future meetings. I think
one of the most important topics is a common language definition so that
we can continue our discussion more effectively, the definition of
quality and risk, again risk in the context of what we are talking
about, not redefining the word \"risk\" again. I don\'t mean that.

Risk models and management approaches. I think there are several models
out there that I think we need to bring in for discussion, and we really
would need this committee\'s help to do that. We will bring this back. I
think David has a group working on this. I think each working group
within the GMP initiative, drug quality system, will have an impact on
this, so we\'ll plan a whole committee meeting on this.

Manufacturing science and process understanding. Process understanding
and control strategies for mitigating risk. I think the words are fine,
but we need to flesh it out and actually define some working definitions
and an approach for this.

Process validation and capability I think is a topic for discussion.

Manufacturing science and process understanding continued from the
previous one. I just put everything under this right now.

Continuous improvement. Use of prior knowledge ‑‑ Bayesian approaches
too ‑‑ for example, development data, for risk mitigation and
justification of less burdensome reporting. For example, \"make your own
SUPAC\" or \"create your own SUPAC.\"

Design of experiments and failure mode analysis for assessing and
mitigating risk. This is linked to the development. This is linked to
how we set specifications and so forth.

Specifications and in-process controls. Interim and final
specifications. I actually like better what Gerry mentioned, the life
cycle of this. I think that\'s a better way of looking at it. Risk- and
mechanism-based approaches for doing this.

I will leave those thoughts with you. I think we really need your help
to identify. I may have missed some of the topics, so you need to let us
know what topics we need to do and how we want to bring them.

We did provide to you, hopefully in your background packet ‑‑ it\'s not
in the handouts that were given at the meeting, but in your background
packet you should have more detailed summary reports of the workshop.
There were some very important points captured in that, especially on
risk- and science-based. You have that in your background packet.

What I will suggest ‑‑ and I\'ll stop my presentation here ‑‑ is I think
subcommittee membership here reflects very diverse backgrounds. It will
help FDA and other subcommittee members if each member shares their
individual perspective on the initiative and the proposed topics and the
challenges they believe FDA will need to address before we get into
subcommittee discussions and recommendations of the list of proposed
topics for discussion. Clearly the objective that we have in mind today
is these discussions will range from addressing specific questions posed
by FDA working groups when they come back to you to addressing broader
discussions of FDA proposals. So when we come back to you, often we
bring questions to you, but also we\'ll bring our proposals to you and
we\'ll take your recommendations back to all the working groups under
this committee.

So I will stop with that and hand it over to Judy.

DR. BOEHLERT: I think that Ajaz has outlined for us the discussion
topics for the remainder of the day, starting on the second slide where
he talks about the desired state and he\'s given us a lot of examples of
what might be included in that desired state. I think the focus of this
committee now should be on whether we agree with Ajaz\'s outline. Do we
have suggestions for things that should be added? Do we want to change,
perhaps, some of the things that have been put on the list? So I would
open the committee to general discussion.

I had one issue. I\'ve been sort of quiet letting all my committee
members ‑‑ but I think there are some things that also may change in the
future. You talked a little bit about specifications should reflect
process capability. I think over the years on pharmaceutical products,
we\'ve set specs based on tradition, not on science. NSA on a dosage
form is 90 to 110 and it\'s sort of traditional. It\'s not based on any
process capability or anything of the sort.

I can envision a future where specifications will be set on process
knowledge, that perhaps these traditional limits are still there in the
compendia or whatever. Those are sort of the outlying limits, but in
fact your process may have different limits.

I think that\'s something we need to think about because if you make a
product and I make a product, we may have different process
capabilities. Does that therefore lead to different specifications? And
if it did, is there a public standard then that covers those? And how
would that be addressed by the agency? Because process capabilities are
going to differ manufacturer to manufacturer depending on what level you
are in those pyramids and knowledge of your process and a lot of
factors. So we\'re going to need to think about that, and I think the
agency is going to need to think about how they might need to address
that.

DR. HUSSAIN: I think at least the initial thought process for the
discussion is I think the whole initiative, I think the PAT initiative
as we started, we are not worried about the quality of products
available today. It\'s the question of process understanding, improving
efficiency and so forth. That was the basis for that.

So, for example, if you have a public standard which says 90 to 110 and
if your process is capable of doing a much narrower range, I think
you\'re better off. Your process is more capable. But that does not mean
that somebody who is less capable but still meets that standard is not
safe and efficacious.

DR. BOEHLERT: And that\'s, indeed, the point that I\'d like to make.
They may both be fine standards, but the fact that his process is
capable of 98 to 102 and mine is 90 to 110 doesn\'t preclude the
acceptability of the 90 to 110 process.

DR. HUSSAIN: Correct.

At the same time, I think the thought process could be that since you
have understood and controlled your variability so remarkably, then you
understand your process better, so you would have less regulatory
scrutiny than somebody who is reaching the limits with a highly variable
product. So that\'s the approach, rewarding good science.

DR. BOEHLERT: I guess the fear on the part of industry always is if
somebody does improve their process to the point that they can get to
the 98 to 102, or whatever limits are very narrow, then indeed that does
become the public standard. That\'s the \"c\" in current GMP and
there\'s an expectation on the part of the agency that everybody meet
that same standard.

DR. HUSSAIN: No. We understood that very well, so that in fact the first
question we posed to the Science Board was \"c\" in cGMP really has to
be dealt with differently. So PAT, for example, is not a requirement.
You don\'t have to do it.

But at the same time I think I really want to look toward the future.
Today the clinical variability that we have, the development model that
we have is, say, X right now. But as we go with pharmacogenomics,
pharmacogenetics where we start targeting toward a more narrowly defined
patient populations, that clinical variability may be different than
what we have today. So I think we just want to be ready for the
challenge also in the future.

DR. BOEHLERT: Gary.

DR. HOLLENBECK: Indeed, I wanted to follow up on the specifications
discussion a bit. I guess I\'d take exception with your comment earlier,
Ajaz, about the current state of things relative to specifications
because specifications have never been sufficient and meeting
specifications has never been regarded as sufficient for the agency. It
is for release of product on a routine basis, but if you make a
post-approval change, for instance, you may still be held to higher
additional requirements. So following up on Judy\'s point, that is one
of the things that this discussion really need to focus on, meaningful
specifications, whether they\'re in-process or post-process.

DR. HUSSAIN: I think that\'s an important point. That\'s the reason
we\'re calling it a drug quality system. You cannot discuss GMP without
discussing specifications. That was the point I was trying to make.

MR. FAMULARE: Going to your point of in-process specifications, how much
of that should be flexible in control of the firm in terms of optimizing
their process as opposed to a specification that\'s a market standard. I
think that goes to what Ajaz was saying about looking at least
burdensome approaches or going back to Gerry\'s remark in terms of being
able to have this life cycle type of a situation. In terms of optimizing
the process as tight as it can be, that\'s to the firm\'s benefit. To
the degree that cGMP is a minimum standard, that\'s even beyond that. So
it\'s better to look at it in that sense as opposed to ratcheting up the
\"c\" in cGMP.

DR. BOEHLERT: Tom and then G.K.

DR. LAYLOFF: I don\'t think ratcheting it up is going to improve quality
treatment, clinical outcomes. With pharmacogenomics, I\'m concerned that
if you do identify those paths, are you going to try and titrate
patients, which means that you\'ll have a multitude of dosage levels
controlled between 98 and 102, or are you going to keep the same thing
that we have now which is economies of scale where you have maybe two
dosage forms for treating the whole universe?

DR. HUSSAIN: I don\'t have any answers to that. I think we\'ll have to
wait and see how that unfolds. But the only thing we know possibly is
the variability structure that we have in the clinic could be different
from what we have today.

DR. LAYLOFF: That may require a more critical titration of the dosages,
which means that the PAT and economies of scale will not follow through.

DR. HUSSAIN: Actually the opposite. They will.

DR. LAYLOFF: Okay. They\'ll become more viable, essential.

DR. RAJU: I actually wanted to continue from where Gary left off and go
back to the question of specifications and what does it mean and what is
this whole process capability argument.

Specifications are supposed to be the voice of your customer. That\'s
what, in terms of safety and efficacy, gets translated into
specifications in your process. Those should not be changed based on
your process or your process understanding because the voice of your
customer for the bottom of the pyramid is still for safety and efficacy.
That does not change.

As you climb to the next level of the pyramid, you have a different
customer. It could be a business customer. It could be the FDA customer.
And you want to now, based on your process capability, maybe set control
limits. That could be a basis of your negotiations for your internal
customer for the business or maybe your understanding customer, maybe
the FDA. But the basic specifications should not be changed based on the
process. They can be changed but only based on what you are now learning
from the customer in phase IV or as they\'re trying out more things.

We should not be changing specifications because we\'ve been improving
our processes. Our process capability goes up. We leverage that to make
a deal with the regulator or with our business people. We should never
change the specification for anybody else but the customer.

MR. FAMULARE: So that our level of scrutiny on specifications should be
established based on the safety and efficacy and stay right there.

DR. RAJU: Yes.

MR. FAMULARE: Then in terms of process, process capability, and so
forth, that\'s in terms of ‑‑

DR. RAJU: Control limits or capabilities.

MR. FAMULARE: ‑‑ control limits, inspection, and those types of issues.

DR. BOEHLERT: Go ahead. We\'re scheduled to take a break at about 3
o\'clock, but I don\'t want to interrupt in the middle of a sequence
here.

DR. HUSSAIN: I think I agree with Joe, and I will just build on that. I
think what happens then, as the development programs emerge, your
customer voice essentially is the safety and efficacy database that sort
of defines what the broad specifications are, and they essentially
become our public standards.

Now, if you keep improving your processes to become more and more
capable, then I think the benefit comes, as G.K. said, in terms of
regulatory relief because now it\'s a low-risk situation.

DR. BOEHLERT: I think I would agree with G.K., that it\'s process
control you\'re talking about, not final specifications.

A few more and then we\'ll take our break.

DR. HOLLENBECK: I would just point out that I don\'t think our
specifications have necessarily been developed that way. I think you\'re
giving them too much credibility in many cases. They are just things
that we do. They\'re often not related to any quality attribute to the
dosage form at all. I think that\'s some of the win part of the win-win
that Ajaz talked about.

DR. RAJU: Just kind of taking off from that, that is a very key point.
If we agree ‑‑ and we should because this is a discipline that comes
from every place on the planet ‑‑ that the specifications are about the
voice of the customer, we have to now challenge our practices of how we
define our specifications in that context because I\'ve seen in many
situations when, let\'s say, we have a 6 sigma process and so we don\'t
have too many investigations, we still set our specifications to be at 3
sigma so that we always have a few investigations so that we demonstrate
that we investigate.

And I\'ve heard many cases of people coming in from their own company\'s
quality side or from the external investigators where they say that if
you have a very wide specification, that\'s not a good thing. If you\'re
very capable, it could work backwards on you.

So the key isn\'t theory. It\'s the voice of the customer and it should
not change. It should be changed based on the better understanding of
the voice of the customer.

But in practice, we have the self-fulfilling prophecy. It\'s because we
have an asymmetry in the knowledge we get from our customer because
there are so few people and so difficult to measure, that we\'ve ended
up having our specifications being set by the process which is creating
a real chicken and egg problem. I think we have to go back to the
customer and change the specifications based on the customer, and we\'ve
got to do better than that. It\'s not perfect, but we\'ve got to create
an internal business, a regulatory benefit for the next level and try to
see them separate, although it\'s very difficult in this industry, but
it\'s very difficult in most other industries too.

DR. BOEHLERT: Nozer, did you have something you wanted to do before the
break?

DR. SINGPURWALLA: I\'d rather do it because then I want to leave.

(Laughter.)

DR. BOEHLERT: Okay, by all means then.

DR. SINGPURWALLA: Ajaz gave a very nice presentation. If I was a
student, I would give him an A plus, but I\'m going to just reverse the
role now. You asked us to give individual perspectives on the
initiative.

My assessment is that your heart is in the right place and your head is
getting there.

(Laughter.)

DR. SINGPURWALLA: You covered all the technologies quite nicely and the
big challenge you asked is how to apply these things.

The second comment I want to make is that risk analysis is fundamentally
a mathematical endeavor involving fault trees, prior information, fusing
information, experimental design, eliciting expert testimonies,
probability calculations, control theory, time series analysis, and
I\'ll throw in econometrics even though I don\'t think much of
econometrics.

The question is, is this community ready to bite that particular bullet?
Are you prepared to invest the time and effort it takes to understand
this whole technology before you want to apply it? I think there\'s
going to be a process of education.

There is the question of defining quality and defining risk. Yes, we
should talk about it, but I think these matters should be dismissed very
quickly. And the risk models and management approaches and how to put
all this to work is where the challenge lies, and that is where I think
we should focus and not try to reinvent the wheel because you\'ll be an
isolated community.

Thank you.

DR. BOEHLERT: Nozer, thank you very much for your contributions today.
We really appreciate your input.

I would remind the committee that we got started on some really good
discussions here. They should not continue through the break. Hold off
on the discussions and we will continue again when we reconvene about
3:20.

(Recess.)

DR. BOEHLERT: I hope we didn\'t lose our initiative for discussion when
we took our break. Well, yes, Nozer is gone.

(Laughter.)

DR. BOEHLERT: But I think he managed to get a few last comments in. We
thank him for his participation.

I\'d like to open the discussion up further to the committee. If you
look at Ajaz\'s slide number 2, he talked about the desired state,
identify and prioritize topics for discussion, and recommend format and
background information FDA should prepare for discussion of identified
topics. I\'d like you to take a look at those and address those, if you
might.

Have we talked enough about the desired state? Ajaz, have you gotten the
information you need from us?

DR. HUSSAIN: I have but I think Gary wants to change it. No, just
kidding.

DR. HOLLENBECK: I don\'t know if I want to change anything, but let me
throw a couple of things out.

We talked a lot about risk. I guess traditionally we think about risk in
terms of the active or in terms of a therapeutic outcome. Certainly the
barometer for risk assessment in the SUPAC initiative was based on the
active. We looked at therapeutic index. We looked at solubility and
permeability.

Now in Gerry\'s slide, there is this new barometer of manufacturing
science. Are you anticipating that one will replace the other, or do you
still think there will be a preeminent emphasis on the drug?

DR. HUSSAIN: I think, in my mind at least, the systems will evolve in a
more comprehensive and systematic way. I think SUPAC looked at one piece
of the thing, and just looking at one piece of the thing, you never
achieve what you are trying to achieve. I think you have to look at it
from an entire quality systems perspective.

You raised the issue before, specifications do not tell the whole story.
I think there are dramatic examples of that. In the mechanical industry
sector, for example, Ford versus Mazda transmissions. The same
specifications and different reliability and so forth. So there is value
to that. And in a multifactorial system, just meeting specification
would mean that you might be on edges on different parts of the
different specifications, and truly in a collective way, that really
doesn\'t tell the whole story. I think that was the debate that we had
in FDAMA and the SUPAC. Specifications do not tell the whole story and
process is important. So I think you will see a merger of the two
concepts in a whole systematic way.

DR. SHEK: With regard to this bullet, specifications based on
mechanistic understanding of how formulation and process factors impact
on the product performance, I would assume there is some kind of a
situational limits. And I don\'t want to take the car example. For
performance of a car, you need, I assume, four wheels, a steering, an
engine, transmission, a battery, and if you want to stop, some brakes.
Right? But you can have a BMW or you can have another car. Now, both of
them are going to bring you from A to B and function. If you are
developing two products maybe for the same purpose but being made in two
different processes, you might come out with different relationships.
The question is where do you stop, and is one of them being chosen or
both of them can be used for specification justification?

DR. HUSSAIN: From an FDA perspective, I think what we do is we define
the minimal standards, whether it\'s the CMC review or GMP. These are
the minimal standards. If something is acceptable from that perspective,
and essentially the determination is this is safe and efficacious for
use, that\'s what it is.

If you use the analogy for a car, in that analogy it\'s actually easier
to determine whether one is better than the other or not. We can look at
how many times the car has to be in the shop and this and that and so
forth, but in a clinical setting that\'s not easy. So the safety and
efficacy is the starting point and that\'s the foundation on which you
have to base that. Then I think the manufacturing process provides a
means for minimizing the risk of poor process quality, and I think
that\'s the angle that we wanted to bring in.

DR. SHEK: But what will be the standard for this product? We talked at
the break about the evolution of technology and capabilities. We talked
about analytical areas. You have the factors and you had columns and one
drove the other with regard to sensitivity, and to some extent I believe
and I hope that we will see those and the manufacturing sciences will
have tools today that they can measure something. And the limit will be
the tools that we can measure, and then we\'ll have a process, I would
assume, which will now overpass the detection system that we have. The
question is, in this case will the safety and efficacy will be the
baseline or if I\'m improving on my product, will that not become the
standard for other products?

DR. HUSSAIN: I\'m not sure I got that.

DR. LAYLOFF: I wanted to go back to what G.K. said. The client is the
patient and safety and efficacy is all there is. Now, I don\'t think any
company would use 90 to 110 as a release specification, would they? If
you intend for your product, throughout the course of its life cycle, to
meet 90 to 110, if you release at 90 to 110, you\'re asking for trouble.
So your release should be significantly better than that so that your
product throughout the life cycle or any group of 10 tablets will meet
that 90 to 110, which means statistically you have to be narrower than
that.

DR. SHEK: Yes, I\'m not talking about the 90 to 110. I\'m having 95 to
105, and then I can find that I can make 97 to 103. It\'s to some extent
what Gerry was talking about, the life cycle. Now, where will be the
standard for this product? Do we always go back and say if 90 to 110
satisfied them ‑‑

DR. HUSSAIN: I think you\'re missing the point here. The point simply is
that as an approval decision, we said that suppose the specification
that was the basis for approval was 90 to 110 and that will then throw
to exactly what Tom said, is if you don\'t meet that, you recall that or
you don\'t release that batch. But to manufacture that in a consistent,
reliable, reproducible way, you cannot have that as your release
specification. Some companies may have much more variability and may be
prone to more failures. Therefore, the variability would be a reason to
consider them high risk. Companies which meet a much finer one as an
internal one would be low risk. That\'s the way we look at it.

DR. DeLUCA: I guess I have a little problem with this. If at 90 to 110
percent you have a safe and efficacious product, I don\'t think meeting
a pharmacological outcome should deter one from trying to improve the
product from a manufacturing standpoint. That shouldn\'t be the end.
We\'ve accomplished a pharmacological effect. We don\'t have to improve
the product any more.

I think we should be striving to make improvements in the product. And
it seems to me, from the standpoint of specifications, those
specifications should be what the process is able to provide. If 90 to
110 percent is fine pharmacologically, that doesn\'t mean if you\'re
capable of producing that at 98 to 102, that you should have 90 to 110
as your spec. I think your spec should be tighter.

DR. LAYLOFF: I disagree with that, and I hate to end up on this fence.
When we get to that curve that Gerry talked about, if you keep improving
the quality, you can continue to, but the investment doesn\'t improve
the quality of the product in terms of therapeutic effect. So you\'re
really not improving the product in terms of the patient application.
You\'re intellectually improving it, which is increasing the cost which
is reducing availability, and I think that\'s a critical factor. You can
talk about purifying a drug substance down to 99.999 for your mass
production, but you drive the cost up, and you don\'t improve the
therapeutic outcome. Now, is it useful to drive up the quality of
product and cost without an improved therapeutic outcome? And I don\'t
think it\'s valid.

DR. DeLUCA: How do you know you haven\'t improved the therapeutic
outcome?

DR. LAYLOFF: Because you established that in the clinical studies.

DR. DeLUCA: Yes, but you may improve a process ‑‑ there may be things
that you haven\'t tested. There are a lot of products on the market that
after five-six years, they find things wrong with them.

DR. LAYLOFF: Right.

DR. DeLUCA: Okay, then why didn\'t they find it out in the clinical
testing? They found it out after a lot of use. I\'m not saying there are
no benefits pharmacologically. What I\'m saying is that once you have
achieved the pharmacological outcome, that shouldn\'t be a deterrent to
not to improve the process from a manufacturing standpoint.

DR. LAYLOFF: I think you should improve the process to reduce well-time,
to reduce cost, because reduced cost is improved availability. I think
that\'s the only rationale for doing it. You\'re reducing costs of
manufacture which improves availability, which I think is important.

DR. BOEHLERT: I would add there are other reasons to improve the process
as well and those are if you\'re getting OOS, out-of-spec, results or
aberrant out-of-trend results and things of this sort, you\'re wasting a
lot of time on investigations, where if you improve the process, you
would save that time, reduce cycle times because investigations drive up
cycle times tremendously. While you still have that same specification
limit, you\'ve reduced the variability in your process.

DR. LAYLOFF: You\'ve reduced the cost of production.

DR. BOEHLERT: Absolutely, yes.

DR. LAYLOFF: And I think that\'s a very worthwhile endeavor.

DR. BOEHLERT: So there are lots of reasons to improve the process
without changing the specifications or having an impact on changing.

DR. PECK: There are still those items, however ‑‑ not many of them ‑‑
that have narrow therapeutic windows, and I think we always have to be
attentive to that particular situation. Some people have tried to forget
that. Many of them are low-dose drugs. Now the process becomes extremely
important as far as those particular drug substances. And we are
concerned about the patient, the customer that we are dealing with. So
we can\'t forget that.

The other thing is the interchangeability. I will pick out one
particular device, a mixer. We have specifications on products, but I
think we need to look closer at some of our devices to see where they
fit in in our particular process. That can be significant also.

DR. BOEHLERT: I think there are also products that have many different
strengths within the product line to the point where if your
specifications are too wide, they actually overlap, so that in fact you
could release two different strengths at the same number and be within
specifications. But I don\'t know what the answer to that is.

DR. HUSSAIN: I think this has been a very valuable discussion sort of
building on what Pat talked about. One of the challenges and one of the
reasons why this industry, especially in the manufacturing sector, has
become stagnant is that thought process in terms of if you improve, the
only option is you get tighter and tighter and tighter specifications.
And that actually is a big hurdle for continuous improvement in this.

Now, I think that itself is a major topic for discussion. I\'m not sure
that is for this committee. I think it\'s more for the clinical folks.
We have to have that discussion.

But the point here is this. If you talk about science-based
specification setting, now what is the most logical way of looking at
that? We have humongous clinical trials that are designed to essentially
establish safety and efficacy. Yes, they will not cover every patient
population, and yes, they will not cover every patient. But that is the
standard today.

So if we approach specification setting saying that if you improve your
process, you have to tighten the specification, first of all, there\'s
no incentive for doing that. Secondly, what is the scientific basis for
that? Yes, tightening is better, but on what basis is it better? Because
I think just the variability and the time of how you take the drugs and
so forth really defeats that purpose.

I think we really need to think about that very carefully because I
think in principle what we say is the tighter the specification, the
better. I agree with that, but the question comes back to on what basis.

I also have referred to an encounter I had with our traditional
specification. I was at a meeting in Tennessee and giving a lecture. I
said if the content uniformity is 85 to 115, and they just started the
stage one, and somebody from the audience came up. He was in the paint
industry. He said, you mean to tell me it\'s 85 to 115? Our formulations
are far more complex. We have a tolerance of 1 to 1.5 percent. So I just
kept my mouth shut.

(Laughter.)

DR. HUSSAIN: But again, the intended use is what comes back. When you
have a paint, visually you can distinguish whether the content is more
than 2 percent off. So there is a requirement for the intended use. You
really need to have that. I think, yes, for intended use we need to
define that. If it\'s a narrow therapeutic index drug, the specification
setting at the approval process should account for that and it sort of
needs to define that at that point.

DR. LAYLOFF: I think also you\'re looking at comparing quality in
suspensions as compared to heterogeneous compressed solids.

DR. HUSSAIN: Suspensions are more complex.

DR. LAYLOFF: Not when you have to stir before you use them.

DR. HUSSAIN: Judy, let me go back to Efraim, sort of reflecting back.
What do I mean by mechanistic basis for establishment of specifications?
Let me build sort of an example on that. And I\'ll take a very simple
example of an ICH Q6A decision tree and how do you set specifications
for dissolution.

Now, for an immediate release dosage form, as you look at what are the
acceptance criteria that you define, one of the questions is, is the
drug highly soluble? If the answer is yes, then the question that is
being asked is, is the dosage form rapidly dissolving? If the answer is
yes, the ICH Q6A decision tree allows you to move toward a
disintegration test as a means for that when you establish a
relationship disintegration and dissolution.

I have a fundamental problem with that because you\'re comparing two
different test methods, but the principle I think is right. If you know
what the mechanism is ‑‑ for example, in your studies you have
documented that dissolution is not rate limiting. You have a related
bioavailability study that shows solution and tablets are essentially
superimposable in the blood-concentration time curve, so dissolution is
not rate limiting. So why would we want to set a dissolution
specification is a logical question to ask. And we don\'t ask that
question today.

So that\'s what I think is an example of getting to the mechanistic
basis of what is the mechanism of absorption. Is it rate limiting? Is
dissolution becoming rate limiting? I think we need to get that
discussion going before we automatically say we need a dissolution
specification or not. That\'s what I was trying to say.

DR. BOEHLERT: Other comments? I would just add to the dissolution, it
also has to be a meaningful dissolution test. I\'ve seen dissolution
tests imposed. You must have a dissolution test even if it\'s in 0.1 N
sodium hydroxide, which at least one is. And I\'m not sure what the
relevance of that is, but it\'s the only thing that dissolves the drug,
so there\'s a dissolution test.

DR. LAYLOFF: That\'s for caterpillars. Caterpillars have a very basic
gut.

DR. BOEHLERT: Oh, now I understand.

(Laughter.)

DR. BOEHLERT: Other discussion comments?

DR. LAYLOFF: I\'ll put a hypothetical here. I think one of the things
that you\'re trying to accomplish is to encourage the industry to use
new equipment. Right now I think you can legitimately argue there are
disincentives to doing that.

So are you envisioning a situation where I could replace a mixer or
maybe a whole series of unit operations with a new \"phenozerator\" that
does all of these things and I can take out my old stuff and plug this
thing in and whatever in-process controls I have in place will be
sufficient to determine whether the process has changed the outcome?

DR. HUSSAIN: No. I think you have to look at it from this perspective.
Let\'s stay with immediate-release conventional tablets as an example.

Now, let me step back before I answer your question. One of the products
I did, after we had completed the University of Maryland research
project, for example, is to take the University of Maryland database on
the formulation changes that we had and so forth for the six different
drugs that we had. I said, now that I have a designed experiment here, I
know what is critical and so forth. Can I use that to learn and predict
what the behavior of submission data is? I think we actually did this
study.

So, for example, for metoprolol tablets, the experimental formulation
that we had at the University of Maryland and the scale-up and all that,
we used that data and developed a model to predict the dissolution
behavior of data in our submissions. So we have about 9 or 10 generic
formulations and innovator formulations. We had about 11. So we could
actually predict nine of them on the dot. Two of them we could not
predict well.

But what that told me was you have slightly different compositions,
different unit operations. Literally everything is different in these
formulations. Yet, I think all are bioavailable, all meet the shelf
life, and dissolution was sort of a signal. So essentially the system
works in the sense you can have big differences in formulation and
processes, yet you can have the same safe and effective product. That\'s
essentially what it is.

Now, each of those formulations came about from different starting
points. So it is quite possible to come up with a safe and efficacious
product from different ways that is bioavailable, that meets the shelf
life and so forth.

Now, if you have process understanding and so forth, how do these
factors affect my shelf life or stability and bioavailability? So if you
know what the factors are and how they impact, then changes should be
easier to manage. That\'s what I was trying to get at.

DR. HOLLENBECK: I guess my point is, how do you have process information
on a process you\'ve never used before or one that didn\'t even exist
when you were developing your product? And the reason to ask that
question is if there\'s no way to do this, if there\'s no way to
substitute in your new piece of equipment without invoking the existing
strategy, then why do it?

DR. HUSSAIN: I think it would be ludicrous to do something without
knowing what you\'re doing.

DR. HOLLENBECK: Well, that gets back to my original question.

DR. LAYLOFF: But we\'ve always held as an anchor like the pivotal lot.
That\'s been sort of the anchor that you hang onto. The content
uniformity, the assay, the dissolution of the pivotal lot is what you
hang all the safety and efficacy data on. You say anything that you do
you come back to that, which is why you say dissolution is important
because it relates you back to the pivotal lot.

Now, if you want to change that, then you have to go back and redo the
pivotal lot, and I don\'t think that\'s reasonable. I think you can
change production, but you relate everything back to the performance of
that pivotal lot. So you define it very carefully so you have that
anchor on which to hang changes. Otherwise, you end up in a safety and
efficacy study again.

DR. HUSSAIN: I\'m losing track. I\'ve lost the chain of thought here.
I\'m not sure what the discussion ‑‑

DR. HOLLENBECK: You\'re probably not the only one.

(Laughter.)

DR. HOLLENBECK: I think Tom is referring to post-process testing. The
pivotal lot is characterized primarily by a dissolution test. We\'re
envisioning a new era. Products are released by in-process testing. My
question is, I\'ve got a brand new piece of equipment that will do
multiple unit operations. I want to plug it in because I want better
products, I want to do all the things that you want me to do. Yet, as I
understand it, I\'ll still have to do a biostudy or something to prove
that I have equivalence.

DR. HUSSAIN: Well, I think if it\'s a black box, in the current paradigm
I think the answer is yes because we don\'t know what the system will
behave like and so forth.

But, for example, if you can imagine a future where we have understood
the attributes of in-process materials as it relates to, say, end
product performance. To accomplish that, you will have to move away from
the current types of controls to process endpoints. For example, you
will blend until it\'s homogeneous, so you have an acceptance criteria
which is independent of ‑‑ it defines the acceptable variability in the
blend itself. Then if you have to granulate, you\'ll granulate to a size
and porosity of something that actually reestablishes similarity to
dissolutions. So you\'ll have to move in that. We\'re not there yet, but
that\'s what will need to happen to get to that stage.

DR. HOLLENBECK: And that\'s exactly the answer I wanted to hear. That\'s
quite a change from the agency\'s perspective because I recall process
being a critical consideration during SUPAC. We\'ve had that whole table
full of excipient changes, often large percentages, but a minor change
in a process really sort of caused concern. So that ought to be one of
the working groups here really focusing on those in-process tests that
can identify the attributes that you want of a blend of a granulation
and of a tablet independent of how they were made.

DR. HUSSAIN: I agree, but I think reflecting back on that experience,
since that was my start of my career at FDA and working with you guys,
my read was one of the things that created that discussion and ‑‑ the
concern was lack of process understanding within the agency, especially
in the review chemists because they really did not have that information
to evaluate and so forth. So that was a complete black box to them. So a
minor change might have a dramatic effect. That was the concern that was
coming out again and again.

So in this paradigm, I think from a systems perspective, you really have
to bring that information into the decision making process. Then only we
can move forward. Otherwise the same system will continue.

MR. FAMULARE: So you would take the most ‑‑ I don\'t want to use the
word \"onerous\" but the most conservative approach based on your lack
of knowledge. So it goes back to the slide that Gerry presented, aside
from the defects that were pointed out about it.

(Laughter.)

MR. FAMULARE: But if you go back to that slide, as you increase your
knowledge, the amount of information that you would need to file would
be less. Again, the real basis would be, on a risk-based, the safety and
efficacy data.

DR. HUSSAIN: Right.

I think just to sort of build an example here, we just completed a
study, but I think we wanted to look at magnesium stearate as an
example. If you recall the SUPAC ‑‑ I don\'t think I can recall the
exact percentage number, but at level 2, component and composition
change, I think a .2 percent change in magnesium stearate is a level 2
change. Maybe that\'s not the exact number. Now, we did not allow that
change to occur for narrow therapeutic index drugs. We did not allow
that change to occur for class 4 drugs, say, for furosemide, BCS class 4
drugs.

Now, we know magnesium stearate is important for dissolution and other
things, and we have known that for 35 years. We actually have known the
mechanism of how that thing happens for a long time.

But at the same time, what I would argue is there are formulation
strategies that can negate completely the undesirable effects of
magnesium stearate. In certain formulations, you can formulate the
product to be so robust that it will not be affected by how much mixing
you do and if you have more magnesium stearate or not. Today we do not
recognize that science at all in our decision making.

So that\'s what I want to say because at least in 1977 we knew this,
that if you include about .01 percent of sodium lauryl sulfate, you can
actually overcome the hydrophobic nature of magnesium stearate on
dissolution. But we don\'t use that knowledge today in decision making.
We say magnesium stearate was implicated in dissolution failure, so it
is applicable across the board. So that\'s the example I wanted to show.

DR. DeLUCA: I guess what you\'re talking about, though, was you\'re
doing mechanistic studies here and moving up the pyramid there or up the
scale in Gerry\'s. So you\'re gaining knowledge to make those processing
changes, and I see that.

I guess what I understood Gary to say here is without gaining any
knowledge, just putting in a new piece of equipment and getting the same
thing, if you then meet the same specs that you\'ve set with that new
piece of equipment, doesn\'t that fall into here, what Helen pointed out
in one of her slides, changes without prior approval?

DR. HUSSAIN: Right. But I think that becomes a basis ‑‑ and you\'ll hear
about it tomorrow ‑‑ of a comparability protocol that defines and that
shares the knowledge. In the absence of that knowledge, there\'s no
change in our system. You have a prior approval supplement. You probably
have a biostudy. You have three batches of stability. Without that
knowledge, we\'re not changing. That\'s it.

DR. BOEHLERT: Other comments? Gentlemen on this side who have been
quiet, no comments? Not right now. That\'s fine.

Efraim.

DR. SHEK: I don\'t know whether we got stuck on specifications, but we
are talking now about knowledge and it came across quite a few times.
And that\'s also connected to the development of pharmaceutics. We are
talking about we are transferring ‑‑ we assumed the industry or the
applicant is transferring a regulatory document, but at the same time we
are trying to transfer knowledge. It\'s very similar maybe to technology
transfer. It\'s not only the tech transfer. You have to transfer the
knowledge that you gain for somebody who is going to use it.

Maybe that goes a little bit back to the stick and carrot I was talking
about in the morning because that can become another, let\'s say,
regulatory hurdle because it\'s more information where the dilemma will
not be transferring knowledge, but arguing whether it was done the right
way. And then we\'ll have different perspectives. At least from my part,
it would be nice if we have a system. This is a transfer of knowledge.
That\'s an explanation, a rationale for how this product was developed.
And that should help. It shouldn\'t prevent. And the question is how we
will build a system, at least from perspective ‑‑

DR. HUSSAIN: That\'s the reason we have advisory committees, to seek
advice.

(Laughter.)

DR. SHEK: So my advice is use it as a knowledge transfer not as a
regulatory hurdle.

DR. HUSSAIN: But what we will do is, when we bring the topic up for
discussion, clearly we\'ll come up with a proposal and we\'ll seek your
advice and input on how to do that. But I think I have learned through
the PAT process is the \"don\'t use/don\'t tell\" approach. In a sense
this is the \"don\'t tell\" approach. If there\'s anything I have
learned from the PAT experience, right now I\'m scrambling to get the
team together because the flow of submissions have started coming in
before we even have a guidance.

So I think the question of trust and so forth essentially is if you
don\'t require this and if we can simply focus our discussion on
science, these things get resolved. That\'s the way I\'m thinking right
now.

But the reason for the advisory committee is to seek your advice and
input on those critical questions that you are asking me today.

DR. BOEHLERT: Ajaz, have we addressed the issues that you need us to
address today, or is there something that we haven\'t touched on that
you would like us to?

DR. HUSSAIN: Maybe for the next three or four meetings that we will have
with you, I think there are key topics that we would like to bring to
you. David\'s group is getting ready with a potential discussion on
risk, quality, and so forth, but I think that has to be approached by
every working group. That needs to be honed in, defined, and at least
build consensus on the words we use to describe this so that the rest of
the discussion can happen more smoothly. So the first topic probably for
the subcommittee discussion could be terminology or whatever you want to
call that, defining what we mean by quality, risk management, and so
forth. It would be one of the first topics that we discuss with you.

Then following that I think there are a number of things we really need
to seek your help on. Process understanding. What is the level of
process understanding and how do we link it to risk or what are the
metrics for process understanding? Is process capability a metric for
process understanding? All those things.

So what I have done for you is listed some of those topics that we are
actually discussing internally and working on and wanted your sense of
what is the right sequence of discussion topics from your perspective
and how do we structure that discussion that will be more effective from
your perspective. If we can get that feedback, I would appreciate that.

DR. BOEHLERT: Feedback?

DR. HOLLENBECK: Well, I\'d give you feedback on page 5 of your handout,
the desired state slide. You asked what the committee thought of that.
As a member of the committee, I like that. I think that\'s a well-stated
objective.

DR. BOEHLERT: Other comments or thoughts?

MR. PHILLIPS: I just have a question. On page 5, the first slide on page
5, product quality and performance. Was there a reason we left product
quality and safety off?

DR. HUSSAIN: Quality is the foundation for safety.

MR. PHILLIPS: I think it is.

DR. HUSSAIN: That\'s the way to interpret that.

MR. PHILLIPS: I don\'t see a problem with it. I would probably add it
in.

DR. HUSSAIN: Because the way I approach this is in a sense if you don\'t
have quality, you cannot make safety and efficacy decisions. That\'s the
foundation you have to build on.

DR. BOEHLERT: Was somebody else going to make a point?

MR. PHILLIPS: Aside from that, I like those slides on page 5.

DR. BOEHLERT: I think what you\'re hearing is lack of disagreement with
what you presented.

DR. HUSSAIN: So the point is proven. It is a shared vision.

DR. BOEHLERT: This has been a very interactive group and suddenly
they\'ve run out of anything new.

DR. HUSSAIN: If the committee would go through the list of topics and
the sequence, if we can agree on the sequence of discussion. I don\'t
promise that we\'ll bring all of them to this.

DR. BOEHLERT: Is that page 6?

DR. HUSSAIN: Starting on page 6. And if we identify the topics for the
next meeting, keeping in mind you have tomorrow\'s discussion that will
discuss change and so forth, if you could help us how you would like us
to prepare in terms of what type of background information would be
helpful for you, how should we structure the discussion.

I heard this morning a model which seems attractive to me. I don\'t have
that information. G.K. mentioned that. Nozer mentioned that. That was
the DOD approach. If we could get some discussion on that, would that be
a framework for maybe a subsequent discussion? If we could get some
input on all those aspects and topics that we may not have listed and
you think would be important for discussion.

DR. BOEHLERT: Any comments from committee members?

DR. DeLUCA: On that first, the definition of quality and risk, we
started talking about risk. We talked about risk quite a bit this
morning and used a definition of it. When we talk about risk, just
focusing on loss of safety, efficacy, and economics? How far do we go on
that?

MR. HOROWITZ: That\'s the question. What is the harm or what is the loss
that we want to focus on? Depending on how we define that, I think it
will have very different applications. Our preliminary thinking on this
and the emerging consensus seems to be that the focus seems to be
emerging on safety and effectiveness and reductions in quality of the
drug that impact safety and effectiveness.

Now, that doesn\'t mean that there aren\'t other reasons, other
customers, and other objectives to further improve and tighten up
quality. But for our regulatory purposes, our definition of quality
might be different than the definition that\'s used inside the
manufacturing facility where they\'re thinking not just about the safety
and effectiveness of the drug, but they\'re also thinking about how to
most efficiently manufacture the product. And they may want, for
example, a margin of safety. Maybe that\'s not the right word. A margin
that would ensure consistency that would be even greater than we would
want for safety and effectiveness considerations.

But I think that\'s what we want to come back to the group with. We want
to do some more thinking. We want you to hear what Gregg Claycamp has to
say tomorrow about applying risk concepts and come back with a more
detailed and thorough discussion on the subject. But, of course, we\'re
interested in preliminary thoughts that you may have today as well.

DR. DeLUCA: These risks could be perceived as well as real, and the only
way you know that they\'re real is you have to do some investigation. So
the question is do you proceed to try to reduce these or prevent these
things without that kind of information. You just perceive that there\'s
going to be a loss of safety or efficacy, and you proceed on that basis
with trying to reduce the perceived risk. These are questions too.

DR. BOEHLERT: And I think it came out of the discussion earlier today
that the application of that risk is what we need to focus on, not
necessarily the definition, because those are fairly well known, but
just how was that going to be applied. I think that\'s something ‑‑ I\'m
not speaking for the committee ‑‑ that we\'re all interested in. I see
nods.

DR. HUSSAIN: There\'s a classical dichotomy in terms of setting
specifications. When we say quality is the foundation to make safety and
efficacy decisions, then if it\'s safety and efficacy that defines
specifications, that\'s the circular argument that we often get into.

I think the process by which a company develops the clinical trial
material ‑‑ because keep in mind they\'re investing significant
resources in doing the pivotal clinical trials and so forth ‑‑ the
design aspect, knowing the drug, knowing the intended purpose, knowing
the intended population, the thought process that goes into designing
your clinical trial material that yields the safety and efficacy
database, I think that sequence of thought is often not considered when
we set specifications internally. I think that is an important point
that we need to probably discuss also.

DR. BOEHLERT: You said something with regard to safety and efficacy, and
safety and efficacy in setting specifications is not always the issue.
Very often it\'s not. If you set limits on impurities, for example, they
may be more based on process capability and what you actually see rather
than on safety. You may be able to demonstrate that 5 percent is safe,
but if you only find .2 percent, you\'re not likely to set a spec at 5.
So there are a number of issues here that need to be considered. So we
need to be careful in defining something in a manner that may not apply.

DR. HUSSAIN: Within the context of SUPAC ‑‑ tomorrow in my presentation
I have some slides on risk management, the SUPAC model sort of a thing.
There I think the risk that we define is risk to quality in terms of
having a different shelf life after a change or having a different
bioavailability. So the SUPAC structure was designed to minimize those
risks so that we assure the same shelf life or better shelf life and
bioequivalence between pre- and post-change models. And we use that as a
model for SUPAC. So the criteria there essentially then became the
bioequivalence standards, 80 to 125, and then the shelf life itself
became the decision making point.

DR. BOEHLERT: But a change in the shelf life is not necessarily bad.
That\'s a business decision perhaps. You don\'t want one that\'s six
months, but whether it\'s three years or four years may not matter.

DR. HUSSAIN: No. But the shelf life reflected on the label should be
accurate. That becomes the basis for that.

DR. BOEHLERT: Yes.

DR. HOLLENBECK: I guess I\'m looking at the third bullet now, the
manufacturing science and process understanding. I\'ve sort of been
reflecting on the catch 22 that we always have in these situations. The
repository of this information is in the industry, and justifiably, if
you\'ve invested in better processes and better understanding, it gives
you a competitive advantage that you may not want to share with the
world. How are we going to get this information in the public domain so
that there can be a broader way to take advantage of it?

DR. HUSSAIN: Well, I don\'t have a solution for public domain, but I do
have a solution for utilizing that information effectively at least for
that company. The SUPAC guidance, for example, had to be very broad,
somewhat superficial in terms of what we could do because we could not
get deep into each product and each formulation type and so forth. But
the comparability protocol or \"make your own SUPAC\" concept allows a
company, if it has this information and knowledge, to share and take
advantage of that in a private way, but it does not bring that into the
public domain. That is sort of a different challenge probably not within
the scope of what we are doing here. I think we need to take that up in
a consortium type of a scenario.

DR. BOEHLERT: Tom, you look like you\'re about to say something.

DR. LAYLOFF: I was. I was thinking about what Gary said about
substituting a blender in maybe some functional process. I was wondering
if that is a significant issue for a heterogeneous solid state
compression on the same scale as changing an excipient by plus or minus
20 percent. I don\'t think so. I think allowing a change of plus or
minus 20 percent is far more drastic than changing a blender or
something else along the stream in terms of product quality issues, and
they allow that.

DR. DeLUCA: But you could probably run some tests, Tom, pretty quickly
that would give you a better feel for that too to get some information.

DR. SHEK: You will be surprised about the efficiency of different mixers
or granulators and a plus/minus 20 percent of excipients might be
minimal. But there should be a way to test for it because what you do,
you just show that the product that you get is the same product. You
might have to change your parameters that you\'re using, and that\'s
basically one of the issues that we are struggling with. As you scale up
and so on, you are switching, there are differences. But again, if we
know how to test it, whether it\'s the PAT or another one, I think that
becomes, to my understanding, a nonissue.

DR. LAYLOFF: I think PAT is a way of assessing homogeneity. You\'re
looking at homogeneity of process, and if you change blenders or
whatever, you\'re still going to be assessing homogeneity, and I think
homogeneity is a reasonable endpoint, but I think again a 20 percent
change in excipients is a more startling thing to do to a product.

DR. BOEHLERT: Aren\'t the PAT concepts also being used to test for
performance parameters, to look at those functions of the product that
will impact performance using acoustical technologies and things that we
don\'t use today? So it\'s possible that a technique like that might be
able to tell you that if you changed to this blender and eliminate a
whole number unit steps, you do preserve the integrity of the product.

DR. PECK: I think PAT is going to be the answer to our ability to change
certain pieces of processing equipment. We\'ve demonstrated this
already, and we feel strongly about it. I think that\'s going to be our
key to more flexibility in processing.

DR. BOEHLERT: Joe?

MR. PHILLIPS: I just want to comment on the change of equipment. We were
faced with this same challenge when we first got into the SUPAC domain.
FDA came out with a statement that if you use a similar piece of
equipment, you got certain regulatory relief in the filings.

The first thing FDA had to do was define what is similar. I think they
had something like 250 questions in the first week, what is similar? We
ultimately went to ISPE, the International Society of Pharmaceutical
Engineers, and said, can you make us a list of what is similar
equipment? Can you tell us a blender is a blender is a blender? And they
took that upon themselves, on a volunteer basis, put about 60 engineers
on the project, and in a matter of a few months, came up with a list,
which is now FDA\'s list of similar equipment.

And it was based on two principles: engineering design and operating
principle. If it had the same in those two cases, then it was a similar
piece of equipment. If it was a different operating design, it was
different and it fell out of the SUPAC domain. It had to be considered
in other domains.

DR. HUSSAIN: I think the SUPAC development experience was very valuable,
let me put it that way. The equipment addendum was actually an
afterthought. We scrambled to get that done.

But at the same time, I think the challenge that we face in the future
is very different. To give you an example on that list, we do not
distinguish encapsulator machines, all in the same category. Now, you go
from a Zanasi to a Genkay ‑‑ this is the Ph.D. thesis at the University
of Maryland, and we just looked at that ‑‑ then the challenges come. One
is a dosing disc, one is a dosator type. I think you run into an
interaction between formulations and so forth. It\'s not as
straightforward.

I think SUPAC worked from one perspective as a broad general guidance.
In the future, what you\'re looking at, if you want to recognize the
level of science, it cannot be a general guidance. It cannot be a
general SUPAC and so forth. The guidance would be more principles rather
than if this it, do this. So I think that\'s the model we have to move
towards.

Now, that opens the challenge of consistency. Keep in mind one of the
driving forces for SUPAC was consistency across review divisions, but as
we go towards more science-based principles-driven guidance, the
challenge would be maintaining consistency, and that has to come in
through training, certification programs, and so forth.

So we didn\'t have training and certification programs from that
perspective for SUPAC. It was getting the consistency done. We did that.
Now the next evolution in this process is more science-based that the
company can bring different levels of science to justify different
changes, so it\'s a custom SUPAC, and the consistency will have to come
from the ability of our inspectors and our reviewers to recognize and do
good scientific assessment of that information. So you\'re looking at
those two principles coming in.

DR. PECK: There are individuals currently who are trying to model
certain unit operations, and there have been some encouraging results
about the modeling and trying to associate either the mechanistic part
of the process and then also relating sort of in-process controls that
are necessary for it. We\'re seeing this bit of light on modeling of
processing in the pharmaceutical field. Others have done it and it\'s
time that we took a look at this approach to process evaluation.

DR. GOLD: Ajaz, one of the things I\'ve been wrestling with this
afternoon is the issue you just raised, and that is, in the past we\'ve
given our reviewers very defined guidance or guidelines, if you will.
SUPAC is very clear, what\'s permitted and what\'s not permitted.

For years I\'ve heard complaints from regulatory people about
inconsistency in the review divisions. Different divisions have
different standards and information requirements are very differently
accepted by the different divisions.

Now, if we get into a one type of affair where information is provided
by a company and saying we have sufficient knowledge, the reviewer has
to agree or not agree that it is sufficient, and this poses a new burden
on the review division. And I don\'t know how we can cope with that
because we haven\'t been able to cope, apparently, with the differences
that already exist.

DR. HUSSAIN: That is a very good point, and I think that\'s the
challenge that we do not underestimate. We actually recognize that quite
well. Let me share the background.

As we started the PAT process, this was one of the challenges, and quite
early in the process we decided that we will have a team approach to
this and the team will be trained and certified. So the PAT-based
submissions that will come in will not got to any person randomly or the
way we assign it. It only goes to the team which is trained and
certified.

Now, we had the luxury at least from the perspective we anticipated
submissions coming, so we had time to train ourselves and the team and
be ready for that. In fact, we have to hurry up now because the
submissions are coming faster than we anticipated. But we\'ll be ready
for that. But that\'s a small sector.

Now, if this is successful, we have two options. One is to ramp up and
train the rest of the staff quickly to be ready for that. At the same
time, we have strategically hired some other individuals with the right
expertise to be part of this team. Training/certification only takes you
to a certain level. Having the right experience, having the right
technical know-how from the start is also critical. So we have a
strategic hiring program where we\'re actually aiming for chemical
engineers. We\'re aiming for industrial pharmacy types. So that\'s sort
of a two-pronged attack to that.

Now as we move forward in this initiative, you will see a transition
whereby we have already announced a quality system approach to the
review process. Now, science- and risk-based approaches to review have
to come in. In a quality system approach, one of the components could be
a scientific peer-review process. So that\'s brings in a level of
consistency.

So I think we are looking at a different number of mechanisms to bring
not only the scientific level up through training, hiring the right
people, quality systems for review, and actually move towards a
continuous learning concept within the system. But we\'re doing that not
by saying we have to change the system. This system is functioning. We
have created a new system for PAT. It\'s a small one and we\'ll learn
from that and move into a continuous improvement model without
disrupting the current system. That\'s an evolutionary process.

DR. GOLD: Ajaz, I hear you and it sounds great. I think we better be
certain we have dispute resolution in place before we try it.

(Laughter.)

DR. BOEHLERT: We\'re winding down as far as our time. Are there last
comments from members of the committee? This is your opportunity.

DR. RAJU: Since the word manufacturing science and process understanding
has come up so many times ‑‑ and there is an absolute nature to it ‑‑ I
think it makes sense to have a general putting on paper of some of its
components and then a more specific set of specific circumstances in
which it applies that might be similar to SUPAC. SUPAC is more of a
level 1 or level 2 kind of a situation, but I think we have to have a
framework piece done. Otherwise, we\'ll have another level 2-and-a-half
piece, and we\'re going to all fight one by one with data and
information.

So I think it makes sense to have an overall framework piece around what
is process understanding, its dimensions, its characteristics, and how
might you measure it. And then with that kind of backbone structure, we
can have individual pieces based on equipment or technology and changes
that has a regulatory context to it.

Now, the question then is, if that\'s the case, who should write it? And
it should be broad enough and it should be general enough and it should
be objective enough and neutral enough. I think it would make sense that
there would be that general framework and then the specific pieces, like
a hub and spoke or something like that. That\'s my thought based on what
I heard today.

DR. BOEHLERT: Others? Going, going, gone. This is your last chance. I
think it\'s the end of the day and folks are ready to call it a day.

Ajaz, any last comments?

DR. HUSSAIN: No.

DR. BOEHLERT: If not, we will close the meeting. Meeting is adjourned.
Thank you all.

(Whereupon, at 4:22 p.m., the subcommittee was recessed, to reconvene at
8:30 a.m., Thursday, May 22, 2003.)