1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

PROCESS ANALYTICAL TECHNOLOGIES SUBCOMMITTEE

OF THE

ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

Tuesday, February 26, 2002

8:00 a.m.

Holiday Inn Gaithersburg

Two Montgomery Village Avenue

Gaithersburg, Maryland

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PARTICIPANTS

Thomas Layloff, Ph.D., Acting Chairperson

Kathleen Reedy, Executive Secretary

MEMBERS

Gloria L. Anderson, Ph.D.

Joseph Bloom, Ph.D.

Judy P. Boehlert, Ph.D.

Arthur H. Kibbe, Ph.D.

SGE CONSULTANT

Melvin V. Koch, Ph.D.

GOVERNMENT PARTICIPANT

William F. Koch, Ph.D.

OTHER GUESTS/SPEAKERS PARTICIPANTS

Thomas J. Hale

Leon Lachman, Ph.D.

Kenneth R. Morris, Ph.D.

G.K. Raju, Ph.D.

Eva M. Sevick-Muraca, Ph.D.

INDUSTRY GUESTS/PARTICIPANTS

Robert S. Chisholm

Rick E. Cooley

Doug Dean, Ph.D.

Steve Hammond

John C. James, Ph.D.

Ronald W. Miller, Ph.D.

David Richard Rudd, Ph.D.

John G. Shabushnig, Ph.D.

Leon Shargel, Ph.D., R.Ph.

Efraim Shek, Ph.D.

Jozef H.M.T. Timmermans, Ph.D.

Judy Wong, M.S.

Jerome (Jerry) Workman, Jr.

FDA

Yuan-yuan Chiu, Ph.D. (Sessions I, II, IV)

Douglas I. Ellsworth (Sessions I, III)

Joseph Famulare (Sessions II, III)

Ajaz S. Hussain, Ph.D. (Sessions I, II,IV)

Moheb M. Nasr, Ph.D. (Session III)

Michael C. Olson (Session IV)

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C O N T E N T S

PAGE No.

Call to Order, Thomas Layloff, Ph.D. 4

Conflict of Interest, Kathleen Reedy 4

Charge to the Working Groups, Thomas Layloff, Ph.D. 7

Introduction, Overview and Objectives of the

Subcommittee, Ajaz Hussain, Ph.D. 9

Working Group Summaries:

PAT Applications and Benefits,

Arthur Kibbe, Ph.D.,

Acting Working Group Chair 14

Subcommittee Questions and Answers 24

Product and Process Development,

Judy P. Boehlert, Ph.D.,

Acting Working Group Chair 32

Subcommittee Questions and Answers 44

Process and Analytical Validation,

Leon Lachman, Ph.D.

Acting Working Group Chair 52

Subcommittee Questions and Answers 58

Chemometrics, Melvin Koch, Ph.D.,

Acting Working Group Chair 62

Subcommittee Questions and Answers 72

Summary, Ajaz Hussain, Ph.D. 97

4

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

2 Call to Order

3 DR. LAYLOFF: I would like to call the

4 meeting to order, and we will start with Kathleen.

5 Conflict of Interest Statement

6 MS. REEDY: Acknowledgment related to

7 general matters waivers for the Process Analytical

8 Technologies Subcommittee of the Advisory Committee

9 for Pharmaceutical Science, February 26, 2002: The

10 Food and Drug Administration has prepared general

11 matters waivers for the following special

12 government employees, Drs. Judy Boehlert, Gloria

13 Anderson, Joseph Bloom, Thomas Layloff, Robert

14 Lodder, Melvin Koch, and Arthur Kibbe which permit

15 their participation in today\'s meeting of the

16 Process Analytical Technologies Subcommittee of the

17 Advisory Committee for Pharmaceutical Science. The

18 subcommittee will discuss strategies to explore

19 issues in the following four focus areas: a)

20 product and process development; b) process and

21 analytical validation; c) chemometrics; and d)

22 process analytical technology, application and

23 benefits, being held by the Center for Drug

24 Evaluation and Research.

25 Unlike issues before a committee in which

5

1 a particular product is discussed, issues of

2 broader applicability, such as the topic of today\'s

3 meeting, involve many industrial sponsors and

4 academic institutions.

5 The committee members have been screened for their

6 financial interests as they may apply to the

7 general topic at hand. Because general topics

8 impact on so many institutions, it is not prudent

9 to recite all potential conflicts of interest as

10 they apply to each member. FDA acknowledges that

11 there may be potential conflicts of interest, but

12 because of the general nature of the discussion

13 before the committee these potential conflicts are

14 mitigated.

15 We would also like to note for the record

16 that Leon Shargel, of Eon Labs Manufacturing, and

17 Efraim Sheik, of Abbott Laboratories, are

18 participating in this meeting as industry

19 representatives, acting on behalf of regulated

20 industry. As such, they have not been screened for

21 any conflicts of interest.

22 With respect to FDA\'s invited guests,

23 there are reported interests which we believe

24 should be made public to allow the participants to

25 objectively evaluate their comments. We would like

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1 to disclose that Dr. Leon Lachman is the president

2 of Lachman Consultants Services, Inc., a firm which

3 provides consulting services to pharmaceutical and

4 allied industries. Dr. Kenneth Morris would like

5 to disclose that his department receives funding

6 from pharmaceutical companies directly or in

7 consortia programs. Dr. Gokaraju Raju would like

8 to disclose that he has contracts and grants from

9 Pfizer and the Consortium for the Advancement of

10 Manufacturing of Pharmaceuticals. Dr. Raju also

11 serves as a consultant and speaker for these firms.

12 In addition, Dr. Raju is employed by and has a

13 fiduciary relationship with Light Pharma Inc.

14 Finally, Dr. Raju has affiliations with MIT and

15 Purdue University.

16 In the event that the discussions involve

17 any other products or firms not already on the

18 agenda for which FDA participants have a financial

19 interest, the participants are aware of the need to

20 exclude themselves from such involvement and their

21 exclusion will be noted for the record. With

22 respect to all other participants, we ask in the

23 interest of fairness that they address any current

24 or previous financial involvement with any firm

25 whose product they may with to comment upon.

7

1 Charge to the Working Groups

2 DR. LAYLOFF: Thank you.

3 I have a few remarks I want to make.

4 First of all, Ajaz has pulled together the most

5 knowledgeable people he could find to work on these

6 topics. For all of us it is a great opportunity

7 and a great responsibility for us to advance the

8 application of good science to process control and

9 the application of good science to regulation,

10 which we frequently hear.

11 \[Slide\]

12 Our focus has always been on the active

13 pharmaceutical ingredients, from alpha to omega.

14 Alpha is the incoming active pharmaceutical

15 ingredient and the technology change that came with

16 chromatography brought a revelation to us about

17 impurities. In the other technologies we also

18 focus on the active pharmaceutical ingredient.

19 Omega is the bioresponse or bioavailability. That

20 became known to us primarily through the RIA

21 studies on digoxin in the \'70\'s where the drug was

22 probably killing several thousand people a year.

23 \[Slide\]

24 So we focused on the alpha and the omega,

25 and that big middle part is where the process is.

8

1 Some people may disagree with me, but we have

2 treated the API as the process surrogate marker.

3 It is a univariate handle on a polyvariate process.

4 That focus has had little regard for excipients and

5 the process itself in the past. We have shown in

6 many instances that it is actually a poor surrogate

7 for many components in the process through failures

8 at the omega stage.

9 \[Slide\]

10 The tools \-- the assessment tools and

11 technologies are available; the data support

12 systems are available to improve product

13 consistency, reduce bad products and reduce

14 recalls.

15 \[Slide\]

16 Our job, should we agree to accept it, is

17 to help guide the guidance development to bring it

18 together. The FDA is waiting for our help and

19 assistance. Will we be able to answer the call?

20 \[Slide\]

21 Keep it general. Leave for another venue

22 and time assessment technology details on

23 calibration, repeatability, reproducibility and so

24 forth. Focus on the questions posed in the

25 handout. Raju has his pen poised ready to draft.

9

1 Chris is ready to manage the process. The ball is

2 in our court. Now I would like to call on Ajaz.

3 Introduction, Overview and Objectives

4 of the Subcommittee

5 DR. HUSSAIN: Thanks, Tom. Some thoughts

6 before you break out into the four working groups.

7 As Yuan Yuan yesterday mentioned, I want to

8 reiterate that the guidance that we are planning is

9 not a how-to guidance; it is a general regulatory

10 process guidance. For that, the information we

11 seek is to be in terms of what are the acceptance

12 criteria for a new technology to come in; not how

13 you would develop that technology or how you would

14 bring that process through. The focus is on a

15 regulatory process rather than how do you calibrate

16 or things of that sort. So, keep that in your mind

17 as you sort of break out.

18 If you could focus attention on the

19 questions that we have asked and help us, at least

20 at the end of this meeting, to identify the key

21 topics that need to be in the guidance, essentially

22 create an outline for the guidance that we are

23 planning to develop. I have provided you an

24 outline that we have right now. When we come back

25 to meet with you for the second meeting, we hope to

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1 have at least a draft in our minds of what the

2 issues to be addressed in the guidance will be and

3 how we plan to address that. So the next meeting

4 will be very much focused on very specific

5 questions that we will bring to you at that time.

6 So, for today keep the focus on the general

7 principles, as well as what needs to be covered.

8 That is about it. Thanks.

9 DR. LAYLOFF: Thank you. We will be

10 breaking into our working groups shortly. The

11 target for each work group is a fifteen-minute

12 presentation this afternoon, which will be timed,

13 followed by a fifteen-minute timed discussion.

14 For those of you who are agenda watchers,

15 we had no one ask for a public hearing or statement

16 at a public hearing. So, we will take that time

17 and fold it into our program time. Our morning

18 sessions will run from 8:30 to 12:30. We will

19 reconvene at 1:30 for presentations and, hopefully,

20 pick up half an hour on the agenda. Again, a

21 fifteen-minute presentation is the target, and I

22 will turn it over now to Kathleen.

23 MS. REEDY: A couple of details, the name

24 of the working group and the list of people who are

25 attending that group are on the door of each of

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1 these rooms, and the questions are on the table,

2 once you are in there. The questions are also in

3 your folder.

4 In this room, which is the Walker-Whetson

5 room, is the process and analytical validation

6 working group. Leon Lachman is the facilitator,

7 acting chair, Thomas Hale, Jozef Timmermans, Robert

8 Chisholm, Kennedy Chibwe, Carl Anderson, John

9 James, Sonja Sekulic and the FDA liaison and

10 support are Doug Ellsworth, Moheb Nasr, David

11 Morley and Lucinda Buhse.

12 In the very next room, the Goshen room \--

13 you need to go out and back in the next door, is

14 the process analytical technologies, applications

15 and benefits working group, chaired, facilitated by

16 Arthur Kibbe, William Koch, Eva Sevick-Muraca, G.K.

17 Raju, Steve Hammond, Kenneth Leiper, David Reed,

18 Doug Dean, Claudia Okeke, Russell Madsen, Silvano

19 Lonardi, and the FDA liaisons, Tom Layloff, Chris

20 Cole and Peggy Cunningham.

21 Chemometrics group, Potomac room. As you

22 leave this room, go down to your left, right where

23 the restrooms are, to the next corridor and to the

24 left. The Potomac room is also the second door on

25 the left. Melvin Koch, acting chair, Robert

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1 Lodder, Rick Cooley, Jerry Workman, Brian Curtiss,

2 Dwight Walker, Andrew Lange, Edgar Neil Lewis,

3 Svante Wold, and the FDA liaison, Ajaz Hussain,

4 Marilyn Welshenbach, Jonathon Cook, Jack Spenser

5 and Everett Jefferson.

6 Washington room, also past the restrooms,

7 to the left but the second door on the right,

8 product and process development working group,

9 chaired by Judy Boehlert, Kenneth Morris, Ronald

10 Miller, Dave Rudd, Judy Wong, John Shabushnig,

11 Walter Dziki, Thomas Cambron, Gopi Vudathala,

12 Richard Remmele, Anserd Fraser, and the FDA, Yuan

13 Yuan Chiu, Frank Holcomb, Kathy Taylor, Ron Lyon,

14 Lawrence Yu.

15 DR. LAYLOFF: Thanks very much, Kathleen.

16 We will adjourn now to our working groups. Break

17 your session at 12:30. Have your presentation

18 completed before you break. At 1:30 we reconvene

19 in here for reports from the working groups. Thank

20 you.

21 DR. HUSSAIN: Just to clarify, all our

22 open meetings so people from the audience can

23 attend those meetings.

24 DR. LAYLOFF: Yes, this is an entirely

25 open meeting so feel free to attend whichever

13

1 session you wish.

2 \[Whereupon, the proceedings were recessed

3 at 8:15 a.m., to convene in working group

4 discussions, to be resumed at 1:30 p.m.\]

5 - - -

14

1 A F T E R N O O N P R O C E E D I N G S

2 DR. LAYLOFF: Thank you. Our first

3 presentation will be by Dr. Kibbe, on applications

4 and benefits.

5 PAT Applications and Benefits

6 DR. KIBBE: Greetings. First, I want to

7 thank the committee for their efforts, the working

8 group. I have always aspired to be in a meeting

9 populated by brilliant people working towards a

10 common goal without rancor and disagreement, and I

11 have had the privilege today and I really

12 appreciated that.

13 One of the difficulties of being

14 vertically challenged is you have to move the

15 microphone. I always tell people I am not

16 overweight, I am under-height. If I was the height

17 I wanted to be, I would be the ideal weight.

18 What we did during the morning is we

19 examined the issues that were given to us. We have

20 a few slides which I hope I will be able to get

21 started here.

22 \[Slide\]

23 We started out as we first looked at the

24 definition of PAT, and our discussion revolved

25 around some of the word-smithing, and we have made

15

1 a small change in the definition that was

2 originally presented to us. One of the concerns we

3 had is that people not think narrowly of the word

4 \"analytical,\" that analysis and analytical applies

5 to more than just what we normally deal with in

6 terms of chemical analysis.

7 \[Slide\]

8 So even though we left the word \"analysis\"

9 in there, we did a little bit of word-smithing with

10 it. First, we took out the term \"continuous\" and

11 we added the word \"critical\" because we were

12 concerned, in some parlance, that there would be a

13 lot of information gathered and not all of it be

14 critical and, therefore, even though we are

15 gathering tons and tone of information we wanted

16 the process, as it is defined within guidances, to

17 reflect more the critical parameters than every

18 single parameter we could pick up.

19 We then looked at the list of questions

20 and we used them as a stimulus for discussion. We

21 didn\'t specifically respond to each question,

22 although we discussed each question. We used them

23 as a way of carrying on a discussion of PAT and the

24 applications of it to the industry and the benefits

25 to the industry. We generally agreed that PAT

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1 could be applied to any process and that it would

2 have a benefit if applied correctly. And, it would

3 have a benefit if we did not limit it to any

4 specific tool but expected that multiple tools

5 would be used and new tools would be invented. At

6 the rate of the evolution of technology nowadays,

7 new tools come to us at a moment\'s notice.

8 Barriers, we thought, really revolved

9 around cost and money. If there was a perceived

10 loss of revenue because the process slowed the

11 introduction of a drug to the marketplace, then the

12 companies would not be as prone to go along with

13 developing PAT. If there was a perceived negative

14 impact of regulatory oversight, then they wouldn\'t

15 go along with it. Both of these really broke down

16 to how much would it cost a company to do it; what

17 it would cost a company in potential risk in terms

18 of dollars, and so on.

19 \[Slide\]

20 Then we got to the real meat of the

21 matter, as you will, and we discussed question

22 eight, which is what has to be in the guidance to

23 give it the kinds of impacts that we want? What we

24 were hoping for is a guidance that really

25 established an environment in which industry was

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1 not only allowed to come forward with PATs, but was

2 actively encouraged to bring them forward in a

3 non-punitive environment where the development of

4 these process control systems would not have a

5 large negative downside.

6 First we said that the guidance must allow

7 the development of a PAT whose endpoint is a

8 signature of the quality of the process and the

9 process is well understand. We didn\'t want to use

10 models because models have certain kinds of

11 implications to them as a terminology. We didn\'t

12 want to use fingerprints because we have used

13 fingerprints in other kinds of analytical tools.

14 So, we used signature. We are not married to that

15 term but we certainly don\'t want to put a term up

16 there that isn\'t specific for this process and

17 would make people think in very specific terms

18 about other processes that they might be involved

19 with.

20 The guidance implies that PATs would be

21 used in an environment of continuous improvement

22 without regulatory burdens that would inhibit that.

23 We are concerned that we see PAT as a way of

24 constantly improving the quality of everything we

25 make and do, and if the regulatory environment is

18

1 such that it would cause the company to put

2 together a particular process and then have to live

3 it for 15 or 20 years we wouldn\'t be getting there.

4 So, somehow the guidance has to stimulate the

5 industry to go ahead and use PATs and constantly

6 improve on them, and use that information to

7 improve on their process and, therefore, improve on

8 their product without concern for an extra burden

9 to be added to the process because of it.

10 \[Slide\]

11 All products have critical quality

12 attributes. We agree that that was true. We say

13 that process variables exist that can be controlled

14 to maintain the critical quality attributes within

15 acceptable limits. We agree then that PATs are

16 applied to achieve both understanding and control

17 of process variables and that our causally linked

18 to product critical quality attributes. We think

19 this is an extremely important set of concepts that

20 need to be incorporated in the guidance so that

21 people know where we are trying to go.

22 \[Slide\]

23 There are new and developing measurement

24 tools and guidances should not limit the selection

25 of a tool for a PAT. The guidance should be very

19

1 clear that it is not a guidance for a specific tool

2 or a specific process. We argued \-- not argued, we

3 discussed because we were brilliant people

4 discussing brilliant ideas the possibility of

5 including examples in the guidance of successful

6 applications of PAT, and we reasoned that to

7 include them would be to bias people in the

8 direction of that tool or application and not leave

9 it open. We would prefer the guidance set rules

10 for general acceptability of those things without

11 undue pressure by giving an example which was

12 acceptable. We know that in the regulatory

13 environment companies often will exactly mimic

14 somebody else\'s successful application just for the

15 purposes of making sure they will make it.

16 We want to encourage companies to move

17 away from the current univariant prescriptive

18 testing to multivariant focused measurements. We

19 use measurements specifically to get away from the

20 implications of analysis.

21 \[Slide\]

22 \"Encourage\" is underlined on purpose. We

23 feel, or felt, or agreed that to allow companies to

24 do it really isn\'t getting to the spirit of where

25 we want to go. PATs seem to us to be a beneficial

20

1 methodology. That beneficial methodology not only

2 benefits the company and, therefore, should be

3 viewed by them as an economic incentive to put in

4 place, but it benefits society in general and the

5 quality of the products that we have.

6 With that in mind, we should recognize

7 that as companies go in this direction, it becomes

8 the norm. It will automatically become part of

9 CGMP and, hence, the agency will eventually get to

10 the point where it is requiring it or looking for

11 it. This brought us to a very interesting

12 discussion, something that we need to include in

13 the discussion and planning for the guidance but

14 not necessarily in the guidance, and that is that

15 if the field people and the review people both

16 don\'t agree on what is going on, and what a PAT it

17 is, and how to review it, and how to evaluate it,

18 and how to look at it this whole thing will fall

19 apart before it gets off the ground.

20 So, part of what has to happen from the

21 FDA perspective and from industry\'s perspective is

22 that field and in-house reviewers have to all be on

23 the same page. If the guidance is going to work

24 and if we are going to feel encouraged enough to

25 submit processes that we have developed through the

21

1 agency, the agency has to be prepared to accept

2 those at both the review level in the Parklawn

3 Building and out in the field in the middle of

4 Denver, or wherever they are going to.

5 \[Slide\]

6 We think that PAT can apply to all six of

7 the manufacturing sub-processes which includes

8 inbound logistics, active ingredient manufacture,

9 bulk formulations, fill and finish, packaging and

10 outbound logistics. One of the areas that we

11 talked a lot about was the quality excipients,

12 variability among excipients, how that variability

13 is translated into variability and quality, whether

14 that variability is an acceptable level or an

15 unacceptable level, and what-have-you.

16 Stability testing should be considered as

17 part of this process, or at least an additional

18 sub-process. So, we didn\'t think that PATs should

19 be limited to any one aspect of what is going on.

20 If someone has PAT they can put in place that will

21 take care of inbound logistics, we should encourage

22 them to do so.

23 \[Slide\]

24 The guidance should recognize that new

25 insight into the process, which does not affect the

22

1 quality of the product for its intended use, should

2 not require mandated changes in the process. One

3 of the fears I think that we all have is if we go

4 looking real hard at new ways of looking at what we

5 do, we will find problems that we didn\'t know exist

6 and what level of change will be mandated from

7 that? One of the things that we want the guidance

8 to be able to say is that if the variable that you

9 discovered, because you have been able to

10 characterize your process much more clearly than

11 you had in the past, is something that will help

12 you in terms of your in-process procedures and save

13 the company money, fine; go ahead and do it. But

14 as long as it isn\'t adversely affecting the product

15 outcome, the usability of the product you make, the

16 health benefits of the product you make to the

17 consumer, then we, as an agency, will not mandate.

18 I think it is important that that be in there to

19 give the companies a little flexibility in how they

20 respond to what will be an ocean of new

21 information.

22 We would like the agency to recognize that

23 PATs have a potential for replacing a lot of

24 classical or current methodology in terms of

25 quality control routine testing methodologies, and

23

1 the guidance should recognize that PATs will, in

2 large measure, replace current validation

3 requirements for process validation. Because PAT

4 goes to the issue of on-line constant validation

5 every time you run the process, why have another

6 set of validations that don\'t really get to the

7 issue when this might very well solve that issue

8 for you?

9 The guidance has to define what records

10 have to be kept and for how long. A sea of data

11 will be generated. Thousands and thousands of data

12 points on a very simple in-process measurement tool

13 could be generated. How long do you have to keep

14 it? How much of it do you have to keep? Is it

15 going to be an electronic storage nightmare? I

16 think the agency has to look seriously at how long

17 does in-process data, generated from a system which

18 is intended for both measurement and control of the

19 process, need to be kept, and which pieces of data,

20 which critical pieces?

21 Then, how do you involve FDA in the PAT

22 development and implementation? One of the things

23 that we talked about and we encourage is the agency

24 establishing a contact place for companies to go to

25 begin the development and implementation of a PAT

24

1 process at their site. Now, we recognize that

2 companies will be playing with this stuff, getting

3 it on-line and feeling comfortable with it before

4 they go to the agency because they are not going to

5 go there with something that will never work. But,

6 at the same time, how do they go there efficiently?

7 Is there some office, some ombudsman who is going

8 to be favorably disposed to help them to make the

9 transition from classic measurements and classic

10 quality control/quality assurance measurements to a

11 PAT that will supplant some of those things?

12 That is pretty much where we got to. I

13 guess we are in line for questions. I encourage

14 the brilliant members of my committee to respond to

15 questions since I clearly was there just to make

16 sure that we all had enough coffee and orange

17 juice, and the rest of you did all the heavy

18 thinking. Tom?

19 Subcommittee Questions and Answers

20 DR. LAYLOFF: It is open for discussion.

21 Any questions for Dr. Kibbe?

22 MR. COOLEY: One question I have, I was

23 wondering why your committee chose to include

24 control as part of process analytical technology.

25 DR. RAJU: We actually talked about PAT

25

1 and said that maybe PAT should stand for process

2 assessment technology in some ways, and just

3 measurement wouldn\'t be enough and we had to find a

4 way to connect the loop back to process

5 understanding. Along with that, we began to define

6 what is analytical. Does that simply mean a

7 chemical measurement or is it a process of thinking

8 and analysis? So, we would like to find a way to

9 put the next steps into the thought process in

10 terms of capturing the benefits, without being

11 limited primarily to the measurement, although we

12 know the measurement is the way to get there.

13 So, we tried to be a little bit inclusive

14 in that sense. And, there is no clear yes or no in

15 there. In a couple of places we tried not to give

16 examples because we didn\'t want to limit the

17 thinking. If you notice, in a couple of places we

18 said the risk has to be managed. Number seven is

19 probably one of the important points in terms of

20 managing the risk of what we see. You can choose

21 whether to include control or not, and this was our

22 thought process around it.

23 MR. COOLEY: Just another comment, the

24 automation community has obviously progressed way

25 ahead of the measurement community as far as at

26

1 least on-line measurements. I am just wondering

2 what the benefit would be in trying to encroach on

3 what is already an established standard, more or

4 less. In most cases the analytical measurement is

5 going to be a totally independent system that

6 provides an output to a DCS or a control system.

7 There may be some cases where that is not the case

8 but probably 99 percent of them will be ones where

9 we are just providing an output.

10 DR. RAJU: I think our focus was on

11 controlling in the abstract sense in terms of the

12 processes. We did focus mostly on the measurements

13 but since the connection back to process

14 understanding had kind of the abstract level of

15 product and process control, I think that was not

16 our thought process.

17 DR. KIBBE: I think it is difficult to put

18 in place a system that measures how well something

19 is going on without it somehow feeding back into

20 continual quality improvement on that system. In

21 that sense, you have analysis and control linked.

22 It is not that we thought this would be necessarily

23 a replacement of your quality control lab \--

24 necessarily.

25 DR. SEVICK-MURACA: May I make a comment?

27

1 I was on the committee and I guess I didn\'t think

2 of Rick\'s point. He makes a very good point in

3 that if you do classical control, the statement

4 \"control\" means that you are leaving the control of

5 the process up to that measurement itself and that

6 requires change in the process. So, I don\'t think

7 that was the intention that we had. I think, if I

8 am correct, that is where you are coming from. We

9 might want to consider getting rid of that

10 \"control\" because if someone at the FDA or somebody

11 else is looking at it from the classical standpoint

12 of that word, Rick is entirely correct in his

13 assessment.

14 DR. MILLER: Could you explain the

15 rationale behind the underlining of the word

16 \"encourage\" and the other comments that you were

17 saying?

18 DR. KIBBE: We accept the premise that the

19 application of PAT is a benefit and it could be,

20 depending on the methodology and the tools,

21 applicable to every dosage form. If that is the

22 case, then why simply allow, why not encourage? I

23 think if the companies come to the realization that

24 there is a benefit gradually the number of

25 companies that have these processes in place will

28

1 go up, and that will become the standard in the

2 industry, which is CGMP, and will eventually become

3 encouraged because it is naturally the standard for

4 quality in the industry. So, why not recognize now

5 that we are really talking about encouraging the

6 industry to move forward with a system that we, at

7 least as an advisory committee, think is going to

8 be valuable for the industry and the public?

9 DR. RAJU: The other thing was to consider

10 the possibility that FDA not only be a policing

11 agent, but I think to help in the education across

12 because we both win together. It is kind of a new

13 role. Simply saying it is allowed, I think is

14 already in place but just allowing doesn\'t seem to

15 be working and maybe we have to have a framework in

16 which we can find a way to both win. So, we are

17 encouraging so we can both be encouraged together.

18 I don\'t know if this will be enough but I think it

19 is one step.

20 MR. COOLEY: One comment on the retention

21 of records, would not this kind of data fall under

22 CFR 21, Part 11 already, which is already a

23 guidance for electronic record retention? Is it

24 really necessary to produce a separate guide that

25 actually may end up conflicting with one another?

29

1 DR. KIBBE: True.

2 DR. RAJU: I think the recording was also

3 an issue of what information should we gather; how

4 long we should keep it; what are we accountable

5 for. So, the CFR Part 11 and the signature and the

6 consistency is, I think, in place for a long time

7 but the other aspects \--

8 MR. FAMULARE: I am sorry, not only the

9 Part 11 but the GMPs themselves, you know, have

10 time frames for record retention at which time, for

11 example, two years after or one year after the

12 expiration date there is no need to keep the

13 records anymore. So, I think that there aren\'t

14 limitations that exist in the current framework so

15 unless an argument is made that the system will

16 outstrip what is already in current regulations, I

17 don\'t think we need to go there in this guidance.

18 DR. MORRIS: But maybe it is enough just

19 to say that the criteria will be the same as

20 covered in the current guidances, just so it is

21 clear in this guidance that it is not a different

22 thing.

23 DR. LAYLOFF: One example that was given

24 to us was a videotape of a mixing process that they

25 were running over and over again. So, each time

30

1 they ran a mixing they ran a videotape. The

2 question is, is the videotape and electronic record

3 that you have to keep? Each time you run the

4 storing action you run a videotape. Does that

5 become a permanent record then that you keep under

6 Part 11? Or, is it something that you dump when

7 you get done and you release the product?

8 DR. KIBBE: I think there is sufficient

9 opportunity for unknowns that it is worthwhile at

10 least for the agency to recognize in the guidance

11 that there might be a concern for the quantity and

12 quality of the information that is retained.

13 DR. LAYLOFF: I think the amount of

14 information that could be generated by this is

15 actually astounding. I think retention for one

16 year or two years after expiration is not

17 unreasonable for the release issue, but if you are

18 talking about end-process controls where you are

19 generating maybe sensors at 20 different sites

20 continuously there is a huge amount of data. There

21 might be something that should be considered at

22 some point by the agency as having an alternate

23 procedure to deal with it, set some specification.

24 Otherwise, under 21, 11 you are going to need huge

25 amount of storage and it is not useful.

31

1 MR. FAMULARE: I think these issues have

2 already arisen in terms of Part 11, and I don\'t

3 think we want to take on Part 11 as part of this

4 guidance in those issues. Those issues preexisted

5 the advent or the encouragement of this technology

6 and the agency already recognizes that there are

7 issues surrounding Part 11, and there is a whole

8 working group working on that. Maybe the best

9 thing to do would be to feed this as a factor in

10 that working group, led by ORS\'s office in

11 enforcement.

12 DR. LAYLOFF: It is just an issue that

13 should be brought to their attention.

14 DR. RUDD: This might sound quite

15 patronizing but I just wanted to congratulate the

16 group on the output. I am very nervous about the

17 output from these four groups because it is very

18 critical, but from the GSK perspective you have

19 captured the concepts and the principles

20 beautifully. I am delighted to see what you have

21 come up with. It is also as if I could have been

22 there myself. Thanks very much.

23 DR. LAYLOFF: Are there any questions from

24 the rest of the working groups? If not, we will

25 now move to Judy Boehlert, product and process

32

1 develop.

2 Product and Process Development

3 DR. BOEHLERT: All I can say to Art Kibbe

4 is that I am as tall as I want to be, so I don\'t

5 know what my excuse is.

6 I would also like to thank my group. I

7 think we had a very productive working session.

8 Everybody contributed and that was very good. We

9 had some lively discussion and, in fact, we were

10 able to get done a little bit ahead of schedule so

11 we addressed an added topic and if I have time, I

12 will go over that as well.

13 \[Slide\]

14 We did go down through the questions but

15 some of them turned out to be redundant. In fact,

16 when we looked at the list we decided that question

17 number one we would hold till last. So, when you

18 see our answers to question number one, they are

19 fairly brief because we addressed everything in

20 question one by looking at the others that were

21 there.

22 This one has to do with what

23 considerations during product development might you

24 consider. This is brief because we are going to

25 address the basic issues in later statements.

33

1 Everybody agreed that the benefits of PAT are

2 under-realized, under-utilized. People don\'t know

3 they are available. Some companies have tried it

4 and perhaps haven\'t see the benefits they have

5 expected, and that has led also to sort of

6 reticence to do more. Until you know that there is

7 a real benefit you don\'\[t want to expend the

8 energies.

9 \[Slide\]

10 There is still some selling that needs to

11 be done. Clearly, everybody is not on this

12 bandwagon yet. And, 6 sigma as a target is really

13 too high. What was suggested by the members of our

14 group was maybe somewhere in the range of 3-4 as a

15 more reasonable target.

16 \[Slide\]

17 We talked about what areas you might want

18 to apply PAT technologies to, and it is applicable

19 to most areas of the manufacturing process but

20 there are different levels of maturity for the

21 analytical technologies that are used. It is

22 probably most mature when you talk about the raw

23 material; less mature when you talk about blend

24 samples; and perhaps even less mature when you

25 start talking about final product. So, yes, it can

34

1 be used in all of those areas but the degree of

2 maturity for the techniques is not the same. The

3 nature of the ingredient is also a factor. It may

4 not work in all cases. Where it works, it may work

5 very well. In some cases it doesn\'t.

6 \[Slide\]

7 The most important thing about PAT

8 technologies is that it allows incorporation of

9 feedback controls, such that you can adjust the

10 batches you are processing and you may not need to

11 lose a whole batch. During development is when you

12 are going to start taking a look at PAT. The goal

13 there is to understand the process and develop one

14 that is very robust.

15 Also during development, and this is a key

16 point we wanted to make, is that you may look at a

17 lot of different parameters using PAT techniques,

18 but what you don\'t want to do is look at all of

19 those parameters once you go to market. The goal

20 during development is to identify those that are

21 important and those that are needed, and then

22 select those that you wish to monitor during

23 product that most critically control your process.

24 It is sort of like doing stability studies and

25 identifying impurities and degradants. You find a

35

1 lot of things during development. You do stress

2 testing. But during actual product what you test

3 is limited. Evaluation from other technologies

4 from other industries may also be helpful for

5 people deciding what it is they want to do, and how

6 they want to do it.

7 \[Slide\]

8 Unit technologies where you have a history

9 and possible technologies that may be used can

10 occur in the guideline but they shouldn\'t preclude

11 the use of alternative technologies and

12 methodologies. We never want to limit the ability

13 of somebody to use something new. You know, there

14 are some well defined examples out there now, but

15 technology keeps advancing and changing.

16 This one had to do with how you anticipate

17 application will change the process for identifying

18 critical process variables \-- definitely a

19 development function, a structured approach,

20 getting to know your process early, optimizing it,

21 identifying critical parameters and developing the

22 metrics. How you control it is going to be up to

23 you. You are going to decide that. On-line

24 sensors give you additional information certainly

25 to control critical endpoints.

36

1 \[Slide\]

2 As was mentioned by the previous speaker,

3 certainly moving from univariant to multivariant

4 approach in strategies may be identifying

5 parameters that are important to the process that

6 we didn\'t look at in the past. We need to be able

7 to correlate PAT with specifications where that is

8 relevant, and there is a lot of work left to do in

9 this area. Looking at the quality of the raw

10 material, of course, is basic to everything we do.

11 You need to control the inputs to the process at

12 the very beginning.

13 \[Slide\]

14 We talked about what are some of the

15 issues that arise during scale-up. Do PATs help in

16 the scale-up situations? The answer is yes, of

17 course, they do. If you know more about your

18 process, it is always going to be a help. You need

19 to know what endpoints you are working towards.

20 You need to know what the process should look like

21 when it is working well.

22 We also talked about a process signature.

23 It was a term that came up in our discussion. When

24 it is working well and you get to know what that

25 is. When you scale-up, of course, it may change.

37

1 Scale-ups sometimes don\'t do what you think they

2 are going to do but by doing the PATs early in

3 development you know what things are important to

4 monitor, and then you can identify those changes.

5 \[Slide\]

6 All of these were questions. Do they

7 cause problems? Yes. I mean, we could make very

8 simple answers to everything. One of the

9 limitations we saw is that some of the off-line

10 testing methods we use as gold standards may not,

11 indeed, be as good as we think they are in showing

12 us product quality, and the example we used was

13 dissolution.

14 There are engineering issues that need to

15 be looked at \-- critical implantation issues,

16 applying design of experiments, business issues and

17 this came up in the other meeting. Addition of a

18 PAT to a process must be value added. For new

19 product sensor applications up-front equipment is

20 easier to put in place and employ. Most people

21 felt that the easiest place to use PAT is with new

22 products. Yes, they can be retrofitted to old

23 products but it is not quite as straightforward.

24 PAT measurements may not match your

25 submission parameters even though your product may

38

1 still meet your submission requirements. This is

2 an issue that came up yesterday, and one that needs

3 to be made clear.

4 \[Slide\]

5 Moving from parameter controls, which is

6 what we are talking about, endpoint control is a

7 desirable outcome. However, we did discuss that

8 even with parameter control you might need to set

9 boundaries, either upper or lower limits; it is not

10 anything goes. Low dose drugs, of course, and low

11 potency may be exceptions and PAT technologies may

12 not be as applicable. Do they make scale-up

13 transitions easier and, if so, why? Yes, of

14 course, because you better understand your process.

15 \[Slide\]

16 In some situations PATs may be used only

17 for certain specific operations within the overall

18 scheme of dosage form manufacturing. And, this was

19 either what are advantage or disadvantages to

20 applying PAT to only a specific unit operation. We

21 didn\'t see any technical downside to doing that.

22 It is a business decision. Whenever you are

23 applying PAT, it should be value added. Accurately

24 reflecting what is going on in a process can\'t

25 really be a disadvantage.

39

1 The overall weakness comes when you do

2 that. For example, if you have blend homogeneity

3 and you are looking at the blend, downstream you

4 could have problems and if you are not looking at

5 anything downstream perhaps you wouldn\'t identify

6 it. So, you need to be careful. If you are only

7 applying it to one unit operation you need to make

8 sure you understand the rest of your process.

9 \[Slide\]

10 When you to for new technologies, of

11 course, you have to pay for the technologies and

12 that is where the business aspect comes in. There

13 are time considerations. There are human resource

14 considerations. They all have to be taken into

15 account. One advantage we saw for applying PAT to

16 unit operations is if you were to develop it, for

17 example, for a dryer for one product. Then, the

18 applicability to other problems that are dried in

19 that same dryer should be there; should have to do

20 a lot less work to bring it into place for those

21 other products.

22 \[Slide\]

23 Can PATs be used to prevent out of

24 specification incidents? Well, certainly,

25 implementing PAT on a poor process is not going to

40

1 change the number of OOS results. But if you are

2 allowed to go to an endpoint in your process, you

3 may be able to control the process in such a say

4 that you do, indeed, eliminate those OOS events.

5 It will decrease these incidents and make the

6 process more rugged. Also, if you have PATs

7 incorporated into your process you will have a much

8 better chance of doing a much more rigorous

9 scientific investigation when things go wrong.

10 \[Slide\]

11 Can PATs be tools for predicting

12 performance of a drug product, for example,

13 dissolution? The answer was it is certainly

14 possible. What we need to do is develop the

15 correlations that are necessary to do that. They

16 are not all there right now. It is an exercise, as

17 always, in benefit-risk assessment and much more

18 work needs to be done. We heard the other day

19 about the use of the acoustic technologies. These

20 are things that can be used. They are just not

21 mature technologies at this point. Also, it is

22 probably going to be on a case by case basis.

23 \[Slide\]

24 Can they be used for predicting the

25 stability of a drug product? If yes, what are the

41

1 factors? Well, what we said is that the use of

2 PATs in a process will not replace stability

3 testing. It may be used as a predictor however,

4 particular for things like physical instabilities.

5 If, indeed, you have more knowledge of your

6 process, then you have more confidence that your

7 product is going to remain the same throughout its

8 shelf life. It may reduce your risk, for sure, and

9 may be able to predict better what your stability

10 will look like.

11 \[Slide\]

12 One benefit for batch release will be

13 higher quality. Product failing during shelf life

14 will be less likely, and that is fewer recalls.

15 More consistent product is always a better option.

16 \[Slide\]

17 Finally, we looked at what factors the

18 industry and the agency should consider while

19 implementing use of new PATs for already approved

20 drug products. We need to look at the benefits of

21 that. In a new product it is easy. You can build

22 the quality in. It is not the same on an old

23 product. Consistent monitoring of an ongoing

24 process is always a good idea because you yield

25 better information on your product and

42

1 considerably, as we said before, much more

2 opportunities for new products.

3 \[Slide\]

4 It could have applications to validation

5 and SUPAC guidelines in the future, and we think

6 this is definitely something that should be

7 considered. If there are no problems with your

8 current process, we did not see a sound reason to

9 make changes. Unit operations validated for one

10 product, and we said this earlier, may be used for

11 other products and we would like to see those

12 incorporated through SUPAC.

13 \[Slide\]

14 The view from industry in general is if

15 it\'s not broken let\'s not fix it. There needs to

16 be a persuasive reason to make changes. If you

17 make changes, like a vendor change or a site

18 change, it may be a very good opportunity to look

19 at your process and look at the need to incorporate

20 PAT. the goal of having team inspections we see as

21 a positive kind of benefit because our concern is

22 the same as the previous group\'s. You have the

23 review chemist and you have the investigator and

24 they may not be looking at these technologies in

25 the same manner.

43

1 \[Slide\]

2 That was sort of the agenda that was laid

3 out for us and the issues that we needed to look

4 at. We took a look at the table of contents to see

5 if what was anticipated to be included in that

6 table of contents correlated with what we had in

7 mind. I won\'t go through some of them because, you

8 know, you can combine this section with others.

9 We did ask that the FDA consider use of

10 PATs in product development and some description of

11 what that entails, enabling technologies including

12 chemometrics \-- some discussion of that. The

13 relationship of PATs to finished products

14 specification. We felt that it would be important

15 to have worked examples of different dosage forms,

16 if not in the guidance then by reference.

17 \[Slide\]

18 Guidance also should address the roles and

19 responsibilities of different groups.

20 Manufacturing, product development are obvious, but

21 also the quality unit, engineering, process

22 technology as well as others, as well as the skill

23 mixes that we might need in the future because the

24 skills that you are going to need from your

25 employees are going to change as we move into these

44

1 new technologies.

2 With that, thank you for your attention.

3 I will ask my committee members also to chime in if

4 they have any comments and we would be happy to

5 address your questions.

6 Subcommittee Questions and Answers

7 DR. LAYLOFF: Any questions for Judy?

8 MR. COOLEY: Judy, could you comment \-- if

9 I wrote it down correctly, you said that a

10 technique validated for one product and unit would

11 be okay to use for another product?

12 DR. BOEHLERT: The operative word I think

13 is \"may be.\" You know, we are looking at things

14 like drying where the principle behind that

15 technique is pretty consistent product to product

16 and what you are measuring is pretty consistent

17 product to product. You may be able to do that

18 database generated for one product to perhaps not

19 do so much work on a second product; that you use

20 that same piece of equipment and technology for it.

21 Do I make myself clear?

22 MR. COOLEY: I think so. I just want to

23 clarify that you are not saying that you do one

24 validation package for a NIR-IR in a dryer, for

25 example, for product A and then, when you bring in

45

1 product B, you don\'t need to repeat your

2 validation.

3 DR. BOEHLERT: Absolutely not. We were

4 looking at techniques such as drying where, you

5 know, you might not have to do as much work on the

6 second product as you did on the first.

7 DR. RAJU: Judy, how did you conclude that

8 we couldn\'t reach 6 sigma and we could only do 3 to

9 4?

10 DR. BOEHLERT: We had a statistician in

11 our mix.

12 \[Laughter\]

13 DR. LAYLOFF: Members of the working group

14 can ask questions also, if you like.

15 DR. BOEHLERT: Or make comments.

16 DR. HUSSAIN: I think one of the

17 challenges, the reason we wanted to have some

18 discussion on this is that at some point my though

19 process was that you really have to do it at the

20 development stage to get the full benefit. To do

21 that, you have to think of setting specifications

22 differently than you are used to, going from time

23 to a performance-based specification. So, that

24 needs to occur early. Then, the scale-up has to be

25 built around that. So, we are shifting the

46

1 paradigm in terms of how we are setting

2 specifications. I didn\'t get much on that part of

3 the discussion, if somebody could add to that.

4 DR. MILLER: Ajaz, we didn\'t touch on the

5 specifications. That wasn\'t one of the charter

6 questions. We felt the chemometric group was going

7 to provide some insight.

8 \[Laughter\]

9 DR. HUSSAIN: That was one of the first

10 questions we posed to you. Chemometrics will not

11 answer the specification question, it is more on

12 the modeling and what sort of criteria we judge

13 those models by. Specifications will have to be

14 product oriented.

15 DR. MILLER: Well, we did speak to what we

16 needed to focus in on the critical aspects and

17 that, on first blush, may be a wide number but we

18 made it very clear that we needed to narrow it down

19 to the specific aspects, specific critical points

20 that control the process and that is what we wanted

21 to go after. Now, to the degree of certainty, we

22 didn\'t quite get into that aspect.

23 DR. HUSSAIN: But if I phrase it this way,

24 that your group would be in agreement with the

25 concept of going to performance-based

47

1 specifications?

2 DR. MILLER: Totally.

3 DR. LAYLOFF: I think that is a universal

4 sense around the table, that process validation

5 like timing and things like that are not

6 appropriate when you can have sensors to move to

7 performance basis.

8 DR. MILLER: And, therefore, there wasn\'t

9 so much debate about that. We were taking other

10 tracks.

11 DR. SHABUSHNIG: I think also it is a

12 little bit of a chicken and the egg situation in

13 the sense that right now we are developing the

14 measurement technology and learning what those

15 measurements tell us. Based on that, you can then

16 set good specifications. I don\'t think we are at

17 the point today where we can determine those

18 specifications a prior and then work our way back.

19 So, I agree. I think we are all certainly in

20 support of that concept as you are describing it

21 but in terms of where we are, from a technological

22 standpoint, I think we are moving to that by

23 getting the measurement technology in place and

24 deciding what new information we can glean from the

25 new measurement technology, and then use that in

48

1 the specification setting process.

2 DR. LAYLOFF: If you said something like

3 blend to consistency, what does it mean? No change

4 over ten seconds or thirty seconds? What does the

5 specification mean?

6 DR. HUSSAIN: This is more for Steve

7 Hammond, if I recall correctly, yesterday he

8 mentioned that one of his new assignments is

9 setting up PAT stability testing. My personal

10 sense is that I don\'t think this technology will

11 give you more information on stability. If you can

12 share some thoughts on that?

13 MR. HAMMOND: Well, there are technologies

14 out there that are super sensitive particularly to

15 the degradation of APIs. I would guess the way we

16 are thinking is focused on the API, although that

17 may not necessarily be correct. But you can use

18 various techniques to look at the surface of

19 tablets or even, indeed, to look at the blend

20 binding stability, techniques like fluorescence and

21 some of the mass spec methods that are there.

22 There are technologies that are very, very

23 sensitive. In fact, some of the indications we

24 have had are that they are actually more sensitive

25 than the traditional methods, which could be a real

49

1 issue.

2 DR. LAYLOFF: I think also that focusing

3 on the API probably is not a very good thing to do

4 in the long run because of things like the physical

5 relaxation of the solid dosage forms that might

6 change the dissolution characteristics also.

7 Polymorphic transitions could occur.

8 MR. HAMMOND: The thing about focusing on

9 PAT measurements, usually one of the main focuses

10 is that you can keep doing it to the same tablet.

11 You don\'t destroy it as you do this and that will

12 give you different sorts of information than we are

13 used to seeing as well. But I take your point. I

14 will repeat one of the comments I made yesterday,

15 if people decide what they want to measure then

16 nowadays there is usually a way to do it.

17 DR. HUSSAIN: I think I share the

18 enthusiasm. We actually have a project in our labs

19 looking at stability using some of these things

20 too.

21 DR. WOLD: Svante Wold from the

22 chemometrics subgroup. We had a discussion about

23 the specifications in our group and I had a

24 different opinion than the others. I want to

25 iterate that here. That is, if during development,

50

1 for instance with the blender, you find that this

2 product with these raw materials, crystal size and

3 all these things, mixes well in 15 minutes, of

4 course, you use PAT to follow and decide on these

5 15 minutes, plus or minus three minutes or so.

6 Then, if later, one day it takes 30 minutes, that

7 is an indication that there has been a change. So,

8 you can still use the ordinary specification and

9 statistical intervals, helped by PAT. But seeing

10 the process as a soft sensor, when the process

11 changes substantially, that indicates that

12 something has happened upstream. If you go to the

13 polymerization industry, or whatever, they use this

14 in exactly the same way. And, I think it would be

15 very dangerous to say we won\'t have any limits and

16 just wait to see if it is mixed. So, you have to

17 use ordinary limits but you are helped a lot by

18 PAT.

19 DR. LAYLOFF: You mean you would use PAT

20 to accumulate data on acceptable performance and

21 you set some acceptance criteria around that, and

22 if it is exceeded by a lower bound you would have

23 some difference occur upstream.

24 DR. WOLD: Yes.

25 DR. LAYLOFF: And that difference should

51

1 be investigated.

2 DR. WOLD: Right.

3 DR. RUDD: If it helps, we did discuss

4 that point in our group. You know, there is

5 flexibility needed, and I think probably Judy

6 brought this out, but we need some kind of

7 predetermined window, exactly as Svante described.

8 You know, you can\'t have infinite flexibility.

9 When do you stop? So, it is about operating in a

10 window and recognizing that if you have to deviate

11 from that window you have a problem, but not

12 working to a fixed point.

13 DR. HALE: I think there is another piece

14 of this pie beyond just the sensor, testing and

15 specifications, and that is the process itself. By

16 implementing these technologies we have the

17 potential to not only measure our current processes

18 better but bring on line better and more

19 appropriate processes for what we are trying to do.

20 In the end, that may be the biggest advantage of

21 doing this, that we could, at the design stage,

22 implement appropriate technologies that aren\'t

23 constrained by our current momentum; that we can

24 reconsider how we fundamentally design and

25 manufacture processes. To me, that falls under the

52

1 encouragement category, that this technology

2 sensing by itself gets us only so far but if we can

3 implement a better way of doing things that can a

4 dramatic leap and, to me, that should be encouraged

5 and incorporated in the sensing and analysis

6 section.

7 DR. LAYLOFF: Rule of the chair, we are

8 going to skip the break and move on to Leon.

9 Process and Analytical Validation

10 DR. LACHMAN: In our working group we had

11 a very interactive session and we had good

12 representation from the regulatory group, both from

13 the compliance point of view and also from the

14 submissions group. So, we had a good dialogue and

15 we have come up with some recommendations as to the

16 purpose of the guidance as well as issues that

17 should be included in the guidance.

18 \[Slide\]

19 The purpose of the guidance, from a

20 validation point of view, is to expand the use of

21 current and future process analytical technology

22 for controlling of both batch and continuous

23 production of existing and new products. That is

24 the purpose of the guidance from validation\'s

25 consideration.

53

1 \[Slide\]

2 Then we had various general guidance

3 validation issues that were brought forth that the

4 body of the guidance should consider. One is

5 dealing with requirements for accepting PAT for

6 conventional testing. What correlation is needed

7 to replace current conventional testing?

8 Utilization of PAT in current processes. How do we

9 accomplish that? PAT as an \"alert\" in the use of

10 old technology, out of trend versus OOS. We have

11 certain limits now for dissolution or for content

12 uniformity, for blend uniformity and those have

13 been accepted for the product and are producing

14 acceptable product with adequate quality and

15 bioavailability, and now we have this PAT and it is

16 going to provide us a narrower window than we are

17 now using in the approved application. The concern

18 is that the agency should not use that narrow

19 window and forget about the approved

20 specifications. We would suggest that this narrow

21 window, as we develop this new technology, be used

22 as an \"alert\" and the current window be used as the

23 acceptance criteria.

24 \[Slide\]

25 PAT on-line to replace conventional

54

1 testing, identifying filing requirements if we

2 change over to on-line controls versus the

3 conventional testing controls. PAT as an endpoint

4 can replace traditional endpoints such as time. We

5 are not going to be using time as a controlling

6 factor anymore because it goes away since this will

7 be continuous data acquisition.

8 If sensors indicate improved process

9 control, existing technology is accepted to meet

10 current quality for release. What we are saying

11 here, as we said previously, is that the currently

12 accepted, approved specifications for product

13 quality attributes will be the governing factor.

14 The improvements, until they are finally worked out

15 completely \-- then there will be some changes made

16 to show improved process controls and what will be

17 submitted to the agency, and how we submit this

18 will be subsequent interaction between agency and

19 the people that are doing this new technology.

20 We were assured by the agency

21 representatives that there is a group that has been

22 formed, both from members of the compliance group

23 as well as from the reviewing group that are

24 actively pursuing this area, and they understand

25 there will be education required for reviewing

55

1 people as well as for the field people to

2 understand that as this technology is developed it

3 should not be considered that we are having tighter

4 specs and these should be replacing the approved

5 specifications.

6 \[Slide\]

7 How to allow for improvement? The

8 question is how do we go about this with regards to

9 reviewing the improvements, self-assessing? Do we

10 need approval or can we submit this as part of GMP

11 that requires pretty much current good

12 manufacturing practices; this can be considered GMP

13 without a reviewing requirement.

14 New technology cannot delay time to

15 market. We had considerable discussion regarding

16 developing this new technology and we regards to

17 filing, because here we are talking about economics

18 and it is customary right now to have approval of

19 your applications before the validation. The

20 validation is subsequent to approval and it is part

21 of the marketing requirement. So for the most

22 part, the group felt that we should continue with

23 the three batch initial filings because that is

24 what is expected from us right now, and as the new

25 technology develops this shouldn\'t delay the

56

1 marketing and we can always put that in the SUPAC

2 as the product is on the market.

3 \[Slide\]

4 Dual development, we spoke about dual

5 development, fast to the market with conventional

6 testing and how this would switch over when the

7 database is ready. Do we file both performance

8 testing versus the current testing at filing? Do

9 we file both or do we go ahead and finesse the

10 performance testing and come in with a SUPAC filing

11 once the product is already marketed based on the

12 conventional three batch validation?

13 GMPs allow for process improvement, and

14 the agency indicated that we are going to encourage

15 ease of submissions of these PAT improvements as

16 they become well developed.

17 \[Slide\]

18 Update of method/algorithm model more

19 frequent than conventional, this may take place as

20 we learn more of the performance evaluation. The

21 methods should reference the validation guidelines

22 including ICH. This was a suggestion by one of the

23 members since this is currently being looked at by

24 the reviewing group task force, and by referencing

25 these guidelines, this indicates that this

57

1 particular guidance has already considered these

2 and it is not intended to redo those guidances.

3 \[Slide\]

4 Here we talked about the validation of the

5 continuous process and definition of batch size and

6 impact of OOS. Here we discussed that the current

7 approved specifications for a product for content

8 uniformity or blend uniformity, the ranges that are

9 approved in the application apply, and that the

10 continuous process is intended to provide an alert

11 currently until that has gone through a

12 considerable amount of work and is finalized. So,

13 the current process of reject or approval will be

14 the current quality attributes that have been

15 approved in the application.

16 Integration of unit operations into larger

17 steps, it was felt that by using performance

18 qualifications we could eliminate the individual

19 unit operation testing. They can flow one into

20 another and reduce the number of testing that we

21 have to do even in performance assessments.

22 How process set points are treated in

23 feedback loops, and this is something that we are

24 going to be listening to the next speaker about

25 when we talk about the use of statistics, math and

58

1 computer into the feedback mechanism for

2 controlling a process.

3 \[Slide\]

4 The validation of the appropriate

5 parameters will have to be defined as part of the

6 modeling and development of the performance

7 testing, and chemometrics is one approach and there

8 are probably other approaches to data treatment

9 that use different computer or statistical

10 programs.

11 Those were essentially the issues that we

12 came up with for consideration as part of the

13 guidance document for the FDA group when they start

14 drafting it from a validation consideration. Thank

15 you.

16 Subcommittee Questions and Answers

17 DR. LAYLOFF: Any questions for Leon?

18 DR. BOEHLERT: Leon, I have a question for

19 you regarding reference to ICH for validation of

20 these technologies. Did your group feel that that

21 would be adequate? Because ICH addresses the

22 validation of small quantities of material, like

23 milligrams of an active ingredient or small

24 quantities of dosage form, and here we are talking

25 about validation of technologies that are used in

59

1 very big containers or on-line, and I think there

2 are different issues that are going to be involved.

3 DR. LACHMAN: I think what the suggestion

4 was is to list the current guidelines that are

5 available, ICH or FDA guidelines, so that we don\'t

6 address those as part of the details that we will

7 get into later on with this guidance. There is no

8 doubt that the performance testing is going to be

9 quite different than the individual testing.

10 DR. BOEHLERT: But even looking at

11 accuracy, precision and some of these other

12 measurements when you are talking about testing in

13 kilograms in a blender may be different than they

14 are when you are talking about testing small

15 quantities of material, and I am just wondering if

16 some guidance might not be necessary to avoid many,

17 many different interpretations of how to accomplish

18 this.

19 DR. LACHMAN: Well, I think what can come

20 out of the details here could be a separate

21 guidance, but I think the main purpose of

22 referencing the present guidances was that these

23 are available and what do we have to do to make the

24 guidance either fit or change the current

25 guidances. I think it is just a reference to what

60

1 is available. We don\'t have to redo those if they

2 apply. If they don\'t apply, then we develop an

3 appropriate guidance.

4 MR. HAMMOND: On the basis that a lot of

5 the results that come out of this technology will

6 be signatures rather than conventional

7 concentration values, I don\'t see how the ICH

8 guidelines can possibly fit.

9 DR. LACHMAN: It is not really to fit, it

10 is just to list those guidances that are currently

11 available, that have been used in the past for the

12 conventional procedures. Really that is all it is.

13 DR. RUDD: We addressed this in a meeting

14 in London, in October of last year, and we

15 concluded that for process measurement the existing

16 ICH documentation \-- and you are quite right that

17 we shouldn\'t reinvent the wheel; we should go with

18 what is out there already \-- but ICH documentation

19 does not in any way address some of the peculiar

20 issues of process measurement, and there really is

21 a gap to fill. We sort of half attempted that from

22 the meeting we had. We had sort of an arrogant

23 idea of publishing something that could be a

24 supplement to ICH. I think the key point is that

25 the philosophy of ICH does apply, the general

61

1 concepts behind what I see ICH wrote I think are

2 universally applicable. But there are clearly

3 aspects to process measurement that are quite

4 different. We don\'t want to reinvent the wheel but

5 I think we should recognize here and now that there

6 is a vacuum to fill and we would be well advised to

7 fill it.

8 DR. LAYLOFF: I was just nodding in

9 agreement with that. When you are looking at

10 process assessments, the ICH is I think pretty much

11 locked to the API univariant assessment of quality,

12 and this is more looking at signatures, sometimes

13 undefined signatures.

14 DR. LACHMAN: Well, it is an inference to

15 the quality but it is undefined at some times too.

16 DR. RAJU: I notice that you have

17 chemometrics there and that is going to be

18 discussed in the next section, but chemometrics is

19 there as data treatment and, since we are thinking

20 of PAT in kind of a broad guideline which includes

21 different kinds of physical and mathematical

22 measures of measurement and chemometrics is

23 positioned as an analysis that happens later, if

24 you formulated in that sentence, say, independent

25 of the different chemistry and physics of the

62

1 instrument, chemometrics is just another sensor,

2 which is a mathematical instrument, and then the

3 analysis fits into that framework and, just like

4 physical and chemical, you now have mathematical

5 sensors, what would be the problem of incorporating

6 that in this framework in terms of validation?

7 DR. LACHMAN: Well, that was just one of

8 the approaches. The other approach was to design

9 the particular statistics and computer requirements

10 for the feedback mechanism for the controlling of

11 the process. Chemometrics was mentioned because

12 that could be one component, one approach. That is

13 all that is. It uses math; it uses some

14 statistics.

15 DR. RAJU: But what if the math isn\'t a

16 sensor?

17 DR. LACHMAN: Well, then we have a

18 different approach. We don\'t use that approach.

19 DR. RAJU: You need a different approach

20 then.

21 DR. LACHMAN: Yes, no question.

22 DR. LAYLOFF: We will move on to Mel who

23 is going to give us the final answer, chemometrics.

24 Chemometrics

25 DR. M. KOCH: Thank you for that

63

1 introduction.

2 \[Slide\]

3 Let me just make a comment that was what I

4 feel behind the introduction. It is perceived that

5 I understand a lot about chemometrics because the

6 center that I represent was one of those that

7 started in the field. I work very closely with

8 people who take chemometrics and have an impact on

9 it. As a result, when we get into the details of

10 what I am actually talking about, I have selected

11 people in the audience who are going to stand up

12 quickly and defend the positions and explain the

13 reasoning. However, it is not hard at all to talk

14 about this field, and it was mentioned that, okay,

15 this comes now at the end of what you just heard.

16 In our working group we had a very

17 difficult time finishing on time. We had no

18 alternate subjects to get into. This is an

19 emerging field, proven in other parts of industry

20 at a minimum. It has gone far beyond curiosity in

21 terms of mathematical techniques and is, indeed,

22 showing results. I believe in some of the, say,

23 reluctance by the statistician to look towards 6

24 sigma, tools like this take one along the road in

25 designing for 6 sigma. So, we will move along on

64

1 some of this.

2 \[Slide\]

3 This is a little bit of a busy slide but

4 it introduces some of the rationale for excitement

5 in this particular field. The first parallelogram

6 you see up there is a cycle. I call it

7 developmental cycle and you can jump in at any

8 point that you want, but to start with the reactor,

9 the reactor pretty much represents, let\'s take, a

10 process optimization as what we are now developing.

11 The experiments that are being run, be it

12 mini-reactors or other high throughput devices, it

13 is generating samples. Those samples have to be

14 analyzed, the data from those analyses evaluated,

15 and then you get into your design of the next

16 experiments and then continue on.

17 The DOE part of that, the experimental

18 design is represented below in terms of some of our

19 calometric terminology in that the DOE does require

20 a number of pre-processing calibration diagnostic

21 tools for eventual continuation of the process

22 prediction and validation. A quick example of why

23 all this will be important comes in \-- let\'s just

24 do process optimization again and we can borrow

25 from industries that are well advanced in this

65

1 field and take the chemical industry, which is now

2 using these cycles for catalyst evaluation, monomer

3 preparation, a number of process parameter steps.

4 In the operations within these labs, historically

5 they have been running using process chemists,

6 running several experiments a day and relying on

7 well-equipped analytical labs to analyze the

8 samples.

9 With the need to speed up development,

10 time to market, improvements, etc., and reduction

11 of cost, particularly capital costs as they are

12 being translated to running pilot and development

13 scale activities, we are running more and more

14 reactors. We are now easily up to the hundred per

15 day using high throughput approaches, which takes

16 down the need for analysis. You need to do

17 analysis every ten minutes. As this continues to

18 grow, you no longer have time to send things to a

19 lab. You have to make fast decisions. You have to

20 extract things from your analytical profiles. You

21 probably don\'t have time to do full spectrum or

22 chromatographic separations but you have to quickly

23 pull from pieces of that analytical data, which is

24 use of chemometric technology. So, it is not as if

25 one is trying to think of where we can apply it; it

66

1 is going to be forced very quickly and let\'s just

2 assume it is going to be a part of everybody\'s

3 program.

4 \[Slide\]

5 The role of chemometrics in the

6 application of the PAT as we are seeing it is the

7 application of sound mathematical and statistical

8 tools requiring chemical knowledge. This is kind

9 of a distillation of a number of definitions that

10 Jerry gave yesterday, but we are trying to

11 emphasize that the chemist is in a position to

12 understand the statistics rather than to have a

13 statistician come in and try to understand the

14 chemistry that has just been applied here.

15 \[Slide\]

16 How do we see the role of chemometrics

17 more broadly? This is a little bit out of order

18 but it really comes down to monitoring modeling and

19 control, the key aspects. In the monitoring phase

20 we are trying to support the process through the

21 use of the analyzers and sensors and effective

22 calibration, and building models as a result that

23 are deterministic and help us in identifying and

24 deriving the state of the process, and then on to

25 control to actively manipulate the process to

67

1 maintain a desired condition.

2 Very important in all of this is the fact

3 that diagnostics are needed in each one of these

4 steps. Some of you have probably interacted with

5 production people, and any time there is something

6 close to an upset, the sensor is pulled out first

7 and somebody is accused of not getting the right

8 measurement, and long down the list is perhaps that

9 the process has gone bad. So, diagnostics are

10 really to show the status of the instrument and how

11 close it is to defining that which it was intended

12 to do, together with the use of chemometrics to

13 evaluate then the process and to have mechanisms

14 for the feed forward of the results.

15 \[Slide\]

16 Now we are progressing along. If you

17 would refer to the questions that we were given as

18 a working group, I think we have defined now the

19 role of the chemometrics and we get into what are

20 some of the tools that are going to be needed.

21 This is certainly not an all-inclusive list, but if

22 one has a full grasp of this list you are probably

23 in good shape to start seeing the results, things

24 like the pre-processing; regression tools; the

25 classification discrimination; outlier detection

68

1 and that comes back later in terms of how do you

2 effectively gather outliers when you are trying to

3 run a process in compliance; the homogeneity

4 checking; the design of the next experimentation;

5 and the data visualization; and although it is at

6 the bottom of the list, very, very important is to

7 make sure that there is some kind of uniform

8 understanding of the terminology. This is an

9 interdisciplinary concern. It even goes beyond the

10 PAT that we are talking about, but we are

11 dangerously close to having production folks,

12 developing folks and discovery people all trying to

13 use similar approaches and at times you can have

14 similar approaches used by different disciplines

15 and mixing in terms of what it is you are really

16 trying to do. I am seeing a lot of that just in

17 the process analyzer world where what an engineer

18 thinks you said isn\'t quite what the measurement

19 scientist said or meant. So, terminology is

20 important.

21 \[Slide\]

22 What is needed for successful PAT using

23 chemometrics? Certainly adequate measurements with

24 the knowledge and experiments that go along with

25 that; representative samples, again knowledge and

69

1 design that is associated with it; adequate

2 analysis with getting the proper clarity, the

3 reproducibility and, hopefully, the transfer of the

4 data and implications; adequate data management at

5 pilot through production stages; and then the other

6 points of validation, the standard reference

7 samples, emphasizing again some of this

8 auto-diagnostic capability.

9 \[Slide\]

10 What is needed to develop, validate and

11 maintain a chemometric-based PAT? Overwhelmingly,

12 it is quality data. If you want to get into this

13 scenario we referred to yesterday of waiting three

14 generations for the next time you have a chance to

15 do something, you have to make sure you have

16 quality data, and the instrumentation is well

17 understood, the data sets are well presented, and

18 then you begin to apply these techniques. You need

19 it at the reference sample stage. You need it

20 continually from the routine product. Then, the

21 difficult one is you need this data from outliers,

22 or something, to effectively use the tools and that

23 presents some challenges within the industry.

24 \[Slide\]

25 Currently accepted tools in industry \--

70

1 this is not all-encompassing but just referring

2 back to some of what Jerry talked about yesterday,

3 there are things unfolding in industry in general

4 with the use of parametrics, some of the EMEA, etc.

5 and the PASG, and then there are a few others that

6 were in Jerry\'s presentation I believe, slides 22,

7 23 where you can get more data. Then, one of the

8 other ongoing initiatives is something we talked

9 about briefly yesterday, within CPAC we have

10 started to pull together an approach to try to

11 define minimal requirements for ruggedness and

12 other things that one needs to address when taking

13 chemometrics into a production environment.

14 \[Slide\]

15 One of the things that we see that is

16 needed in validation is to make sure that we have

17 both initial and ongoing validation approaches to

18 assure that the DOE does lead to representative

19 data, that measurements are adequate, process

20 sampling and algorithms are okay; the same with

21 model validation and then be in a mode where

22 everything we are doing could be structured to be

23 predictive in final product properties, process and

24 control, and other things that relate to validation

25 considerations.

71

1 \[Slide\]

2 One of the big topics that we found is

3 once we identified what chemometrics was and its

4 role in PAT, very quickly you can come to how are

5 we going to effectively train people in

6 understanding and applying this? There is

7 certainly not an excess of folks who understand it,

8 who can train in it and participate. So, we are

9 encouraging the ongoing participation in these

10 conferences, symposia and workshops in the field.

11 More particularly, I think FDA needs to have

12 in-house short courses for people who are available

13 and, as much as possible, to make these case-study

14 related so one sees a real result and a real

15 problem addressed. Direct involvement with

16 consortium, and we have at least three that jump up

17 in CPAC and the MCEC at the University of Tennessee

18 and the CPACT in the U.K. Those provide certainly

19 a forum for discussion. Then you get to the next

20 part. At least within CPAC we have a calometrics

21 focus group which is multi-industry and has a lot

22 of cross-talk and discussions and the source of

23 initiatives like I mentioned earlier, in fact, this

24 COLI or calometrics on-line initiative.

25 Industry perspective is needed within the

72

1 agency to better understand the background and

2 training for people doing this, and it is always

3 difficult but I think what has worked as quickly as

4 possible being part of the training is important.

5 \[Slide\]

6 Recommendations \-- and I don\'t know that I

7 would say that this is all that we would recommend

8 but coming up early are a look for general

9 exemptions from reporting, the PAT data for batch

10 records collected for the purpose of investigating

11 new technologies, recommendation that the guidance

12 evolve from very simple examples models towards

13 those complex ones, and that chemometrics is a tool

14 for the reviewer that could be explained as to its

15 role in the guidance. I am not sure if that is a

16 clear point but we will work on clarifying that.

17 Then, make it an audit function versus a review

18 function.

19 That is it, and I would encourage any

20 questions, etc. I notice that people who are able

21 to answer them are still in the room.

22 Subcommittee Questions and Answers

23 DR. LAYLOFF: Any questions or comments?

24 DR. HUSSAIN: I have a couple of comments.

25 One is with respect to the design of the

73

1 experiments. For the sake of argument, if I use

2 NIR-infrared as an example, what you learn from

3 your development experiments, which should be

4 design experiments, translating that to a larger

5 scale creates problems. So, I think in terms of

6 design of experiments you are actually limited in

7 terms of developing this on a real large scale.

8 There are limitations to that. How would one

9 address that?

10 DR. WORKMAN: One of the issues we were

11 discussing there is to make sure that you are

12 following good science, not necessarily relating

13 that to the practice of how you would follow the

14 good science, but good science is that if you are

15 calibrating a system, for example, you are

16 interpolating within the concentration space, the

17 multivariate space, and that you have that space

18 well represented; it is homogeneous. Good

19 experimental design requires that. Now, how you

20 implement that is another issue but these kinds of

21 things can be clearly specified.

22 Then, on the validation end also how you

23 select validation tools that represent the extremes

24 of the space and how you test your system to make

25 sure that it is predicting well within the

74

1 interpolated space. So, that is more of a good

2 science issue and how you would describe that.

3 DR. MORRIS: If I could interject, I

4 agree. We sort of discussed this in the group too,

5 but if your model isn\'t working, whether it is a

6 chemometric model or a simpler model, then that

7 tells you that you are not looking at the right

8 things. That is what you want to know. That is

9 exactly you want at that stage so that when you get

10 to full scale, even if the coefficients change, you

11 know you have the right eye ball, you are looking

12 at the right part of the process in your

13 development and in your manufacturing. I think it

14 all comes back to that. So, it should work

15 assuming that you don\'t have some innate problem

16 otherwise.

17 DR. WORKMAN: Another piece of that is

18 that also as you look at any unknown sample, you

19 know where that sample is representative to your

20 space. Is it outside the space or is it in a well

21 represented space. So, the good science is there

22 and it is describable.

23 DR. HUSSAIN: Just sort of an interesting

24 number that I have in my mind is the extent of use

25 of DOE in pharmaceutical development. Do you know

75

1 the number? Three percent of companies use DOE

2 today. This was from a survey Prof. Shangraw had

3 done sometime ago but I think the numbers are still

4 accurate. So, design of experiments is something

5 novel, although it is not novel outside the

6 pharmaceutical field, so that is the challenge you

7 are looking at.

8 DR. LAYLOFF: And you think you are going

9 to ramp up into PAT?

10 \[Laughter\]

11 DR. HUSSAIN: No, I think the point I want

12 to make here is in the sense of for application for

13 PAT in terms of a number of things, at least when I

14 was there with the chemometrics working group, we

15 discussed this. For many applications you really

16 don\'t need any modeling at all. So, you have a

17 whole range of issues to deal with, and in some

18 more complex ones is where you need modeling. I

19 was talking to Doug Ellsworth and I think it was

20 discussed in the validation group that for some of

21 the more complex attributes where you are looking

22 at the multivariate correlation, those will emerge

23 over time when you have real-life data from your

24 sensors being accumulated. I think that would sort

25 of summarize what he just told me in terms of how

76

1 one could validate that using production

2 information. I think that would be helpful.

3 MR. ELLSWORTH: Ajaz may have given me a

4 bigger charge than I realized. No, I was

5 reflecting to Ajaz the discussion that we had when

6 we discussed do you really have to take things to

7 failure to really understand what that PAT

8 technology is showing you, and the point was that,

9 no, you don\'t but oftentimes you are in a much

10 narrower range than the regulatory range would be.

11 We said that was okay, you could validate PAT

12 within that narrower range, and if you saw trends

13 or information \-- I think that was captured on the

14 slide \-- things that were outside that PAT range

15 are not really considered failures; they are

16 considered alerts. That would trigger the use of

17 conventional testing methodologies to determine if

18 a product meets regulatory specifications, and

19 would trigger \-- I don\'t want to use the term

20 investigation, but I think an assessment of the

21 manufacturing process to see what has changed and

22 what can be done to improve that process or get

23 further control of it.

24 DR. HUSSAIN: Or, you are still within the

25 specifications, you can update your model. That

77

1 expands the range of the model.

2 MR. FAMULARE: I think further than that,

3 a discussion that came out of the validation group,

4 and that was somewhat captured on the slide too by

5 Leon, is that GMP allows for continuous improvement

6 so that as these things are found you can react to

7 them, do what is necessary or put in what is

8 necessary under GMP and just move on. So, we want

9 to make the path for doing that as smooth as

10 possible. That was a good bit of the discussion

11 that we had in our GMP group, and we wanted to be

12 able to have the flexibility to make those process

13 improvements without filing under GMP so long as it

14 didn\'t involve a change in specification or a

15 change in the basic principle of what the product

16 was going to be versus the submission batch or the

17 pivotal batch. But continuous process improvement

18 should be a smoother process, we hope, under this

19 than maybe the current paradigm and this,

20 hopefully, will be part of the encouragement aspect

21 of it.

22 DR. MORRIS: Referring to something you

23 had said earlier, Ajaz, whether you are using

24 chemometrics or not, you are always using a model.

25 It may be a linear relationship or something, but

78

1 you have to have some model unless you are just,

2 you know, saying is it there. That is the only

3 thing you don\'t need a model for in the statistical

4 sense. But there is also the physical model, which

5 is the physics or physical chemistry-based model,

6 and the knowledge of that will always help design

7 the other model that you are looking at if you know

8 that there is a physical basis. So, just a

9 clarification.

10 DR. HUSSAIN: The point I was making is

11 that even the simplest design of an experiment,

12 with the number of factors we deal with, I think it

13 is impractical in the sense of pharmaceutical

14 products. So, I don\'t want to put that as sort of

15 a requirement that the design of an experiment is

16 the only way out of this.

17 DR. MORRIS: Yes, and it is certainly not

18 a way to identify variables that you haven\'t

19 identified already. You can\'t design an experiment

20 to come up with that. I don\'t know, maybe you

21 should comment on that.

22 MR. LEIPER: I think the point that Ajaz

23 makes is a very interesting one, and that is one of

24 the reasons that one might ultimately want to go to

25 continuous processing because, obviously, a time

79

1 slice is representative of that process and we can

2 get the dimensionality into a time slice that we

3 can\'t get in scaling-up processes. Of course, the

4 scaling-up that we do in processes now is a gross

5 risk because we don\'t know what the critical

6 parameters are anyway. So, there are probably an

7 awful lot of good ways around this if we care to

8 take the time to think it through. DR. WOLD: To

9 continue the discussion on experimental design, I

10 think there is a general misconception that design

11 of experiments applies when you have three, four or

12 five factors, or so on, that they should be

13 temperature, and pressure, and pH. But there has

14 been an enormous development within chemometrics

15 but also in statistics on the experimental design,

16 and there is a large number of different approaches

17 to deal with as complex issues as you want.

18 But to go back to the practical issues, in

19 this discussion group we did not mean that you

20 should take the results of a design, let\'s say, in

21 lab scale and start to apply that in production

22 scale. What we meant is that whenever you to

23 experimentation, for instance, at least in Sweden

24 when you put the process in use, before that you

25 have to do robustness studies and some kind of

80

1 validation. It pays a lot to do both of those in a

2 designed way. You save experiments; you get much

3 more information and the factors you change are

4 those that you know from development, knowledge and

5 so forth that they influence the process. But

6 robustness means that you ensure that when you

7 change them within your controlled region not much

8 happens to the results. Now, if you do that in a

9 designed way you have a very, very nice basis for

10 calibrating your chemometrics models because you

11 have expanded the space that you are interested in.

12 Of course, there will be a lot of additional

13 factors downstream that result in what you do

14 upstream, and those you can\'t control but you can

15 still include them in the modeling.

16 DR. HUSSAIN: Just to clarify my point in

17 the sense that if you look at my publications

18 before I came to FDA, the are all statistical

19 design of experiments because that is what I was

20 pushing for at that time, and I am still pushing

21 for it but I am being pragmatic and I just want to

22 keep on the table the extreme range of options that

23 we have to bring this technology successfully in.

24 I just don\'t want to have the impression that this

25 is the only one way of doing that. That is the

81

1 point I was trying to make. I am a proponent for

2 design of experiments, especially in pharmaceutical

3 development, because I use the phrase \"I know it

4 when I see it\" and I think the way we set

5 specifications, we have very little information

6 really to set those specifications currently. If

7 we have the design of experiments, we can not only

8 have wider specifications which are relevant and,

9 at the same time, you already have the concept of

10 making your own SUPAC. You know you have a value

11 or you have a range of values that your

12 specifications are final and related back to your

13 process or formulation variable. That is the

14 advantage, but the reality is that the use of sound

15 experimental designs is not prevalent in this

16 industry.

17 DR. WORKMAN: If it would be helpful, we

18 could call it a cookbook approach, but I think one

19 of the issues is that without the design of an

20 experiment you can\'t treat the PAT as a black box

21 at all. You really have to describe everything you

22 are doing.

23 DR. HUSSAIN: I think Tom raised the

24 consistency. I think how you use the tool for,

25 what purpose you use the tool for has to be kept in

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1 mind.

2 DR. RAJU: Tom, one of the recommendations

3 of the chemometrics subcommittee, the first

4 recommendation was a general exemption from

5 reporting PAT data to the batch records collected

6 for the purposes of investigating new technologies.

7 Does that fit already into the CGMPs guidelines and

8 it doesn\'t need to be pursued further?

9 MR. FAMULARE: In terms of collecting

10 additional data in the CGMP guidelines, I think we

11 discussed some of that in our validation group, if

12 that data is there it is part of the record.

13 Whether it is in with the batch record or as a

14 separate set of records, the physical location of

15 the records is not that important. If the

16 investigator sees it, I think the important thing

17 is to look at is if it is part of the process

18 improvement. That is going to be a key part of our

19 training as we work with compliance and field

20 people. Again, I have probably said this three

21 times, as Ajaz started out in his slides, we are

22 taking what we have now as adequate for intended

23 use. So, as we learn more and we record more and

24 it shows a variable we will allow for flexibility

25 to deal with those variables. Over time, the hope

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1 of this whole thing is that the company will

2 improve their process and eliminate the chance for

3 out of specification results, recalls, etc. because

4 this will be plowed into good use, this data, and

5 be able to better control the process. But a

6 process that is already established under the

7 existing paradigm as acceptable will stay that way.

8 MR. COOLEY: I think the concern with what

9 we discussed and why we put that point in is

10 because there have been some behaviors out in the

11 field that would indicate that is not the case.

12 You know, there is a concern I think in industry in

13 general that that data will be used against us

14 somehow rather than be looked on as positive, that

15 you are trying to improve your process. The reason

16 it was put in there the way it was is that if it

17 could be exempted from examination, then that may

18 make the industry a lot more open to experimenting

19 with these technologies, particularly on existing

20 processes.

21 MR. FAMULARE: The data that is generated

22 in a company in terms of exempting that data or

23 putting it somewhere an investigator can\'t see it

24 is a hard thing to parse out in a guidance. I can

25 only think of one example where, in a compliance

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1 policy guide, we asked that internal self-audits

2 not be reviewed by FDA even though they have the

3 regulatory ability to do so. In this case, to take

4 data relevant to a batch and to somehow deny it to

5 an investigator \-- I don\'t think there is going to

6 be a proactive approach or will bring the

7 investigator up to where we want the investigator

8 to be in accepting and learning about this data and

9 working with it. That approach would, to me,

10 indicate that, well, we will just deny the

11 investigator access to that information and I don\'t

12 think that is going to be proactive in the long

13 run, or positive.

14 The key is that as we write this guidance

15 we also have to give this guidance to the field,

16 and Doug has already taken on that responsibility

17 with Mike Olson, to make sure that they understand

18 that this is part of process improvement. We are

19 not taking away the processes as they exist now. I

20 understand the concern. It is going to have to be

21 a strong element of the training. Doug may want to

22 add to that.

23 MR. ELLSWORTH: Yes, I think I have to

24 echo what Joe is saying. Would we never, ever look

25 at that data and conclude that there is a problem

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1 with the manufacturing process? I can\'t say no,

2 but I think that if there is a conclusion that

3 these data show that there is a problem, what we

4 have to do is make sure that is not an independent

5 judgment made by an investigator. That has to be a

6 collaborative judgment made between CDER, the field

7 and the firm that is involved. But I think for a

8 general purpose we are going to want to see process

9 improvement and try not to inhibit that.

10 MR. COOLEY: To clarify what we are trying

11 to say, if you put an analyzer on-line there is

12 some period of time that you are going to go

13 through, particularly with the chemometric model

14 where you are developing that model and you have

15 not validated that analyzer. So, the data may not

16 be an accurate reflection of what is going on in

17 the process. That was the concern. Could that

18 ultimately be used against a company?

19 MR. ELLSWORTH: The answer should be no,

20 and I think we will have to make sure that that is

21 part of the training, not just training but put it

22 into our documents and directives that are issued

23 so that it is memorialized in some policy

24 statement.

25 DR. SHEK: I am not sure whether it is

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1 chemometrics or validation, but as I was listening

2 to the discussion here and talking about the

3 scalability, I mean, that is basically the trick in

4 the industry. We would like to do it in a five,

5 ten liter granulator and be able to know that in

6 1200 it will work the same way. The issue in

7 looking at PAT and whether the technologies is

8 already there, can we, for example, if we position

9 the sensors in a 5 or 10 liters or 75, do we know

10 where to position them in 1200? Which means do the

11 data that we collect on a small scale correlate on

12 a large scale? I don\'t know if people would like

13 to comment whether the technology is there so that

14 at least we can compare data.

15 DR. RUDD: I can offer a comment.

16 Positioning sensors is actually one of the things

17 we addressed in the validation meeting that I

18 referred to earlier. I think it is a

19 characteristic of PAT measurement technologies that

20 is different to laboratory based technologies. It

21 is one of the things you have to go through during

22 the validation of the methodology. Clearly, in

23 order to validate the methodology you need to know

24 the endpoint you are working to, and it is back to

25 the process signature. That, to me, is the crux of

87

1 the whole thing, knowing what it is you ar trying

2 to achieve so that when you transfer scale one of

3 the things you do to validate your methodology of

4 that new scale is to look at the influence of, for

5 example, sensor position in order to recreate the

6 signature you are talking about.

7 DR. SHEK: And that might change from one

8 product to another?

9 DR. RUDD: Yes, yes.

10 DR. SHEK: And change from a small mixer

11 to a larger one?

12 DR. RUDD: Exactly, yes.

13 DR. MORRIS: But, Dave, a point you made

14 actually during our committee meeting is that to

15 the degree that you can use the information you got

16 during one process. I mean, typically you will

17 keep the same equipment, so the next time you go

18 through it, even though there may be minor

19 adjustments, if you have established from one

20 product and you go from a given piece of equipment

21 to a larger piece of equipment, at least you have

22 some starting point for your product. I think that

23 was the point you made during our meeting.

24 DR. RUDD: Yes. Could I just ask perhaps

25 a question to the experts in the working group

88

1 about availability about chemometric tools,

2 developing this idea of process signature perhaps

3 will allow us to arrive at that broadly based on a

4 combination of fairly diverse measurements, for

5 example, you are going to develop the signature

6 from a spectroscopic measurement, maybe an acoustic

7 measurement, maybe some imaging data, maybe some

8 traditional classical measurements, pH and so on,

9 and so on. I just wonder if the chemometric tools

10 are out there to allow this sort of combination of

11 diverse measurement techniques to get an overall

12 picture of the process signature, as we are calling

13 it, or whether that is an area of research that we

14 need to recognize before those tools become

15 available. I don\'t know if anyone wants to pick up

16 on that.

17 DR. LAYLOFF: The only way I have ever

18 seen it is treating one homogeneous set at a time.

19 I have never seen, you know, linking together

20 diverse databases, except on bounds \--

21 DR. RUDD: And I guess that is the major

22 difference that we are talking about, combining

23 diverse data sets here, apples and oranges and how

24 it balances out.

25 DR. LAYLOFF: I think you are going to be

89

1 stuck with doing acceptance bounds on each segment

2 of the signature.

3 DR. RUDD: My question is are we, or are

4 there more sophisticated tools that are out there

5 that we need to be more aware of?

6 DR. HUSSAIN: David, I don\'t think that is

7 a limitation of the chemometrics, it is simply

8 availability of data. I mean, all you are looking

9 at are dependent and independent variables so you

10 have to treat it that way.

11 DR. WORKMAN: Can I address that? I am

12 sure Svante wants to say something but there are

13 data augmentation methods and standard classical

14 approaches are applied to two-dimensional image

15 data. So, it is a basic chemometric problem, but

16 data augmentation allows you just to string these

17 things and deal with them, and to normalize the

18 data so it has similar scales, and then to deal

19 with it as a large segment.

20 DR. RUDD: I don\'t want to get stuck on a

21 technical detail but I think we shouldn\'t

22 underestimate the complexity of what we are trying

23 to do. We are talking about, for example,

24 spectroscopic data. We are talking about

25 univariate measurements like pH and temperature.

90

1 We are talking about acoustic data where, you know,

2 I showed some wavy lines yesterday and, you know,

3 it is about feature detection from traces like

4 that. It isn\'t as simple as looking at tables of

5 Excel numbers.

6 DR. LAYLOFF: Svante has the answer up

7 there.

8 DR. WOLD: Well, I am not sure about that.

9 What we can say is that in about 1985 or so the

10 problem arose. We started to have too many

11 variable to put into one block. There is a variety

12 of so-called hierarchical multivariate models where

13 you put your different types of data into blocks,

14 and then on a lower level you make some modeling of

15 each block and then you take the resulting scores

16 and carry them up to the higher level. There is

17 nothing that prevents the blocks from overlapping

18 and in that way see the information sifting in a

19 more clear way. It solves this problem that, for

20 instance, two or three univariate measurements will

21 otherwise be masked by 300 NIR-infrared light

22 results.

23 It has another advantage too, and that is

24 if you have a model and you have 4000 FID

25 measurements, you don\'t turn everything upside

91

1 down. You just add another block and it is a very

2 mild operation.

3 DR. RUDD: All right. Forgive my

4 ignorance. Thanks.

5 DR. LAYLOFF: That is why we came here.

6 DR. M. KOCH: I was just going to add that

7 we are probably further towards being able to do

8 all of that than we are in the limiting regard that

9 you mentioned in terms of just the separateness.

10 One of the other initiatives that we have

11 undertaken at CPAC in conjunction with a food

12 industry initiative is to try to develop algorithms

13 on raw material quality and its effect, or the

14 variations in raw material quality and its effect

15 on final product properties. That is going to be

16 adopting a lot of different technologies. That,

17 coupled with some of the things that are going on

18 with multi-dimensional chromatographies and other

19 array approaches I think will put us further along

20 that road than would initially be thought.

21 MR. CHISHOLM: I think, at the risk of

22 people having to be here all afternoon and all

23 evening, it leads me to reopen something. It is

24 not just about not having enough data. One of the

25 discussions that we had, and in fact one of the

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1 things on the overhead which I thought would

2 provoke questions from the whole team was that a)

3 we mustn\'t threaten time to market under any

4 circumstances and, b) this means that we may have

5 to go back and still submit three validation

6 batches. I thought that would bring gasps of

7 concern because, obviously, if you do that you are

8 sticking with the old methodology before you move

9 to the new.

10 So, in terms of such predictive

11 technologies and lack of data, when we try to make

12 a submission how do we get around not having enough

13 statistical data to actually persuade the agency

14 that we can, in fact, go ahead and do it the new

15 way because we will not have enough statistical

16 data? I think in terms of validation, that is

17 probably one of the most significant questions

18 because time to market will be a big driver in

19 stopping us from going ahead if we don\'t manage to

20 get into some of these areas.

21 DR. HUSSAIN: To respond to that, in that

22 case PAT becomes a post-approval activity.

23 MR. CHISHOLM: We may have to face up to

24 that. I am trying to be realistic. I don\'t know

25 the answer to it, but I just wonder if in anyone

93

1 has any ideas about it because we didn\'t come up

2 with an answer in the validation group, and one of

3 the things you asked us to do, Ajaz, was to come up

4 with stoppers. Well, that is a pretty big one if

5 we don\'t solve it.

6 DR. LAYLOFF: Deathly silence!

7 DR. HUSSAIN: I think the solution has to

8 come from you, not from us.

9 MR. CHISHOLM: I am just an engineer!

10 MR. FAMULARE: We had the discussion,

11 Ajaz. This was a good point brought up by Bob, and

12 Bob felt that the regulators would want to see PAT

13 development from beginning to end in the process

14 and in scale-up and validation. The one thing that

15 I tried to emphasize is that validation in and of

16 itself is a post-approval activity. So, we

17 wouldn\'t want to hold up approval based on

18 validation. Then, all right, the product is

19 approved and if time to market is longer using PAT

20 versus doing three batches under the conventional

21 methods, well, that will be a discouraging factor

22 to companies. Until such time as data can be

23 developed for PAT, it may be a dual approach. They

24 may use their three batches to get to market, but

25 then move ahead with PAT, and PAT at some point may

94

1 overtake what was the conventional validation. But

2 not all of this is beyond the filing realm and the

3 flexibility should be there for companies to do so.

4 DR. DEAN: I would like to come to your

5 point, Bob. I don\'t think this is an answer to it

6 but perhaps another perspective. I think the way

7 we currently do these things, there is a functional

8 separation between the people that are trying to

9 get a product to market and the people that are

10 trying to produce it at commercial scale

11 afterwards. As long as that separation is there,

12 that is a problem to sacrifice time to market for

13 potential benefits that are further downstream. We

14 have seen some cases of organizations taking an

15 interesting step to give life cycle responsibility

16 for cost structures in an operational environment

17 that really cut across some of these

18 organizational, functionally oriented structures

19 that currently exist. When you do that, you

20 actually have the possibility to look at the

21 trade-off between time and getting it better. You

22 know, it is not always clear what the right thing

23 to do is, but at least then you have some degree of

24 accountability and someone who is tasked with

25 making that evaluation. Right now it really

95

1 doesn\'t happen and you have the situation that you

2 are talking about where time to market is never

3 compromised, and there may be cases where it would

4 be good to do so.

5 DR. KIBBE: In fact, the dollars push

6 towards avoiding anything that slows you on an

7 innovative scale, but we can look at different

8 segments of industry and imagine different segments

9 being interested in PAT at different stages in the

10 development. A company that has a lot of mature

11 products on the marketplace might see a real

12 benefit for going forward in terms of cost

13 containment. In a competitive arena generic

14 companies would gain a strong advantage in terms of

15 cost containment as a way of fighting out in the

16 commodity market and, yet, the innovators might

17 still view the risk adversely in terms of first to

18 market. I don\'t know whether we can change that

19 with a regulation.

20 I think that is the single biggest barrier

21 that we talked about in our group to fully

22 implementing PAT as drugs are going through method

23 development or development stages for a new drug

24 entity. What we also see internationally is that

25 companies go to market first some place else. If

96

1 that is the case, and that environment allows them

2 to go to market with PAT already fully developed,

3 our willingness on this side of the world, the

4 United States, to accept PAT as part of the

5 submission will just make it that much easier for

6 them in the long run.

7 So, all of those factors are in place and

8 we can\'t control all of them, and there is no use

9 us addressing all of them but we certainly can make

10 the environment here friendly and encouraging for

11 people to go to PAT.

12 I think the other thing is that as long as

13 the spirit of the regulation and guidelines are to

14 encourage, as problems come up with individual

15 submissions or individual companies with individual

16 products, if they find an encouraging and open

17 environment within the agency it is going to

18 promote them taking a little bit more risk in terms

19 of first to market or first on the shelf.

20 DR. LAYLOFF: Svante says he has one small

21 comment, and this is the last point on the

22 discussions.

23 DR. WOLD: I would just point out that you

24 have now renamed yourself to post-approval

25 technology committee. PAT has a new meaning.

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1 DR. LAYLOFF: Okay, Ajaz? While Ajaz is

2 getting ready, is it possible for each of the

3 working groups to get copies of each other\'s

4 slides?

5 MS. REEDY: They will be on the web site

6 by Friday.

7 DR. LAYLOFF: Thank you.

8 Summary

9 DR. HUSSAIN: Well, two days have passed

10 and I think the discussion would have continued. I

11 am pretty excited to give the closing remarks.

12 Trying to reflect back, I went to my office to try

13 and put some of this together and I was a bit

14 apprehensive about what will come out of these

15 working groups. That was a bit scary to me but I

16 am pleased with how things have turned out.

17 \[Slide\]

18 The question was why are we here, I think

19 from my perspective, to find a better way to sell

20 to our customers. I think industry and FDA have

21 one common customer and that is the U.S. patients.

22 We wanted to do this by improving our manufacturing

23 and also associated regulatory processes. In some

24 way, we did a gap analysis, at least in some parts

25 of the meeting early on.

98

1 We wanted to build some consensus on

2 better understanding the potential role PAT can

3 play, and also to come on the same page to some

4 degree. I was talking to Ken Leiper and he said,

5 come on the same page? We will be happy if we come

6 in the same book. But based on the summaries that

7 we have seen, I think we do have consensus on the

8 benefits. We did achieve a lot at this meeting.

9 We wanted to identify real and perceived regulatory

10 hurdles and initiate the process of finding

11 solutions.

12 \[Slide\]

13 We didn\'t come here to do this. I don\'t

14 know if you can read this, \"unable to determine the

15 structure of this byproduct by spectroscopic method

16 \-- you are worthless; you will never amount to

17 anything!\" So, we are not here to do this. This

18 comes from the chemical innovation journal. I

19 thought that was interesting but we didn\'t do this.

20 I was very pleased to see that.

21 \[Slide\]

22 Expectations and challenge at the end of

23 this meeting, in my opening remarks I said we

24 expect to have topics covered in the guidance, some

25 sort of an outline; lay out general principles for

99

1 setting specifications, validation and

2 chemometrics; and consensus on benefits,

3 definitions and terminology. That is work we

4 wanted to achieve. Listening to the discussion and

5 the summary presentations, I think we did that.

6 You can correct me if I am wrong in my assessment

7 of that.

8 The challenge I have seen was that we come

9 from different perspectives, expertise and

10 affiliations and I was worried about this issue,

11 can we come to the same page at the end of this

12 meeting. Again, you will correct me if I am wrong

13 but I think we did. I think we are on the same

14 page; not in the same book, on the same page.

15 \[Slide\]

16 So, I think we have accomplished what we

17 started to do, and that leads to my sense of PAT.

18 After listening to the discussion, I was not

19 expecting you to change the definition or the name

20 but I thought I would let you make the proposal so

21 this is not exactly what one of the groups made the

22 presentation on.

23 In listening to the discussions, I felt

24 that in my mind PAT are tools and systems that

25 utilize real-time measurements, or rapid

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1 measurements using processing of evolving quality

2 and performance attributes of in-process materials

3 to provide information to ensure optima processing

4 to produce final product that consistently conforms

5 to established quality and performance. It is a

6 bit wordy but I think that is my sort of take-home

7 of how PAT is starting from the definition I gave

8 you at the beginning of the meeting. It is not

9 perfect; it needs polishing but I will look at the

10 definition you have prepared and see whether we can

11 merge the two.

12 \[Slide\]

13 I still think options for introducing PAT,

14 the three I mentioned earlier, are still valid and

15 I think we need to have a guidance that covers

16 existing products in sort of a post-approval

17 activity to new products, and I think we need to

18 have a broad guidance that allows for these options

19 to be utilized by the industry.

20 The one which I labeled (b) where you have

21 current manufacturing problems is an opportunity to

22 improve, and to improve not only by trying to

23 understand your process better, not just tweaking

24 the process and hoping the auto-specification rate

25 goes down. So, I think in the current situation

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1 with the high level of manufacturing difficulties

2 that companies are having, option (b) is really an

3 option. But I believe all three options should be

4 considered and are useful for the guidance.

5 \[Slide\]

6 Next steps, we have to report back to the

7 parent committee so we will have a report on our

8 activities here at the next advisory committee for

9 pharmaceutical science. The meeting dates are May

10 7 and 8. I think Tom will make that presentation,

11 but we have Art and a number of people from that

12 subcommittee already here so the group will make

13 the presentation to the parent committee.

14 We plan to have a subcommittee meeting in

15 June. I don\'t have a date yet. I was hoping to

16 give you a date but I don\'t have a date, but we are

17 aiming for June, maybe the June-July time frame.

18 We hope to have a more focused discussion because

19 we intend to go back, reflect on this meeting, get

20 the transcripts and study those transcripts very

21 carefully, and come up with more focused questions

22 for you. In fact, my hope is that we actually will

23 have an internal draft before we come to you so

24 that we know exactly what questions to ask and get

25 you to give us some information that is useful for

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1 us.

2 One thought in my mind was if we can have

3 a real-life example, if we can sort of go through

4 one example of a PAT application, that might be

5 helpful. There is a question mark there because I

6 don\'t know whether that is feasible or not.

7 As you leave, I would like you to think

8 about what we need to do to prepare for the second

9 meeting. One aspect which I would ask you to do is

10 to seek input from your other colleagues within the

11 company so that you start bringing them in and

12 start bringing their questions to the meeting also.

13 I think this was a very good start, not only for

14 the information we received but I saw the

15 participation of our FDA colleagues and you saw it

16 too. I think we are working together as a team

17 internally and with you, on the external side, and

18 so the possibilities and opportunities are great

19 and we have to move forward beyond this. But give

20 some thought to what you think you could do to

21 prepare for the second meeting. Please feel free

22 to share your thoughts with us on how we can

23 improve the second meeting agenda. you have my

24 email, or you can send email to PAT@CDER.FDA.Gov.

25 So you have a simple email address for PAT and we

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1 will prepare for that.

2 \[Slide\]

3 I will end my presentation with what I

4 think is a win-win solution and what each of us has

5 to do to create that win-win. From an FDA

6 perspective, we are not going to bring the

7 technology. All we will be doing is provide an

8 unambiguous regulatory process for PAT. That is

9 what we can do. We can\'t do more than that. So,

10 the general guidance for industry will articulate

11 the regulatory position on PAT, our expectations

12 and the regulatory process. That is what the

13 guidance will do.

14 In doing so, we are collaborating with

15 industry and academia at this meeting and in other

16 arenas too. I have also talked about the second

17 track. We want to work with companies which have

18 done this so that we can bring information, train

19 our trainers internally and work with companies to

20 do that.

21 Industry has to do several things for this

22 win-win. It has to have the willingness to improve

23 and change. There are many challenges. I think

24 manufacturing is generally on the radar screen of

25 the higher CEOs and so forth. I think

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1 manufacturing needs to be recognized as an

2 important function. Some companies do and some

3 companies will not. Manufacturing is a side that

4 could be contracted out. So, I think you will see

5 different perspectives on that but I think

6 companies that do recognize manufacturing as an

7 important activity really are the ones which will,

8 I believe, bring PAT into existence. I think you

9 have the technology know-how and I think good

10 science is what you need to develop and apply in

11 your submissions and, again, collaborate with us on

12 how to move this forward.

13 Academia plays a very important role. We

14 do need knowledge, especially in the public domain,

15 so that not only we understand things better but we

16 make sure the field grows as it is supposed to, and

17 also future experts and leaders will come from

18 students who are probably just entering chemistry

19 programs.

20 With that, I really wish to thank you all

21 for your contribution. This has been a great

22 experience and I actually was apprehensive about

23 how this would come out. My feeling is that I

24 think it came out extremely well and useful for us.

25 I hope you will agree with that. Thank you very

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1 much.

2 DR. LAYLOFF: I also would like to thank

3 the presenters, Art, Judy, Leon and Mel for making

4 the presentations, organizing their presentations

5 and sessions. I would like to thank my former FDA

6 colleagues for their openness, attendance and

7 participation. I found it quite exciting. Of

8 course, maybe something is wrong with me. Anyhow,

9 the meeting is adjourned. Thank you very much.

10 Don\'t forget, send your comments to

11 PAT@CDER.FDA.gov. Thank you.

12 \[Whereupon, at 3:45 p.m. the proceedings

13 were adjourned.\]

14 - - -