DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE
Wednesday, May 8, 2002
5630 Fishers Lane
Vincent H.L. Lee, Ph.D., Acting Chair
Kathleen Reedy, R.D.H., M.S., Executive Secretary
Gloria L. Anderson, Ph.D., Consumer
Mary J. Berg, Pharm.D.
Joseph Bloom, Ph.D.
Judy P. Boehlert, Ph.D.
Patrick P. DeLuca, Ph.D.
John Doull, M.D., Ph.D.
Arthur H. Kibbe, Ph.D.
Marvin C. Meyer, Ph.D.
Nair Rodriguez-Hornedo, Ph.D.
Jurgen Venitz, M.D., Ph.D.
Tom Layloff, Ph.D.
(Robert) Gary Hollenbeck, Ph.D.
Michael S. Korczynski, Ph.D.
Kenneth R. Morris, Ph.D.
Leon Shargel, Ph.D., R.Ph.
Efraim Shek, Ph.D.
INDUSTRY GUEST PARTICIPANTS
Thomas Garcia, Ph.D.
Tobias Massa, Ph.D.
Ajaz Hussain, Ph.D.
Richard Adams, Ph.D.
Yuan-yuan Chiu, Ph.D.
Peter Cooley, Ph.D.
Steve Miller, Ph.D.
Bryan Riley, Ph.D.
Helen N. Winkel
C O N T E N T S
Call to Order: Vincent H.L. Lee, Ph.D. 4
Conflict of Interest: Kathleen Reedy 4
Process Analytical Technology
Introduction and Overview:
Tom Layloff, Ph.D. 9
Subcommittee Reports and Next Steps:
Ajaz Hussain, Ph.D. 30
Rapid Microbial Testing - Update
Introduction and Overview:
David Hussong, Ph.D. 70
Bryan Riley, Ph.D. 71
Michael S. Korczynski, Ph.D. 76
Open Public Hearing:
Jeanne Moldenhauer 104
Scott Sutton, Ph.D. 108
Introduction and Overview:
Ajaz Hussain 120
Tobias Massa, Ph.D. 131
Thomas Garcia, Ph.D 137
Regulatory Issues Related to Crystal Habits
Introduction and Overview:
Yuan-yuan Chiu, Ph.D. 176
Steve Miller, Ph.D. 179
Richard Adams, Ph.D. 200
(Invited Guest, Kenneth R. Morris, Ph.D.)
OPS Updates and Topics for the Next Meeting 223
1 P R O C E E D I N G S
2 Call to Order
3 DR. LEE: Good morning. I am Vincent Lee,
4 Chair of the Advisory Committee for Pharmaceutical
5 Science. I am calling the meeting to order.
6 The first order of business is the
7 Conflict of Interest. I ask Kathleen Reedy to read
8 us the statement.
9 Conflict of Interest
10 MS. REEDY: Acknowledgement Related to
11 General Matters Waivers. Advisory Committee for
12 Pharmaceutical Science, May 8, 2002.
13 The Food and Drug Administration has
14 prepared general matters waivers for the following
15 special Government employees: Drs. Marvin Meyer,
16 Mary Berg, Judy Boehlert, Jurgen Venitz, Gordon
17 Amidon, Vincent Lee, and Patrick DeLuca, which
18 permit their participation in today's meeting of
19 the Advisory Committee for Pharmaceutical Science.
20 The committee will discuss: (1) receive
21 summary reports and provide direction for the
22 Process Analytical Technology Subcommittee; (2)
23 discuss and provide comments on regulatory issues
24 related to crystal habits - polymorphism; (3)
25 discuss problems and provide comments to form a
1 scientific basis for establishment of acceptance
2 limits for microbiological tests that use newly
3 developed technologies that do not rely on colony
4 counts, and their application as process controls
5 and product release criteria; and (4) discuss the
6 current status of, and future plans for, the draft
7 FDA guidance entitled "Guidance for Industry,
8 ANDAs: Blend Uniformity Analysis."
9 Unlike issues before a committee in which
10 a particular product is discussed, issues of
11 broader applicability, such as the topics of
12 today's meeting, involve many industrial sponsors
13 and academic institutions.
14 The committee members have been screened
15 for their financial interests as they apply to the
16 general topics at hand. Because general topics
17 impact on so many institutions, it is not prudent
18 to recite all potential conflicts of interest as
19 they apply to each member.
20 FDA acknowledges that there may be
21 potential conflicts of interest , but because of
22 the general nature of the discussions before the
23 committee, these potential conflicts are mitigated.
24 We would also like to note for the record
25 that Drs. Leon Shargel of Eon Labs, Inc., Efraim
1 Sheik of Abbott Laboratories, Thomas Garcia of
2 Pfizer, Inc., Tobias Massa of Eli Lilly & Company,
3 Aziz Karim of Takeda Pharmaceuticals North America,
4 and Jack Cook of Pfizer Global Research and
5 Development are participating in this meeting as
6 Industry Representatives, acting on behalf of
7 regulated industry.
8 As such, they have not screened for any
9 conflicts of interest. With respect to FDA's
10 invited guests, there are reported interests which
11 we believe should be made public to allow the
12 participants to objectively evaluate their
14 Dr. Kenneth Morris reports that he serves
15 as a consultant, speaker, researcher, and has
16 contracts and grants from multiple pharmaceutical
17 companies. Dr. Gary Hollenbeck reports that he
18 owns stock in the University Pharmaceuticals of
19 Maryland and Aerogen, Inc. Dr. Hollenbeck would
20 also like to disclose that he serves as a
21 consultant and scientific advisor to University
22 Pharmaceuticals, as well as other pharmaceutical
24 Finally, Dr. Hollenbeck reports that there
25 are numerous companies contracts within the
1 University Pharmaceuticals of Maryland. Dr.
2 Michael Korczynski reports that he serves as the
3 Senior Vice President of Mikkor, which has a
4 fiduciary relationship with Afton Scientific
6 Dr. Korczynski also reports that he owns
7 stock in Abbott, Johnson & Johnson, Pfizer, and
8 GlaxoSmithKline. In addition, he serves as a
9 consultant for Lighthouse Instruments, LLC and
10 Afton Scientific. Finally, Dr. Korczynski speaks
11 for AAI and is a scientific advisor for Afton
12 Scientific Corporation.
13 In the event that the discussions involved
14 any other products or firms not already on the
15 agenda for which FDA participants have a financial
16 interest, the participants are aware of the need to
17 exclude themselves from such involvement and their
18 exclusion will be noted for the record.
19 With respect to all other participants, we
20 ask in the interest of fairness that they address
21 any current or previous financial involvement with
22 any firm whose product they may wish to comment
24 DR. LEE: Thank you, Kathy.
25 I would like to go around the table and
1 have the members introduce herself or himself,
2 beginning with Mary Berg.
3 DR. BERG: Mary Berg, College of Pharmacy,
4 University of Iowa.
5 DR. DOULL: John Doull, University of
6 Kansas Medical Center.
7 DR. DeLUCA: Pat DeLuca, University of
9 DR. MEYER: Marvin Meyer, Emeritus
10 Professor, University of Tennessee.
11 DR. KIBBE: Art Kibbe, Wilkes University.
12 MS. REEDY: Kathleen Reedy, Food and Drug
14 DR. ANDERSON: Gloria Anderson, Callaway
15 Professor Chemistry, Morris Brown College, Atlanta.
16 DR. BLOOM: Joseph Bloom, University of
17 Puerto Rico.
18 DR. VENITZ: Jurgen Venitz, Virginia
19 Commonwealth University.
20 DR. BOEHLERT: Judy Boehlert. I have my
21 own consulting business to the pharmaceutical
23 DR. RODRIGUEZ-HORNEDO: Nair Rodriguez,
24 College of Pharmacy, University of Michigan.
25 DR. SHEK: Efraim Shek, Abbott
2 DR. SHARGEL: Leon Shargel, Eon Labs.
3 DR. LAYLOFF: Tom Layloff, Management
4 Sciences for Health.
5 DR. KORCZYNSKI: Mike Korczynski, Mikkor
7 DR. HUSSAIN: Ajaz Hussain, Office of
8 Pharmaceutical Science, FDA.
9 DR. LEE: Vincent Lee, University of
10 Southern California.
11 Before I talk about the agenda, I have one
12 clarification to make for the record. When I
13 summarized the meeting yesterday, I gave somebody a
14 heart attack by what I said, not intentionally.
15 Let me see if I can get it right this time.
16 Otherwise, a new Chair.
17 That is, for Class I BCS Type 1 products,
18 since in vivo B was waived for fasting conditions,
19 the committee feels they ought to be waived for the
20 fed conditions, as well. That is for the record.
21 Today, we are going to be talking about
22 four issues. The first one is on Process
23 Analytical Technology, and so on, and so forth, and
24 I think it would be appropriate for me to invite
25 Ajaz Hussain to come up to the podium and give us
1 the introduction.
2 DR. HUSSAIN: Vince, what I would ask is
3 that Tom start the report to you guys for the
4 Advisory Committee, and then I will follow Tom and
5 gave sort of a progress report on what we have done
6 at FDA and propose some next steps, and then we can
7 have a discussion.
8 Process Analytical Technology
9 Introduction and Overview
10 Tom Layloff, Ph.D.
11 DR. LAYLOFF: Good morning.
13 I would like to talk to you today about
14 the Process Analytical Technology Initiative, which
15 is an FDA Initiative and for which I serve as the
16 chair of the committee.
18 In pharmaceutical development, the first
19 thing that happens is an active pharmaceutical
20 ingredient is identified to be a therapeutic agent.
21 My symbols didn't work out. That is supposed to be
22 an alpha on the far left, which is the beginning of
23 a process, and the question mark is supposed to be
24 an omega, which is the end of the process.
25 So we have an active pharmaceutical
1 ingredient, which is a therapeutic agent, which is
2 processed through a series of steps to give us a
3 therapeutic endpoint in the body.
4 The technologies we normally use for the
5 assessment of the active pharmaceutical ingredient
6 typically involve determinations of impurities,
7 looking for the active ingredient, and those
8 technologies often move forward into development
9 and into control, and then again show up again in
10 the body fluid analysis.
11 The question is, is that appropriate.
13 Is the API an appropriate process quality
14 surrogate marker for a process for manufacturing?
15 The focus has been on the API without regard for
16 excipients and processes, so that if you look at a
17 pharmaceutical process, you take the active
18 pharmaceutical ingredient, the technologies that
19 you use, and the identification of a moiety, and
20 you move it into development, and you keep tracking
21 the pharmaceutical ingredient using the same
22 assessment technologies.
23 Now, as you add excipients in blending,
24 you continue to watch the active pharmaceutical
25 ingredient, and the question is, is that a
1 reasonable thing to do. It is a univariate handle
2 on a polyvariate problem and the question is, is
3 the API a good surrogate marker for the process, in
4 many cases it is, and cases it is not.
6 The PAT is to change the paradigm. Look
7 towards broader product quality dimensions. Use
8 new assessment technologies and new product
9 assessment targets. Shift from interrupted unit
10 operations to on-line/in-line assessment on
11 continuous process streams.
12 Now, the way it is done currently, you
13 blend, stop, sample, test, move to the next step,
14 so you have a series of steps, staircase steps as
15 you move to product. The intent of PAT is to move
16 technologies on-line/in-line, so that line streams
17 out to a smooth presentation.
19 This is one of Ajaz's slides which I
20 borrowed, and it shows that if we go to the new
21 technology in-line, you actually have the device
22 sampling the process itself and monitor it to a
23 performance endpoint rather than sample, take it to
24 the laboratory, hold everything until the results
25 come back, and then proceed.
2 The assessment tools and support systems
3 and technologies are available to improve the
4 consistency, reduce bad production and recalls.
6 The consistency assessment tools that are
7 available now for it are spectrophotometric methods
8 like near infrared, laser-induced fluorescence,
9 Raman, various ATR, attenuated total reflectance
10 methods when you are using crystals or optics,
12 There are other technologies, such as
13 acoustic monitors, image field analysis,
14 thermometers, pH meters, oximeters, on-line chip
15 analyzers, many of which are already used in the
16 biotechnology industry. We will come back to some
17 of these.
18 Image field analysis is quite interesting
19 because it's like preparing a stew. You put
20 everything in the bottom and then you stir it up
21 and see if it's uniform. In image field, you look
22 at the image at intervals and see if it's
23 consistent, so it's basically a variance of image.
24 When the variance is reduced, then, it's blended to
25 its completion.
2 These are the members of the PAT Committee
3 - Gloria Anderson, Joe Bloom, Judy Boehlert, Art
4 Kibbe, and then a bunch of individuals who had
5 applied through the Federal Register announcement
6 and are on the committee. The rest of them are
7 listed there.
8 They come from various organizations and
9 industries, and the PAT was developed into four
10 working groups. There is Applications and
11 Benefits, which was chaired by Art, Chemometrics by
12 Mel Koch, Process and Analytic Validation by Leon
13 Lachman, Product and Process by Judy Boehlert.
14 I have asked Judy to give a few remarks on
15 her committee, if she would. Did you want to say
16 anything, Judy?
17 DR. BOEHLERT: When you put it that way,
18 Tom, I would be happy to say a few words. What I
19 did this morning when Tom asked me to make some
20 comments was to go back over the conclusions that
21 came out of my committee.
22 We have a very productive discussion, and
23 this was once again the Process and Product
24 Development Working Group, and I am going to just
25 read some of the conclusions that we came to.
1 First, the group agreed that the benefits
2 are under-utilized, there needs to be some selling
3 done here. People don't realize what PAT can do for
4 them. It would apply to most areas of the
5 manufacturing process, but there are different
6 levels of maturities for some of these techniques
7 that Tom mentioned.
8 Some are ready to go now maybe, others are
9 a bit further away. It may not work in all cases.
10 There are instances where PAT is not going to help
11 you very much. The feedback controls that you have
12 on the process may mean that when something goes
13 wrong, you don't lose the entire batch. You have an
14 opportunity to make corrections while the batch is
15 processing, and that is a good thing.
16 Guidance that FDA comes out with shouldn't
17 be limited to when you think about the use of
18 alternative methodologies and technologies. Tom
19 had a list, but there may be other techniques we
20 haven't even thought of yet, that will be applied,
21 and there needs to be a mechanism for putting those
22 in place.
23 What we are doing is going to a
24 multivariate approach. The variables that may be
25 more pertinent to the process, they might not be
1 the ones we looked at in the past, and there needs
2 to be a regulatory way to be able to submit those
3 because, in fact, the parameters that you filed may
4 not be the ones you are measuring now, and, in
5 fact, you may not comply.
6 There will be engineering issues involved
7 with this approach because if you start trying to
8 apply new technologies to old systems, you may need
9 to look at those old systems. It may only apply to
10 some process or some operations in a process, and
11 that is not necessarily bad. There may be
12 incremental advantages to being a part of the
14 Very often, whether you implement PAT or
15 not is going to be a business decision. People
16 didn't really see technical down sides, but it is
17 timelines, how does it impact on timelines, do you
18 have the resources available to implement these
19 technologies. It has potential for reducing OOS,
20 potential for perhaps predicting product
21 performance, things like dissolution.
22 It is not going to do away with stability
23 studies. It may predict that you have a more robust
24 product, but people don't see that that is going to
25 go away.
1 So the conclusion of the group in general
2 was that there is an advantage to using PAT because
3 it leads to a consistent, more high quality
4 product, however, there was a down side, and I left
5 that to last. There are a number of people in
6 industry say it is not broke now, don't fix it. It
8 DR. LAYLOFF: Art, did you want to comment
9 on your committee?
10 DR. KIBBE: To respond to your question,
11 the committee was filled with wonderful people, but
12 we were looking at applications and benefits, and
13 for us, we started looking at the broadest
14 application. We felt there was application for the
15 technology of PAT to be applied to practically any
16 product in any environment.
17 We thought that there were going to be
18 great benefits and that there would be a learning
19 curve, and as companies began to use technology and
20 put it in place, and begin to see the benefits,
21 that the next step, and the next step would come a
22 little easier.
23 All four subcommittees responded to some
24 general questions, and I think therein lies the
25 direction that we want to give to the agency in
1 terms of its guidance. We started out as a
2 complete group, a definition of PAT, and our
3 subgroup added the word "critical."
4 We felt like just because you can measure
5 it, doesn't mean you should measure it. You should
6 be measuring what is important to the outcomes.
7 One of things that we were concerned about is that
8 the process, the user of PAT generally generates a
9 huge amount of data as opposed to the current
10 method of sampling and getting discrete answers
11 about the concentration of actives in the sample,
12 or so on.
13 So the question arose in terms of the
14 guidance what do you do with all this data, and is
15 that data going to be much tighter than our general
16 requirements for any individual product, what is
17 the agency going to do about that data, and so on.
18 So the issues surrounding the guidance
19 boil down to hoping that, first, the agency and the
20 industry could work cooperatively towards improving
21 the manufacturing process in every area, that it
22 would not be viewed by companies as a means for the
23 agency to become more restrictive on their ability
24 to manufacture or make things. It wouldn't be
25 viewed as something other than it is, which is a
1 way of encouraging or empowering the industry to
2 move forward in a very open and honest way to
3 improve its own bottom line and hopefully, as a
4 result, that benefit the patients and the general
5 cost of health care.
6 We have a set of guidance suggestions,
7 which I think -- I don't know whether we want to go
8 through them now or you want to hold them until --
9 DR. HUSSAIN: I think it will help if we
10 could walk through them. That was an excellent set
11 of points, recommendations that came out I think.
12 DR. KIBBE: First, the guidance must allow
13 the development of PAT whose endpoint is a
14 signature of the quality of the process, because
15 the data that we capture is going to be interesting
16 in terms of the way it looks especially to some of
17 us old hands who expect to see, you know, some
18 nice, discrete numbers, and we get this pattern.
19 If you look at near infrared or some
20 others, you get a pattern of what the process looks
21 like and you say, okay, what does that mean, I have
22 got all these wonderful curves. We are going to
23 have to start accepting a signature or an pattern
24 as an endpoint rather than a discrete number.
25 It implies that we use it in an
1 environment of continuous improvement without undue
2 regulatory burden. While we see this as a really
3 beneficial process going forward, as with any
4 technology, when you are early on, you are not
5 going to ever get the best result, and we think
6 especially when most of the data that we looked at
7 was near infrared, and there are lots of other
8 techniques available, we are going to see great
9 improvement as times goes on.
10 All products have critical attributes,
11 quality attributes that need to be assessed, but
12 not everything needs to be assessed. Process
13 variables exist that can be controlled and
14 maintained, and these critical quality attributes
15 within acceptable limits, PATs are applied to
16 achieve both understanding and control of the
17 process and are causally linked to the product's
18 critical quality attributes.
19 We think it's a great way of making sure
20 that you never have to eliminate a batch, and we
21 were talking about continuous manufacturing
22 processes, how do they batch them now. Well, if
23 they are in a continuous process, they just take an
24 arbitrary time and they say everything produced
25 today is one batch, everything produced tomorrow is
1 another batch.
2 I think we are going to have to change
3 some of our thinking about how we lot and batch and
4 examine things, but that is going to be something
5 to look on down the road.
6 There are new and developing measuring
7 tools and guidances should not be limited to a
8 selection of a tool, and that is clear if you look
9 at the technology.
10 We want to encourage companies to move
11 away from current univariate prescriptive testing
12 to multivariate process focus measurements. We
13 want to identify the essential or critical factors
14 that should be considered.
15 PAT can apply to all six of the
16 manufacturing subprocesses, which is inbound
17 logistics, active ingredient manufacture, bulk
18 formulations, fill and finish packaging and
19 outbound logistics, and the only thing -- and I
20 agree with Judy -- the only thing we left out was
21 short-term and long-term stability studies, because
22 they happen in parallel to the in-process.
23 Getting back to my example of a continuous
24 manufacturing process, you would then take samples
25 off the line and put them into stability testing on
1 a regular basis throughout the process, so you
2 would always have samples of your well-controlled
3 process at different stages of stability to look
4 at, to make adjustments, and so on.
5 It really I think will be a powerful tool
6 for that end of it, too. The guidance should
7 recognize that new insights is the process which
8 does not affect the quality of the product for its
9 intended use, should not require mandated changes
10 in the process.
11 Because we are going to use these tools,
12 we will learn a lot about blend mixing and what
13 happens, we will learn a lot about the process
14 itself and the individual steps, and if we are
15 still making a product well within the ramification
16 or the quality rubric that we have now for the
17 product, that shouldn't make the companies have to
18 do master reworks.
19 Now, I think that companies, when they
20 learn more and more about their product, are going
21 to make changes because they will see the benefit
22 of it, but if they are getting into this in fear of
23 the agency coming in on them and making them do all
24 sorts of, quote, unquote, "unnecessary" changes, I
25 think that is going to be detrimental.
1 We allow for the replacement of current or
2 classical methods with PAT for routine testing
3 methodologies. The guidance should recognize PATs
4 will, in large measure, replace current validation
5 measurements, and the guidance has to define what
6 records have to be kept and for how long.
7 Because we have the ability to take
8 real-time measurements on a continuous basis, how
9 many hard drives do we want to fill up and keep,
10 and how much of that is worth keeping, and is it
11 worthwhile, then, to establish a snapshot
12 recordkeeping system for an in-process.
13 Those kinds of questions we didn't have
14 real answers for, but we know that it is possible
15 for large manufacturers, who are making 30 or 40
16 different products, to fill up computers with data
17 and no one look at it, and no one need it, but
18 because of the system we have now, requiring all
19 the data to be kept, and how do we involve the FDA
20 in the PAT development. I think that is another
21 important aspect.
22 Classically, regulated industries don't
23 like the regulator in there helping them improve
24 their process, and I think this is an opportunity
25 for it to happen in a productive way.
1 Let me just say that the group of people
2 that we worked with on the subcommittee -- and I am
3 sorry I don't have all the names -- but it was
4 really a wonderful working experience, and I really
5 enjoyed it a lot. We had some good thinking and
6 some input from industry and from academia, and
7 some good statistical look to see what is going on.
8 I think that a lot of the results of that
9 are in the minutes of those meetings and really
11 DR. LAYLOFF: Thank you, Art.
12 I have asked Ajaz to comment on the
14 DR. HUSSAIN: I would sort of summarize
15 the Chemometric discussion, not go through the
16 presentation that you already have in your handout.
17 The Chemometric Working Group was chaired by Dr.
18 Mel Koch from the University of Washington at
19 Seattle, and it was a mix of several individuals
20 from different backgrounds.
21 The classical chemometrics, I think what
22 chemometrics is was the sort of first business
23 point that the group focused on, and generally, we
24 tend to think of chemometrics are statistical
25 principles applied to chemistry and tools, such as
1 partial least squares, principal component
2 analysis, and artificial neurometrics are generally
3 considered to be part of chemometrics, but we will
4 have to look at chemometrics very broadly.
5 I think the key point that was raised
6 before was moving towards a multivariate approach
7 for assessing quality and performance of products
8 and move away from the current univariate system.
9 That itself is part of the chemometric paradigm
10 that we will have to develop.
11 Another most important part of the
12 chemometrics would be the design of experiments,
13 statistical design of experiments and how we use
14 that information to optimize formulation, and so
16 The group actually stressed quite heavily
17 on the need for design of experiments. I had
18 raised some concerns at that meeting, and I will
19 bring those concerns back to you also. The aspect
20 I think which would be important in the
21 chemometrics would be how do we validate some of
22 the software and statistical tools that would have
23 to be used in using multivariate approaches.
24 One of the concerns that was raised by one
25 of the speakers that we had invited from
1 GlaxoSmithKline was under the current system of
2 computer validation, for example, the perception
3 out there is we can't validate well-established
4 tools, such as MATLAB or SAS. Those commercial
5 software packages have some validation issues, and
6 so forth.
7 I think that would be a challenge, and I
8 think we will have to address software validation,
9 as well as validation of the statistical models
11 The discussion tended to be more on a
12 concern, I think concerns were raised with respect
13 to these, but I looked at that from a very
14 different perspective. The reason is I think we
15 make very critical decisions in Office of
16 Pharmaceutical Science based on modeling, PK/PD
17 modeling, and all, I think we have had tremendous
18 experience with pharmacometrics.
19 So my concerns with chemometrics were not
20 truly reflective of the group's, and the reason for
21 that was I was coming from the pharmacometrics
22 background, and I can see many different ways of
23 validating and being very pragmatic approaches to
25 The other suggestion that I had at that
1 meeting was to look at how the Center for Devices
2 approaches software validation, off-the-shelf
3 software validation, and you have very good
4 pragmatic approaches for validation of software.
5 So the concerns were with respect to validation,
6 but I feel we have potential solutions to address
7 that, and I will probably bring that up for
8 discussion at the next subcommittee meeting.
9 The issue of experimental design. The
10 reason experimental designs were brought up and
11 discussed at length were because you really would
12 need to understand the causal links between
13 formulation of process variables and it is best to
14 do this in the development area where you can
15 actually design an experiment and sort of identify
16 the critical process variables and formulation
17 variables, and then that becomes a basis for
18 identifying which of those should be controlled,
19 and so forth.
20 The concern I raised was I think at the
21 University of Maryland, our research adopted a lot
22 of those principles, and I think Gary is here.
23 My concern was a survey that Professor
24 Shangra [ph] had done in '93, and it was published
25 in Pharmaceutical Technology, and one of the
1 questions there was how prevalent is the use of
2 statistical designs in R&D work in pharmaceutical
3 industry, and the number was very disappointing.
4 Less than 5 percent companies use design of
5 experiments in their development work.
6 That was '93. Has the situation changed?
7 I don't think so, and, in fact, my concern is more
8 and more the pressure on R&D has increased to a
9 degree that development itself is rate-limiting now
10 and more and more, people are going towards drug
11 bought in a bottle, and not even formulating until
12 you have some Phase I/Phase II data.
13 So more and more, I think attention to
14 process and product development has shift towards
15 end of the clinical or towards the end of the
16 development studies or, in some cases,
18 So we will have to work through it, and if
19 statistical designs are essentially necessary, I
20 think we have to look at it from a different
21 paradigm, so that we can provide a means of
22 understanding your processes better and
23 understanding how to model some of the systems, but
24 when will that occur is going to be a great
1 My sense was, in the sense, the
2 Chemometrics Group was heavily dominated by people
3 who were thinking mainly in terms of the absolute
4 need for multivariate analysis, and one thing which
5 we did not pay much attention to in the
6 Chemometrics Group, but was done in Art's group,
7 and so forth, was a process signature, because you
8 could actually not have to do a lot of chemometrics
9 if we find a way to address process signatures and
10 control those process signatures, so that would the
11 first step that we could take before further
12 understanding could be developed.
13 A point that was made by Joe Famulare in
14 the sort of closing remarks, which was in the
15 Validation Group, is I think we would need to have
16 very flexible approaches for validation, not only
17 of the processes and analytical methodology, but
18 also of the computer software and models. So I
19 think we will have to think very differently and be
20 very pragmatic about how we bring this to bear
21 without adding undue burden.
22 So I think that is sort of a nutshell of
23 what the discussions were, and you have the
24 specific points in your handouts.
25 DR. LAYLOFF: Thank you, Ajaz.
1 I wanted to mention a few comment on the
2 validation issues, which is one of my favorite
5 If you talk about validation, like to
6 think of buying a horse. When you go out to buy a
7 horse, you define what functions you want the horse
8 to perform. You know also that visual acuity is an
9 issue, but you frequently don't measure the acuity
10 of eyesight of the horse. You know that kidney
11 clearance is important, but we frequently don't
12 challenge the kidney and look at clearance. We
13 look at the overall performance of the creature to
14 see if it performs to meet our intent needs.
15 Signatures are going to bring a new
16 paradigm because people are comfortable looking at
17 the API, because they look at it at the beginning
18 and they look at it at the end, and they want to
19 keep looking at it, but that paradigm is not useful
20 for multivariate processes especially these
21 fingerprint technologies.
22 Validation is going to be a very key
23 feature because our concepts of validation have
24 been built around the API and those separation
25 technologies. Moving to signatures is going to be
1 disquieting, but to get people that buy horses to
2 come in and look at those computer systems because
3 when you start talking about 11 megalines of
4 coding, there is no way that you can plow through
5 that except as an animal.
6 Now, the assessment technologies, near
7 infrared, laser-induced fluorescence and things
8 like that are going to bring new problems for us in
9 validation because we have traditionally looked at
10 single variable processes.
11 Moving to multivariate detection is going
12 to be a big problem, and validation is going to be
13 a keystone in this whole business, and data stream
14 that Art mentioned, the data that you generate to
15 reach the endpoint is voluminous, huge volumes of
16 it, and unless you focus just on the endpoint,
17 validate the endpoint and then just look at the
18 endpoints, it is going to bury everybody.
19 I would say, all in all, it was a really
20 very exciting and interesting experience. I really
21 enjoyed it.
23 The working groups addressed guidance
24 document issues and helped build consensus on
2 It is a world which is opened up to us by
3 the computers. It is useful to note that I think
4 cGMPs, as we have them now, can't accommodate the
5 changes. There is much to be done. The keystone
6 to the whole thing will be education and training
7 especially in the FDA. The barriers are going to
8 be conservatism in industry, as we saw with the
9 BCS, conservatism in FDA, which is always a hidden
10 stone, but we have a great beginning to move
11 forward from.
13 The FDA initiative to come up with a
14 guidance document will help diffuse industry
15 conservatism, give a focus to the FDA reviewers and
16 investigators, which will help move the whole
17 thing. A well-trained cadre of FDA people to
18 address the new issues of validation and
19 performance-based process quality systems will be
22 I like to think of it like making a good
23 cup of coffee. You buy beans, which are raw, and
24 you roast them, and you roast them to a certain
25 pyrolysis temperature, the color, you roast them to
1 light, dark. We can measure that by measuring
2 temperatures. We can also look at the color of the
3 beans and use that to monitor a process.
4 Grinding beans, if you have a little
5 grinder at home, you find out you can tell it
6 acoustically. You can listen to how the blade is
7 striking the particles and tell how fine the grind
8 is. So you can envision putting a microphone on
9 there and setting a specification that you are
10 going to grind it to a certainly sound level, at a
11 certain frequency, as an endpoint for the grinding.
12 Of course, in preparing the drug extract
13 that we like to drink, the temperature, time,
14 extract volume, air exposure, and stability are all
15 issues because if you make a pot of coffee and let
16 it sit there for two days, stability is a big
18 So I think that we have in our world these
19 technologies already. If you grind coffee, you
20 could hear it. We roast beans to color. You buy
21 dark roast, light roast, and those can all be done
22 visually or they can be done by machines, it can be
23 done in batch or on line.
24 So we do interact with these things, but
25 you talk about now how do you validate a microphone
1 to show that it is meeting its performance
2 specification on a daily basis.
3 It is going to be very interesting.
4 Now, I will turn it over to FDA.
5 Next Steps
6 Ajaz Hussain, Ph.D.
7 DR. HUSSAIN: What I would like to do is
8 give sort of a progress report and sort of next
9 steps. Following that, I would like to have the
10 committee discussion and recommendation on two
11 major issues.
12 One is we are planning the next PAT
13 Subcommittee meeting on the 12th and 13th of June.
14 I would like your suggestions and help in framing
15 the agenda for that. In fact, we are working after
16 this meeting to put a packet together that needs to
17 go out by the end of this week, so the timing of
18 the discussion is very appropriate, so I seek your
19 input on what should the second meeting focus on.
20 I think after my presentation, you have a
21 better sense of the direction on that, so that
22 would be one point.
23 The second aspect would be discussion on
24 an outline for the guidance, the draft general
25 guidance that you are preparing, and your
1 recommendations on the next steps, are we on the
2 right track, what should we do more, and so forth.
3 In the discussion that will follow, I am
4 hoping to get input on those aspects from you.
6 Let me give sort of a progress report and
7 next steps.
8 To summarize the motivation from an FDA
9 perspective why did we start this, and what is the
10 sense of urgency, let me just explain that.
11 When we started looking at the
12 manufacturing processes and the issues related to
13 manufacturing processes that we are facing today,
14 we felt there was a significant potential and also
15 a need for improving the efficiencies of
16 pharmaceutical manufacturing and associated
17 regulatory processes.
18 When I say "efficiency," I am talking
19 about FDA efficiency, as well as industry
20 efficiencies, not just industry.
21 We felt technological opportunities were
22 available to realize this potential, and PAT, or
23 process analytical technologies, are just one
24 example of the opportunity that we have.
25 We heard at our FDA Science Board,
1 industry is reluctant to take advantage of such
2 opportunities due to regulatory uncertainties or
3 risk of uncertainty when you come to FDA, and has
4 preferred to adopt a "Don't Use" or a "Don't Tell"
6 Under the "Don't Use" approach, they
7 actually have corporate policies not to do this, so
8 I know of several companies where there is a
9 corporate policy not to include PATs in the U.S.
10 The same companies have done it outside.
11 The "Don't Tell" approach essentially is
12 you do this, but not register it, and you would
13 actually use that data to better understand your
14 processes and control your processes, but for the
15 FDA, you will provide the routine testing that you
17 Again, both situations are undesirable
18 from a public health perspective, as well as from
19 an industry economic perspective. I think if
20 regulatory uncertainty is the cause of the low tech
21 aspect of pharmaceutical manufacturing, and I use
22 the phrase very carefully, and the phrase was used
23 by Dr. Ray Scherer, the senior VP for
24 GlaxoSmithKline, at our previous Science Board
1 Our industry is very high tech in the R&D,
2 but from one perspective, it is low tech in
3 manufacturing, and that perspective is from the
4 perspective of process understanding, and so forth.
5 I think we have much more than equipment, and so
6 forth, so I am not talking about low tech in terms
7 of the equipment, and so forth, but the thought
8 process, the understanding, and so forth.
9 Again, those are very difficult concepts
10 for FDA to deal with, and I think we are dealing
11 with those in a win-win situation, a win-win
12 approach, so that we all benefit, and it is not
13 criticizing one part or the other part. I think we
14 will have to look at this as a mirror for all of
15 us, not just industry.
17 Why PAT? We think PAT provides an
18 opportunity to move forward and to move from the
19 current testing to document quality paradigm to a
20 continuous quality assurance paradigm that can
21 improve our ability to ensure quality was built-in
22 or was by design. We think this is the true spirit
23 of cGMP.
24 The "c" in cGMP, current Good
25 Manufacturing Practices, I think Dr. Woodcock has
1 said several times I think we cannot use
2 enforcement to help in a way of bringing innovation
3 to manufacturing, it has to be a different
5 So the true spirit of cGMP is what we want
6 to capture in this PAT initiative, and I think we
7 can do that.
8 Why PAT? I think At/On/In-line
9 measurements of performance attributes are
10 feasible. When we measure or test in-process
11 material right now, you will hear about plan
12 uniformity. We test for drug substance, as Tom
13 pointed out. It may or may not always give you a
14 performance measure, but I think in a collective
15 multivariate way, we need to look at in-process
16 information that you can start predicting
18 We have real-time or rapid feedback
19 controls, which is not the case now. We currently
20 test and if the test results are acceptable, we
21 proceed to the next step or we throw away that
22 material and start again.
23 Real-time feedback controls are not truly
24 ingrained into pharmaceutical manufacturing.
25 Real-time feedback control moves us to a prevention
1 mindset. I think that is an important aspect.
2 We will get greater insight and
3 understanding of process. When I talk about
4 win-win, I think improved process understanding is
5 I think a key to be one part of the win-win,
6 because that is how you would improve quality and
7 improve efficiency, and decrease regulatory
9 Why would PAT help in terms of improving
10 of process understanding? Current methods, as Tom
11 correctly pointed out, we focus on impurities, we
12 focus on chemistry, wet chemistry. Functionality
13 of excipients, the physical attributes are not well
14 understood, are not well managed, and not well
15 controlled, because we don't truly have the tools
16 that have focus in this area, so PATs allows you to
17 bring physics and chemistry together to address all
18 those issues.
19 Potential for significant reduction in
20 production and development cycle time. You have
21 seen Professor Rogers or Dr. Rogers' presentation
22 to you at least once where he showed you the cycle
23 times of current manufacturing of simple tablets,
24 and the numbers were quite disturbing.
25 Reduce regulatory concern and potential
1 for remote inspection strategies. I say that with
2 a -- I will just skip that.
4 Goals and objectives of the PAT
5 initiative. We are using PAT as a model
6 technological opportunity, to develop a regulatory
7 framework to facilitate introduction of new
8 manufacturing technologies that enhance process
9 efficiencies and understanding. I underscore
10 "understanding," because that is how public win-win
11 comes from both industry and us.
12 To do this, we need to identify and
13 eliminate perceived or real regulatory hurdles.
14 The more I listen, there are more real hurdles in
15 this issue. We have to develop a dynamic,
16 team-based, scientific approach for regulatory
17 assessment, review and inspection of these new
19 I think, as I mentioned to you yesterday,
20 the Manufacturing Subcommittee is trying to bring a
21 mechanism for providing technical dispute
22 resolution for GMP manufacturing issues. We don't
23 have any mechanism. PAT will help us move in that
24 direction very quickly.
25 Clearly, we have to go for international
3 The strategy that we adopted was very
4 simple. It has to be a win-win approach, and this
5 was my first presentation to you on the 19th of
6 July, if you remember that presentation. I said
7 this has to be a win-win, otherwise, this will not
9 We started with input from you, Advisory
10 Committee for Pharmaceutical Science, but didn't
11 stop there. We went to the FDA Science Board, and
12 the reason for that was this is not just a CDER
13 issue or an OPS issue. It is an issue that
14 addresses all manufacturing and associated
15 organizations within FDA - Office of Regulatory
16 Affairs, Office of Compliance, Office of
17 Pharmaceutical Science, so you have to have the
18 highest endorsement for this project.
19 For that reason, as well as the potential
20 paradigm shift that occurs if this project is
21 successful, because this changes the entire
22 manufacturing system potentially.
23 So that was the strategy, to seek approval
24 from the highest levels at FDA. We set up internal
25 collaborations between CDER and Office of
1 Regulatory Affairs, and that collaboration has now
2 been effective for some time, and it is in the form
3 of a PAT Steering Committee. I will show you the
4 membership of that in a minute.
5 We needed external collaboration. We
6 don't have the technical knowhow to do this alone,
7 and we need to work together, and we use
8 subcommittee model to do this under your direction,
9 the PAT Subcommittee which Tom chairs. This was
10 the first report to you.
11 Clearly, PQRI is another mechanism and
12 soon we would like to sort of develop a program
13 under PQRI for research and technical issues that
14 need to be addressed here, and also build other
15 relationships, Dr. Gordon at the Pharmaceutical
16 Engineering Program at Michigan. There are many
17 other opportunities also available to do this.
18 We started with two parallel tracks. One
19 track is a general guidance on PAT. This guidance
20 will only focus on general principles and the
21 regulatory process. It will not focus on any given
22 technology, because I don't think we want to
23 identify a preferred technology, and so forth,
24 because one technology may not work for everything.
25 So at this time, we only want to issue a
1 general guidance which will delineate the
2 regulatory process and remove the regulatory
3 uncertainties. One important aspect of that
4 uncertainty is a Safe Harbor concept that we
5 discussed at the last FDA Science Board meeting,
6 and I will come back to that in a minute.
7 The Safe Harbor concept simply means that
8 as Art was mentioning, you may find something which
9 would indicate that the process may not truly be
10 under control, it may be a completely validated
11 process right now, and its intended use, so we
12 don't want to sort of penalize and then create a
13 situation where doing the right thing can get a
14 company into trouble, so you want to create a safe
15 harbor and move forward on this.
16 We are encouraging submissions now and for
17 that we are planning a team approach for review and
18 inspection during development and implementation of
19 PAT. What that will do is essentially as a company
20 decides to implement PATs now, they would have a
21 reviewer and an inspector working with them, so
22 that concerns, regulatory concerns are identified
23 and addressed, and not wait until a submission, so
24 that the investment a company will do and have to
25 wait for an answer which might not be acceptable,
1 so we want to sort of partner and help companies do
2 this now.
4 So in terms of a progress report, I used a
5 timeline of our meetings. The first meeting was on
6 the 19th of July, and then we had two Science Board
7 meetings, the 16th of November and 9th of April, so
8 that is essentially what the progress there is, and
9 the next step follows this meeting and the next
10 subcommittee meeting on June 12th and 13th.
12 So the progress so far has been we have a
13 wonderful collaboration between CDER and Office of
14 Regulatory Affairs right now, and this is in the
15 form of PAT Steering Committee. The members are:
16 Doug Ellsworth, he is the District Director for New
17 Jersey District; Mike Olson and Diane O'Brien from
18 Division of Field Science. They represent the
19 field labs. Then, you have Joe Famulare from
20 Office of Compliance; Moheb Nasr from Office of
21 Testing and Research; Yuan-yuan Chiu from Office of
22 New Drug Chemistry; Frank Holcomb from Office of
23 Generic Drugs, and myself.
24 So that essentially is the Steering
25 Committee. The difference here is we don't have a
1 working group. The guidance is being developed
2 through the PAT Subcommittee and the Steering
3 Committee without a working group, so that is a
4 deviation from our norm, because I don't think we
5 want to put a working group of internal groups to
6 write this guidance.
7 We have had several consensus building and
8 awareness activities within the Center. We had a
9 Center for Drug Evaluation research scientific
10 rounds where we discussed, debated a lot of these
11 issues. We had several seminars, and we just
12 completed a Visiting Professor Lecture Series. We
13 had several invited guests who came and talked to
14 us about the PATS including folks from industry.
16 With respect to external collaboration,
17 the PAT Subcommittee, you already know about that,
18 and the PQRI is something that we will pursue the
19 next few months, but I want to focus on an academic
20 collaboration that we have put together that is
21 developing a curriculum right now.
22 We have selected three National Science
23 Foundation process centers. These are the major
24 centers on Process Analytical Technologies. One is
25 a Pharmacy School, University of Purdue. One is a
1 Chemical Engineering School, University of
2 Tennessee, Knoxville, and the other one is the
3 University of Washington, Seattle, is a Center for
4 Process Analytical Chemistry.
5 What we are doing with these three groups
6 is to develop a training and a certification
7 program. I think the certification program is
8 something that have not made the final decision on,
9 and there are several reasons for that. Also, we
10 would need a continuing education program for all
11 the reviewers and the inspectors. These training
12 programs are for internal reviewers and inspectors.
13 Just one more point. At the next
14 subcommittee meeting in June, we will propose and
15 discuss this curriculum. We won't finalize this.
16 We will have this discussion at the next
17 subcommittee meeting.
19 The general guidance that we are working
20 on, the goals are as follows. General principles
21 and terminology essentially bringing the community
22 on the same page. I think we start with the
23 definition of what is on-line, in-line, and going
24 to chemometrics and all other definitions and
1 Address issues related to regulatory
2 uncertainties. That will include a Safe Harbor
3 concept whereby, for example, now if a company
4 wants to apply PATs on-line to an existing
5 manufacturing line, they fear that numbers or data
6 coming out of that could be misused by us, FDA.
7 You might see its strength, and so forth.
8 So you want to think about a Safe Harbor.
9 So a Safe Harbor concept, I think would be one of
10 the agenda items for a discussion at the next
11 subcommittee meeting, what is a Safe Harbor that
12 would allow a company to investigate, and not fear
13 a negative regulatory in back of that, so how
14 should we define the Safe Harbor.
15 In addition, other issues with regulatory
16 uncertainties would be validation, I think computer
17 validation, batch, recordkeeping, and so forth, are
18 all regulatory uncertainties, so we will have to
19 deal with those in a general sense. I am not sure
20 we will be able to provide detailed resolution of
21 all of those issues in the first guidance, but I
22 would like to hear from you how should we address
24 We have to clarify regulatory process. My
25 way of thinking with PAT is you have the current
1 system, which is adequate for intended use. With
2 PAT, we potentially are creating a totally new
3 regulatory system for manufacturing CMC. So that
4 is the level of potential difference we are seeing.
5 So we may have a completely new review
6 inspection system for PAT, which is distinct from
7 the current system. That is one possibility. I
8 think we have to look at that. The other
9 possibility is I think technical dispute resolution
10 is how we would do that, and maybe create a
11 technical resolution team which would address
12 disputes between reviewers, inspectors, and
13 industry that may come about in this process.
14 So those are the type of thoughts that we
15 are thinking about, and we will bring some of these
16 to the second meeting of the subcommittee.
17 We also hope we have other tangible
18 benefits of this general guidance. We think, we
19 hope it will serve as a tool for building
20 within-company consensus. I do want to sort of
21 emphasize I did not appreciate the lack of
22 consensus within companies until I started visiting
23 many companies.
24 Manufacturing, R&D, regulatory affairs are
25 not on the same page with respect to PAT. I think
1 you will see champions of PAT in the manufacturing
2 area, and the R&D area do not want to touch us,
3 they don't want to be bothered with it. So it is a
4 huge challenge.
5 I think you also have to think about this
6 in a cultural setting. This, I hope will not lead
7 to a disciplinary fight. What I mean by that is a
8 traditional pharmacy for development was chemical
9 engineering. I think you are looking at different
10 cultural aspects because traditional pharmacy
11 schools, industry pharmacy programs, they will have
12 to learn how to use the near IR signatures and
13 other things, and use that to optimize their
14 formulations. They don't have the knowhow, and so
15 a multidisciplinary team concept comes about this,
16 so that is a major challenge.
17 We don't have pharmacy schools, in fact,
18 most pharmacy schools have cut down on their
19 industry pharmacy program. Where will these people
20 come from, who would do this? One interesting
21 aspect, as I have been talking to companies, many
22 companies would prefer to do this manufacturing
23 outside the U.S. This is one of the reasons, the
24 talented pool of qualified people, where will they
25 come from.
1 So other tangible benefits of building
2 within-company consensus, hopefully, when you
3 reduce regulatory uncertainty, that will help that
5 We also need to promote research and
6 development activities in this area. I think this
7 is just starting from scratch. We plan to work
8 with NISD, National Science Foundation to make a
9 case for public funding in this area.
11 Options for introducing PAT. I think this
12 is an important aspect. I would prefer to see PATs
13 being developed during the R&D process, but that is
14 a dream I think. In the current situation and
15 timeline pressures, I think we have to look at all
16 different options of when a company can bring PATs
17 to apply.
18 There are several options that we plan to
19 discuss and introduce in the draft guidance.
20 Option 1. A company might decide to use a
21 currently marketed, quote, unquote, "robust"
22 product that helps the company to focus on just PAT
23 issues, and not process-related issues, and then
24 apply PATs for improving efficiency and for
25 probably learning at the same time.
1 Several companies have done this. One I
2 have visited in Plankstadt, Germany, AstraZeneca.
3 They have done it for the reason of very important
4 compounds, and I will just mention that as I wrap
5 up my presentations.
6 Here, you would essentially bring on line,
7 and at some point, then, routine end product
8 testing may not be necessary if you bring
9 everything on line. The broken green line
10 essentially indicates that you will do routine
11 testing for shelf life, as we discussed.
12 A company, I think this will be a
13 challenge, but a company experiencing significant
14 manufacturing problems now where the product is
15 highly variable, and that is my depiction of the
16 variable product, a company might choose to get a
17 handle on that product, a step-by-step fashion,
18 where they will focus on each unit operation and
19 eventually have that process under control and move
20 towards on-line analysis of that.
21 Ideally, this should occur in a new
22 product development situation, but being pragmatic,
23 I think this will take time. Delay in drug
24 approval, the fear is so great that I don't think
25 companies would be ready to do that. I wish they
1 would, but let's see how.
2 At the same time, I think Dr. Woodcock,
3 when we were preparing for the Science Board
4 presentation, felt that this was not included in my
5 presentation to the subcommittee, is this is going
6 to take time. I think emotional high and emotional
7 excitement is building with PAT, but that has to be
8 followed with intellectual high at the same time,
9 and if you don't keep the two together, you have a
10 potential problem.
11 So what can we do to keep the momentum
12 going? Her suggestion was to think about unit
13 operation by unit operation, and to bring PATs and
14 provide guidances where you can just do one unit
15 operation at a time. You won't go for the entire,
16 but one at a time. So that is a concept that I
17 will just mention in a brief.
19 Let me just tell you about Track 2, which
20 is not part of the PAT Subcommittee, but Track 2 is
21 to encourage companies to provide submissions now.
22 For that, they have to contact the Office of
23 Pharmaceutical Science, and we will work with the
24 companies to set up the meetings necessary with the
25 compliance office of the field, and so forth, to
1 create a team effort to address issues and concerns
2 for individual applications.
3 So you are looking at a concurrent
4 development review-inspection strategy that we are
5 trying to develop right now. To date, I am happy
6 to say that we have received two formal requests.
7 The first company submission meeting is next week,
8 so I am happy to say we are moving on this already.
9 So two major U.S. companies have sent us letters to
10 request the meeting, so we are moving on the Track
11 2 also.
13 Track 2a is Dr. Woodcock's suggestion to
14 encourage established PAT technologies now. To do
15 this, we will encourage application of selected
16 on/in/at line measurement tools for unit operations
17 and/or as alternate tests.
18 For example, unit operations, such as
19 blending, drying, I think a lot of literature,
20 publications are already existing, data exist, so
21 we can use that and move with this right away.
22 The technologies could include near IR,
23 Raman, chemical imaging, on-line HPLCs, and so
24 forth, so well-established technologies for each
25 unit operation, we will try to encourage that now.
1 But to do that, we have one option, I
2 think, or several options. One of the options is
3 to start including PATs in the existing guidances
4 that we are working on.
5 For example, the draft Blend Uniformity
6 Guidance document that we will talk about, we will
7 focus on revising the guidance to bring in the
8 stratified sampling, the PQRI proposal, but at the
9 same time, it could include a section which could
10 say on-line has this and this benefit, and how you
11 might do that. So that is something I would like
12 your thoughts on also.
14 So just to give you a sense of timeline,
15 what activities are going on and what is happening,
16 I don't have a laser pointer here with me, but the
17 Track 1, the two boxes you see are the ACPS-PAT
18 Subcommittee. We already had one meeting in
20 I think we got valuable information
21 especially from the Benefits Group that laid out
22 the outline for that guidance. I already have a
23 draft available for internal use here. We are
24 actually meeting with the PAT Steering Committee
25 tomorrow, after this meeting, to go with the draft
1 and use that internal draft to put in an agenda for
2 the next subcommittee meeting.
3 We will not share that with the PAT
4 Subcommittee. I think that was reported in one of
5 the magazines that we will present that draft to
6 the PAT Subcommittee. We cannot do that. So the
7 draft is only for internal FDA use.
8 We will use that to set up our agenda, and
9 so forth. I had only planned for two PAT
10 Subcommittee meetings. We may need a third one, so
11 that third meeting is not shown on this, and I
12 think the members of the PAT Subcommittee, many of
13 you are here, and you may suggest that I am right,
14 that two may not be enough, we may need a third
15 meeting to draft all the issues here.
16 So using the PAT Subcommittee to get the
17 information on issues with regulatory
18 uncertainties, when the draft comes out is not on
19 this chart because it is a very difficult
21 We are planning a training program for PAT
22 reviewers and inspectors this summer. In May, we
23 are starting with the Track 2 with the first
24 company meeting.
25 The other information there, we have made
1 several presentations to companies and other
2 institutions, and I am happy to say that we have
3 visited International Federation of Process
4 Analytical Chemistry we visited Aventis,
5 Bristol-Myers, a PDA in Basel, and then when we
6 went to Basel, we took advantage of that and
7 visited Pfizer in Friberg, Germany, and then
8 visited AstraZeneca plant in Plankstadt.
9 So what we are talking about, PAT on-line,
10 it is not a theory, it exists at AstraZeneca, so it
11 was quite impressive to walk through that
12 manufacturing facility. Joe Famulare from Office
13 of Compliance, I, and Helen walked through that
14 plant, and I think it was quite interesting and
15 good to see that this is not a theoretical thing
16 that we are talking about.
17 We had several such meetings, I will not
18 describe all those meetings, but the consensus is
19 building, and I think the highest level of support
20 from Dr. Woodcock, the FDA Science Board, and so
21 forth, I think has helped tremendously with this
24 So the next steps are, for internal, we
25 are establishing a CDER-ORA PAT team for joint
1 review/inspection. We have just started the
2 process of selecting our reviewers, and we will
3 hopefully find the inspectors to go along with
5 The plan is to have four reviewers and
6 four inspectors to be part of the first team, so it
7 is not training the entire group, it just focusing
8 on four reviewers and four inspectors.
9 We plan to recruit expert consultants. We
10 already have started the interview process for a
11 process or chemical engineer, process analytical
12 chemist, a chemometrician, and we already have an
13 industrial pharmacist who is working this. That is
14 Roger Poole. I don't see him in the audience here.
15 So we are going to fill those positions,
16 and these would be part of the technical consulting
17 staff, as well as people who would help develop
18 technical guidances and may be part of the
19 technical dispute resolution team.
21 So developing a training (and
22 certification) program for PAT review and
23 inspection team. The reason "certification" is in
24 parentheses is there are a lot of drawbacks for
1 One drawback is those folks would be hired
2 by industry the first day we certify them. So that
3 is a challenge since we will lose them very
4 quickly. That is not such a bad thing, I think we
5 can work with that.
6 The proposed curriculum will be discussed
7 at the June meeting of the PAT Subcommittee, and
8 then we will put the training program together.
9 I just last week looked at several
10 abstracts that we submitted. We have a tremendous
11 number of abstracts on at least at-line use of near
12 infrared to predict dissolution and predict other
13 attributes, so we have had a quite a good success
14 in using near infrared, chemical imaging for a
15 number of applications including prediction of
16 product performance, that is, dissolution, so we
17 will present those papers at AAPS meeting.
18 We will expand that research. Moheb is
19 here, and we are trying to do some work on direct
20 work and get this program expanded.
21 We will publish the draft guidance as soon
22 as possible after that.
24 Wrapping up next steps, a public workshop.
25 We already have the program developed for the Arden
1 House Conference for this year or for the year 03.
2 The U.S. Arden House will be in January and will
3 focus mainly on technical details and technical
4 aspects of PAT.
5 The program for UK will be a more big
6 picture, economic benefits type, and that is a
7 collaboration between AAPS and Royal Pharmaceutical
8 Society, FDA and MCA. We have been working very
9 closely with MCA. We have had some contacts with
10 the German authorities, so informally, we have
11 started talking about issues with harmonization,
12 but I will come to that in a minute.
13 A FDA/AAPS PAT workshop is being planned.
14 We had one meeting, but have sort of held this back
15 because there are so many issues that are unclear,
16 so we are hoping to understand the issues better
17 before we finally put this program together. We
18 will aim for April 2003 for this. Hopefully, the
19 guidance might be available at that time.
20 We need to formalize efforts toward
21 international harmonization, as I said, currently,
22 informal communications with a few European
24 For example, when we visited the Pfizer
25 plant in Friberg, we had invited the German
1 authorities to visit with us, so we had a lot of
2 discussion, and so forth, but it has been informal.
3 There is no mechanism right now under ICH to
4 discuss this, so we will have to start working on a
5 formal mechanism for harmonization.
6 One of the sense of urgencies we had was
7 when I presented this to you in July of last year,
8 we felt Europe was ahead of us in many ways. In
9 some ways they are, but our thought process, I
10 believe, has matured to such and such a degree
11 right now, I think we probably will regain the
12 leadership in this again.
13 I had better stop and look for your
15 DR. LEE: Thank you very much, Ajaz.
16 How do you want to take the questions?
17 First of all, I think I would like to alert
18 everybody that quite a few committee members have
19 been schedule to leave before 5 o'clock, so I am
20 going to tighten the discussion, and I am planning
21 on a 4:00 p.m. adjournment at the latest.
22 I hope that some of the other presenters
23 later on in the program are here or they would be
24 contacted, so that there will be presentations.
25 Certainly, this is a very exciting
1 project. I think what I would like to see is to
2 keep the momentum going. I have identified a very
3 small subcommittee within this committee to help
4 digest and lead the discussion.
5 I have Art Kibbe, Judy Boehlert, and
6 Efraim Shek to ask the questions in case there are
7 no other questions from the groups.
8 Efraim, would you like to take the floor?
9 DR. SHEK: Maybe I will start and taking
10 the risk, maybe something melodramatic, but I
11 really believe personally that PAT will bring a
12 revolution, and I believe a revolution to the way
13 we are manufacturing and the way we are treating
14 it. If you look really at that aspect and how it
15 is going to influence us, in industry, in R&D, as
16 well as the manufacturing.
17 I think we have to look at it from this
18 point of view. It is a major revolution. Saying
19 that, okay, and talking about Tom, I like
20 analogies, too, but we are not buying horses, and
21 we are not grinding coffee, we are not making
24 What we really develop and manufacture is
25 pharmaceutical products, which I believe, even
1 without the PAT, that, in general, they are in high
3 Also, I think I can say in public, because
4 PhRMA is basically the organization that basically
5 supports this approach. Saying that, I believe the
6 devil will be in the details, as you indicated, you
7 know, a few aspects.
8 Number one, which I think we have to look
9 at very carefully, is the training, both training
10 of FDA, as well as training in the industry. That
11 will be extremely important.
12 How we do the training, who does the
13 training, today, most of the experience is in the
14 industry, those people who have really used it, and
15 I think we have to learn from those companies who
16 already started it.
17 When we look at the curriculum, we have to
18 be very, very careful there. We can go on and
19 list, you know, of details, but if you have to look
20 at just one example, if there is, like any other
21 computer system, a sensor will malfunction, what
22 happened to the batch that you are manufacturing,
23 and those things I believe will happen.
24 The concept of validation, I think will
25 have to be reviewed, but I am encouraged. I
1 personally think, coming from an IND, I think it is
2 stuff that we should get involved with, because in
3 this case, I am using an analogy, the horse is out
4 of the barn, and we should look at it very, very
5 carefully. The opportunity is so great.
6 One that may be fruit for some thoughts is
7 how do you encourage, okay, the industry, their
8 conservatism both the FDA and the industry, and I
9 think we have to think about some ways that we can
10 encourage companies, both there is an economic
11 aspect there, to take this risk, okay, or to
12 invest, and if we can come up with some thoughts,
13 how can we encourage like any other unit forces to
14 make those things happen.
15 I believe that most of the facilities, the
16 issue will be, you know, are there any technical
17 issues, okay, implementing PAT into existing unit
19 DR. LEE: Let me maybe focus discussion a
20 little bit. First of all, I would like to see
21 whether or not these committees like what was
22 presented and are we on the right track, and also I
23 think that we need to, it seems to me from a
24 committee member, I would like to some kind of, not
25 open-ended process. Are we at that stage where we
1 can begin to estimate how long with that take.
2 Is it a process that we would like to see
3 uniformity, I mean can we tolerate two systems, at
4 what point we would like to see one system, and
5 more importantly, how can we put ownership in these
6 stakeholders, what hurdles. Is it realistic that
7 within 10 years, everyone will be doing this
8 on-line monitoring?
9 So those are the issues that I would be
10 interested to hear from the committee, and see, are
11 we on the right track. Are the horses guided?
13 DR. KIBBE: Let me try to respond to some
14 of those questions, and I want to throw a couple of
15 things into the pot. One of the problems with this
16 is the name of it says process analytical
17 technology, and "analytical" generally conjures up
18 in most of our minds a specific kind of activity.
19 We toyed with, in our subcommittee or our
20 small working group, changing it to "assessment,"
21 because we are really assessing a process using
22 whatever technology is available and whatever tool
23 is available, so that we don't have to do extensive
24 end-stage testing, that we know the process did the
25 job, and if the process does the job, the result
1 must have done the job. I mean the result must be
3 One thing that I am concerned about,
4 whenever we talk about harmonization, I think in
5 terms of making everything down to the least common
6 denominator. In this situation, what we want is to
7 bring everybody with us up to a different level of
9 I think one of the problems we see when we
10 start depending on in-process is the reliability of
11 the process monitors. I liken our situation to the
12 early days of NASA and the way that they made sure
13 that the process monitors worked is redundancy, and
14 I think we are going to see a good company will do
16 Instead of one microphone monitoring, they
17 will have two or three, and then they will say
18 these two said it was good, this one was off, we
19 are going to clear the process, keep it rolling,
20 and we will check out the monitor that was out of
21 sync. I think we can look at that.
22 Now, every process that we put in place,
23 every technology will have a different need for
24 redundancy and a different need for validation of
25 the different robustness, and the more we get used
1 to that particular monitor or method of analysis,
2 the better we like it.
3 I don't know how many people check their
4 balance, you know, between each weighing with a
5 standard weight to make sure it hasn't changed. We
6 all know it balances pretty well, and we will do
7 the same thing here.
8 One of the things that is driving this
9 whole process is the rate of expansion of
10 computational informational technology. We could
11 never have even envisioned doing this until a
12 computer can digest the types of information flow
13 that we are talking about, and it's humongous, but
14 at the rate the computational power goes up, which
15 is doubling every year, the chances of being able
16 to digest these things, if you remember -- maybe I
17 am the oldest one to remember this -- but we used
18 to test for tablet hardness by picking a tablet out
19 of the batch and snapping it and listening for the
21 If it had the right sound, it was probably
22 the right hardness. Well, when Tom said grinding
23 coffee, we tuned engines to sound, but now we have
24 gotten to the point where we have technology that
25 does it.
1 Well, that is the same thing we are
2 dealing with here. We are going to look for that
3 fingerprint, that general look of the product. I
4 know that makes people uncomfortable, but we are
5 going to get there where we can say that looks like
6 a finished product and the reason we are
7 comfortable with that is we have done this 20
8 times, and every time it looks like that, it is a
9 good product, and we will be able to move forward.
10 Incentivizing the industry. The industry
11 is incentivized by one thing, and that's money, and
12 I will predict for the industry, and they can check
13 it with their stockholders, but 10 years from now,
14 the pharmaceutical manufacturers who aren't using
15 this are going to be out of business, because the
16 potential for improvement and economic savings and
17 quality of the product is so great that over a
18 10-year development with the improvement in
19 computational technology going along with our
20 improvement in sensoring devices and our ability to
21 accept that we don't have to do end-stage testing
22 if we did everything right, you don't have to test
23 if you reach New York City, if you followed the
25 You don't make another quality control to
1 make sure you have made it, because you have driven
2 there. If we can accept that change in the way we
3 think about how we manufacture, so what I am really
4 getting down to is the technology is going to race
5 ahead of our human ability to be comfortable with
6 the technology, and the companies and the people
7 who run it, who get comfortable with it first, are
8 going to have an edge on everybody else.
9 DR. LEE: Well, Art, you touched upon a
10 very important issue. I think now manufacturing is
11 done in ways that are most economical. Obviously,
12 this process might be cost-saving, cost-effective,
13 and would there be forces opposing that for being
15 DR. HUSSAIN: The key aspect is the first
16 thing that we established with the Science Board
17 was this is totally voluntary, nobody has to do
18 this as a requirement, and the second thing we
19 established with the Science Board was the Safe
20 Harbor concept, the ability to use a risk-based
21 approach to address problems, some that we may find
22 when they apply more close scrutiny of the process.
23 So the concerns, the two major concerns
24 that industry has, I think has been addressed with
25 the Science Board already, and I think how, the
1 details, I think Efraim mentioned the details. I
2 am hoping the PAT Subcommittee would help us
3 articulate some of those details that will be
4 necessary for the guidance.
5 DR. LEE: Tom.
6 DR. LAYLOFF: A couple of comments. I was
7 going to say in support of Art that it would be
8 redundancies and also orthogonal measurements, so
9 that you are actually looking at several
10 parameters, signature parameters at the same time
12 I think the efficiency will come a lot
13 from a compression where you actually are using the
14 equipment closer to 100 percent of the time, so
15 that the cost, that will be a big driver for it in
16 addition to the reduced analytical load, because
17 these on-stream devices are going to be very
19 So I think it is going to be a tremendous
20 advantage, and it is going to be a revolution
21 driven by the computational abilities and the
22 ability to handle redundancy in orthogonal system
23 signature systems.
24 DR. HUSSAIN: One aspect which I would
25 like to share with you, a question was raised by a
1 FDA Science Board member, what is the incentive
2 especially today when discovery is not
3 rate-limiting anymore, development is
4 rate-limiting, and that is the reason people are
5 shying away from doing extensive development
6 because of the high failure rates of compounds in
7 early clinical trials, it is what incentive and why
8 would a company invest this upfront in the R&D.
9 The answer I think, which I was impressed
10 by the answer of Ray Scherer from GlaxoSmithKline
11 said is most of these unit operations are not
12 specifically new drugs, so a lot of the information
13 would already be existing, and essentially, when
14 you have a new molecular entity, you can actually
15 compute and actually predict what the conditions
16 would be.
17 So, essentially, once you have understood
18 all your unit operations, you will be actually
19 doing very few experiments, but predicting and
20 confirming the experiments, so mathematical
21 modeling understanding brings a level of
22 understanding that will help actually development
24 So today, development is rate-limiting.
25 DR. LEE: Other opinions?
1 DR. LAYLOFF: One other comment. I hit a
2 paradigm wall when I was working on this. I kept
3 thinking of a single process stream in which you
4 had devices to process it through, and I was
5 visiting with one of the industrial presenters, and
6 he told me they were getting ready to move PAT into
7 a manufacturing site where they did 200 different
9 So they were looking at basically the PAT
10 in the specific technology areas, which they then
11 would merge into the product lines. I thought it
12 was going to be more hardened, you know, like a
13 single plant, but they are actually moving to do
14 200 -- a plant where they manufacture 200 different
15 items, which I was really dumbfounded with.
16 DR. LEE: Yes, Pat DeLuca.
17 DR. DeLUCA: I guess that Art mentioned
18 about the title PAT, and certainly the success of
19 this is going to depend on -- this is sensor
20 technology which is developing right now -- and I
21 wondering why somehow maybe that couldn't be worked
22 into kind of the identity of this, that it is a
23 sensor technology.
24 I go back to the mid-eighties when we used
25 NIR in the early stages for looking at moisture in
1 an intact vial, freeze-dried product. It was an
2 end product. But one of the things we learned,
3 too, was presentation of the product to the sensor
4 is very important, and that I think is something, a
5 technological problem that needs to be overcome,
6 and I think engineering that can be voluntary.
7 I guess with regard to immediate release
8 products, I see the application here, you know, in
9 the manufacturing area, and I agree with Art, I
10 think 10 years from now, that this is something
11 that behooves all manufacturing companies to adopt
12 this for survival, but I think the development, it
13 seems to me to be done in the manufacturing area
14 for the immediate release products, where one can
15 build up a history and experience and know just
16 what it is that you need, what parameters you need
17 to be monitoring there and what is the robustness
18 of this and how does that play a role in that.
19 I guess, to answer Ajaz's statement with
20 regards to development, I can see this in the
21 development area for extended release products
22 where you are now dealing with maybe products that
23 are six-month or a year type of products, and you
24 really can't wait around six months or a year to
25 release the product. This would be very beneficial
1 to be able to have this type of technology that
2 would allow one to release a product, you know,
3 without having to go through some release test or
4 some test that is extended over real time in that
6 DR. LEE: Thank you, Pat.
7 Yes, John.
8 DR. DOULL: One of the problems we are
9 having in bringing our students up to speed in
10 genomics and proteomics, and so on, is we find it
11 isn't really enough to teach them molecular
12 biology. You also really have to teach them
14 We can't teach that. We have to bring
15 people in to teach that because that's a
16 specialized field. When we talked about this the
17 last time, it seems to me we asked that question
18 about informatics and whether you have sufficient
19 expertise, Ajaz, on your groups to bring that
20 discipline clearly in. You know, rather than
21 bringing it from in-house, you may have to go
22 outside and get special kinds of techniques and
23 what have you to really use -- Art mentioned they
24 use the computers, and that is a special area, and
25 I am not sure that we have that in-house
1 information. You may need to go outside and get
2 more of it.
3 DR. HUSSAIN: I think informatics, I sort
4 of put that under chemometrics. I think
5 chemometrics is broadly defined as chemical
6 informatics, and so forth. Surprisingly, FDA
7 probably has a lot of expertise, probably cutting
8 edge expertise with pharmacometrics, I think the
9 tools like Jurgen and others would use in PK/PD
10 modeling, and so forth, are essentially similar
11 tools here.
12 Our toxicologists have done extensive work
13 on informatics. So bits and pockets of information
14 is there, but it has not been applied to chemical
15 problems, and that is the reason we felt that we
16 will hire a chemometrician, a chemical statistician
17 to handle this.
18 You are right, I think we need to hire,
19 and I think the four individuals that we are trying
20 to hire, one of them would be chemometrics and
22 DR. LEE: What about Judy, do you have
23 something to add? As a member of the working
24 group, do you feel that we are moving in the right
1 DR. BOEHLERT: There is one other point
2 that Ajaz addressed in his presentation, and that
3 is the lack of consensus within companies among
4 different groups.
5 Clearly, right now it is seen as a
6 manufacturing initiative, and it should be a
7 multidisciplinary initiative, and I don't know to
8 what extent, when you are planning workshops, and
9 things of that sort in the future, you can bring
10 these different groups together, because clearly,
11 the roles and responsibilities of some of these
12 groups are going to change.
13 For example, the Quality Group, they are
14 going to evolve to a situation where you don't have
15 off-line testing. The functions that they perform
16 now are going to go more into the audit kind of
17 mode, and I think we need to begin to educate these
18 folks, not that they are going to lose their jobs,
19 but their jobs are going to change, and start
20 bringing them on board, and if we don't bring
21 everybody on board, regulatory affairs,
22 engineering, product/process development, and
23 quality, then, it is not going to have a high
24 chance of success within companies.
25 That is part of the selling job right now.
1 I would agree that in 10 years, the big companies
2 will be there. I think it is going to be more of a
3 challenge for the smaller companies, and it is a
4 resource issue.
5 You know, they don't have anybody on staff
6 that knows much about informatics very often. They
7 don't have the technical expertise.
8 DR. LEE: Maybe by that time industry will
9 be out-sourcing everything.
10 DR. BOEHLERT: Right, and it is quite
11 possible a whole new industry is going to develop
12 to support this kind of initiative.
13 DR. LEE: So many things are happening,
14 and I would just like to ask the committee, you
15 know, what is the advice to the subcommittee on
16 PAT, do we put a point to prioritize, do we put
17 some effort into certain areas more so than others?
18 DR. HUSSAIN: I think in terms of the
19 focus for the next meeting, we will focus more on
20 the regulatory uncertainty, defining the Safe
21 Harbor, defining all those processes, and sort of
22 wrap the second meeting with that.
23 We had planned for a two-day meeting, but
24 there are many issues with respect to computer
25 validation, with respect to validation itself.
1 From that perspective, I had come to you before, I
2 said we will probably use two meetings.
3 My thinking is we may need one additional
4 meeting about this, even for the general guidance,
5 and then sunset that subcommittee after the third
6 meeting, because their job to provide information
7 for the general guidance will be over.
8 We will have need for more technical
9 guidances, and so forth. What I was hoping is we
10 will sunset the subcommittee and bring on the
11 Manufacturing Committee as a committee under the
12 ACPS, and then address some of the technical
13 science issues either on the PQRI or other
14 mechanisms. That is the thought process for the
15 next few steps.
16 DR. LEE: Gloria, you are the
17 representative of the Consumers. Any comments
18 about this development?
19 DR. ANDERSON: No, I don't really have
20 anything to add other than to say that I think it's
21 a big step forward, and I am particularly pleased
22 with it. I would like to ask if you could take a
23 minute and tell us a little bit about what you
24 observed when you made your visit, what you
25 observed in terms of the technology that was being
1 used in-line, on-line.
2 DR. HUSSAIN: I think, broadly speaking,
3 and I don't want to focus on one company --
4 DR. LEE: She is validating that you were
5 actually there.
6 DR. HUSSAIN: Yes. What I was surprised
7 was, as I said, I was at Aventis, Bristol-Myers,
8 AstraZeneca, Pfizer, and last week Merck, and I was
9 amazed in terms of how much work is already
11 In general terms, use of Raman emerging as
12 inspector methods for controlling particle size and
13 polymorphism at the crystallization stage of the
14 drug substance. I think many companies are working
15 on that in the very mature area in terms of
16 controlling the polymorph that you produce, and so
18 In terms of blending, obviously,
19 laser-induced fluorescence, man companies have been
20 working with that, and near infrared is very, very
21 common. When I sort of talk, and so forth, I bring
22 my bias, the solid dosage form, but the thing I
23 have to guard against myself is there are many
25 When we visited another company last
1 summer, with on-line HPLCs, on-line GECs,
2 everything has been used for several years, but
3 again have not had the regulatory applications. I
4 mean they are doing in addition to what they do for
5 regulatory purposes.
6 So my sense, and what I am very hopeful
7 is, there is a lot of activity that is already
8 ongoing within many companies. The concern is
9 sometimes when we went to these companies, the R&D
10 and the Regulatory Affairs folks for the first knew
11 what was happening, so that is the reason for, as I
12 said, is a disconnect. So my presence or our visit
13 helped them talk to each other, so I am hoping we
14 can do that more.
15 DR. ANDERSON: I would just like to say
16 that I think that anything that improves
17 efficiency, and hopefully cost effectiveness,
18 certainly should be good for the consumer.
19 DR. LAYLOFF: One other remark. I think
20 that the pharmaceutical industry, the traditional
21 drug industry is very conservative, it is very
22 staid, but if you look at the more dynamic
23 industries in the biotechnology areas where there
24 is a rapid flux, you find that there is a lot more
25 assimilation of trying to be more efficient, keep
1 everything moving, because they haven't really
3 I guess they will grow old and
4 conservative also eventually.
5 DR. LEE: Other comments?
6 DR. HUSSAIN: Final talk for the record, I
7 think there is an omission that Tom did and I did
8 in my previous presentation, and so forth, is for
9 some reason, Efraim and Leon, we missed their names
10 on the list, so we just want to acknowledge they
11 participated in part of that PAT Subcommittee.
12 DR. LEE: It seems to me that the
13 committee is gaining some momentum, and I think
14 it's on the right track, and we are going to hear
15 from you again at the next meeting.
16 Thank you very much.
17 Let's take a 10-minute break.
19 DR. LEE: We are going to start out with
20 two individuals from the agency, Dr. David Hussong
21 and Bryan Riley.
22 Rapid Microbial Testing - Update
23 Introduction and Overview
24 David Hussong, Ph.D.
25 DR. HUSSONG: I simply wanted to introduce
1 today's speakers. We are kind of lucky because of
2 the backgrounds of these people.
3 Dr. Bryan Riley is a review microbiologist
4 at CDER. He has as spectacular background in
5 clinical microbiology, and, of course, clinical
6 microbiology is where a lot of the microbiology
7 rapid methods came along.
8 We also have Dr. Mike Korczynski, who has
9 a very good background from Abbott Laboratories
10 where he headed up a major program, and he has
11 since gone on to be an independent consultant.
12 Dr Korczynski also had great input in a
13 technical document produced by the Parenteral Drug
14 Association on the introduction of new methods in
16 We are also blessed that later today, we
17 will be hearing from Jeanne Moldenhauer and Scott
18 Sutton, who were also on that committee.
19 I would like to introduce Bryan Riley.
20 Bryan Riley, Ph.D.
21 DR. RILEY: Thank you, David, and good
23 As an introduction to this session, what I
24 would like to do is give you a quick look at some
25 of the methods that are used for microbial limit
3 I would like to start out with the
4 compendial methods, which around here means USP,
5 Chapter 61, Microbial Limit Tests, and there are
6 essentially two methods that are used. They both
7 rely on the growth of the organisms.
8 The first one are called plate counts,
9 which give us colony-forming units. In that
10 method, you apply the sample either onto or into
11 the solid medium. You incubate the medium, allow
12 the colonies to grow, and then you count visible
14 The second method, which is less accurate
15 than the plate count method, is called the MPN or
16 most probable number method. In this, a series of
17 multiple dilutions are made in a broth culture, a
18 liquid medium. These serial dilutions are
19 incubated. At the end of the incubation period,
20 you look at the different tubes in each dilution
21 that show growth.
22 You then refer to an MPN table, which will
23 tell you what the most probable number of organisms
24 was in the original sample.
1 The advantages of the compendial methods
2 are they are very simple, easy to do, are tried and
3 true methods. They can be done by any
4 microbiologist in any microbiology lab. They only
5 count the viable or living organisms because we are
6 not really interested in the dead organisms at this
7 point. We just want to know what's alive, what to
8 grow in the product cause product problems for you,
9 the product quality, or the patient who takes the
11 The disadvantages are the incubation time,
12 which can be up to seven days for a yeast or mold
13 culture, as well as not all organisms will grow on
14 a single medium, and so you are really sort of
15 getting a subset of whatever organisms that might
16 be present in that sample. So that is a little bit
17 of a drawback.
19 I will say a little bit about microbial
20 viability again. We talked about the compendial
21 methods only will detect living organisms that can
22 grow, and that is all we are interested in.
23 Therefore, any new or rapid method will have to
24 have some way of differentiating between the live
25 and the dead organisms.
1 To do that, you need some sort of marker
2 for viability. As an example of this, for the
3 rapid test, I would like to give examples of a
4 couple of markers that are used for these tests.
6 The first one is esterase detection. The
7 esterases are enzymes that are ubiquitous in
8 microorganisms, and it works by the reagent that
9 you apply to the sample being cleaved by the
10 esterases and releasing a fluorescent compound
11 which can be detected in the sample
13 The method works as follows. The sample
14 is filtered, the filter membrane is exposed to the
15 reagent, and after an incubation period or short
16 incubation period, the membrane is analyzed by
17 laser scanning, and you get a count of the
18 organisms that are present on the filter.
20 The next method is the ATP
21 bioluminescence. ATP is a primary energy source
22 for all organisms, so it is going to be present in
23 any living organism that you have in there. The
24 reagent, which is a combination of luciferin, which
25 is a substrate and luciferase, which is an enzyme,
1 along with ATP will react to produce visible light,
2 which can be measured.
4 The procedure works as follows. The
5 sample again is filtered, much like the esterase
6 test. The membrane is placed on a solid medium for
7 a brief incubation period to amplify both the
8 numbers of organisms, as well as the ATP content,
9 to allow it to be detected.
10 The cells are disrupted to release the
11 ATP. The bioluminescent reagent is added to the
12 membrane, and then a coupled device is used to
13 detect the light, and the results are analyzed by
14 computer to give you again the number of organisms
15 in the sample.
17 The advantages of the rapid methods are
18 they are rapid, they are fast, less than 24 hours
19 in some cases, much less than 24 hours, 2 or 3
20 hours in some cases. They are very sensitive. As
21 I said, they don't necessarily rely on growth, and
22 so they can detect any organism that is present in
23 the sample, whether it can grow on a medium or not.
24 The disadvantages would be increased
25 complexity for these methods. They are much more
1 complex than just plating out a sample on solid
2 medium. They are expensive, both originally the
3 setup costs of the equipment, validation, et
4 cetera, so they are not cheap.
5 In some cases they can be too sensitive,
6 getting back to the increased sensitivity of the
7 test, in some cases you may have an
8 out-of-specification result, because you are
9 detecting more organisms than you would with the
10 compendial method, and that could be a problem.
11 My final slides are going to be a couple
12 of questions for the committee to ponder.
14 First of all, should or could the agency
15 do anything to encourage industry to use these new,
16 rapid micromethods?
18 Finally, getting to the sensitivity issue,
19 since to address the sensitivity issue or the
20 increased sensitivity issue, you may need to change
21 the specification for some of these drugs, and what
22 could be considered as a loosening of the
23 acceptance criteria by making the numbers higher,
24 how can we address this both from a scientific
25 standpoint, as well as a regulatory standpoint,
1 what can we do to make this work smoothly and still
2 provide adequate microbial quality for the
3 pharmaceutical products?
4 With that I would be happy to take any
5 questions that the committee might have.
6 DR. HUSSAIN: Just an additional
7 perspective on this, we had a discussion on rapid
8 micro, the same meeting we first had the PAT
9 discussion, and at that point, I think the
10 recommendation was to either form two separate
11 committees, one for rapid micro, and for PAT.
12 We didn't make progress on rapid micro, so
13 I asked them to come back to this committee to sort
14 of examine these questions, but in addition, to see
15 -- a lot of the issues that we deal with here are
16 the same issues with PAT, so from a general
17 perspective, the general guidance that we have on
18 PAT could incorporate a lot of these issues by
20 So, the general guidance on PAT probably
21 could cover the process, regulatory uncertainty,
22 and risk-based approach that we would need to
23 address the sensitivity of some of these methods,
24 and then follow that up with more technical
25 guidances as you do for the PAT.
1 So that is sort of the perspective as you
2 ponder and discuss this.
3 DR. LEE: Maybe we can hold off questions
4 until the end. Thank you.
5 Dr. Korczynski.
6 Michael S. Korczynski, Ph.D.
7 DR. KORCZYNSKI: I would like to say I am
8 really pleased to have been invited to speak.
9 During my industrial career and thereafter, I saw a
10 number of occasions to use rapid methods. I think
11 they have a real place in industry, and I think we
12 should really all be part of moving those
13 activities forward in the industry.
15 For all of the reasons that we already
16 heard this morning, efficiency, improvement of
17 efficiency, improvement of productivity, shortening
18 corrective action time, so you can respond more
19 immediately rather than waiting a week basically,
20 better utilization of your personnel, more
21 efficient use of your personnel, and finally, we
22 all hope some sort of cost reduction for the
23 industry because that is basically what they are
24 going to be looking for in the implementation of
25 these methods.
1 Now, I heard the word "conservatism" this
2 morning. I think that is a good word. I would like
3 to read some thoughts that I had written down
4 regarding the impetus that must be provided. My
5 analogy, we need to start rolling the stone down
6 the hill basically. Someone has to start to be a
7 champion of these methodologies.
8 While many companies appreciate the
9 potential of rapid methods in microbiology, and are
10 willing to institute these methods, it isn't going
11 to happen unless companies feel that the FDA
12 supports these methodologies.
13 Some companies with the resources and
14 technical expertise are bold enough to be risk
15 takers and have the resources to present the data.
16 You know, they will call a meeting with the FDA,
17 they will eventually do their R&D homework, and
18 maybe eventually that will turn into a supplement
19 and an NDA, but that is mainly some of the major
21 I think what we find in many cases, the
22 smaller companies and smaller companies without the
23 resources are holding back, you know, where is it
24 going, is the FDA presenting this information
25 publicly, does it appear that they are supporting
1 this technology, where does the USP stand, is there
2 an in-process revision for this methodology.
3 So that is the conservative attitude that
4 someone else has to get it moving before others
5 will follow. Therefore, I think that once FDA
6 public endorsement appears to occur, many companies
7 will start employing the specific methodology, and
8 the FDA indeed is a significant factor in
9 introducing rapid methods to the industry.
11 Now, I would like just for a historical
12 basis, the FDA has -- and I think some of us have
13 forgotten about this -- the FDA has played a role
14 in the introduction of some microbiological methods
15 in the industry.
16 Now, one method, some of you may not even
17 recall this, it's about 1974 to 1977, in that era,
18 data was taken from academia and eventually moved
19 over to industry, and that was in the Limulus
20 amebocyte lysate test, which is a test for
21 bacterial endotoxin with a lipopolysaccharide
22 associated with gram-negative cell walls.
23 That is a method that tests the cellular
24 component. Prior to that, the industry had to have
25 huge animal colonies, that you test for LPS's,
1 fibro/fibril producing, or pyrogen, and so in all
2 your lots, you had to do pyrogen testing, mandated
3 that you had a huge animal colony, that that animal
4 colony was inspected. It took time to run
6 Well, the FDA, I think this is really a
7 hallmark, it was a hallmark activity, and that the
8 FDA worked with USP, the industry, academia, and
9 developed a protocol of how to move that technology
10 forward and for a while there was some finished lot
11 testing, I believe by the FDA, but I think it was
12 model system in terms of introducing a rapid method
13 to industry. That is why I spent a little time on
14 that particular topic.
15 The other one was membrane filtration.
16 Many people forgot that it was Dr. Francis Bowman
17 back in the 1960s that was a proponent of membrane
18 filtration for sterility testing. Prior to that,
19 you did a dilution type of test, it would take you
20 14 days. The membrane filtration now allowed you
21 to filter product and test for 7 days basically.
22 It became accepted, it became part of the
23 USP. Now, however, the pendulum is swinging the
24 other way, just as an anecdotal comment, and even
25 though you filter for aseptic fill products, you
1 are incubating for 14 days. EP wants 14 days
2 incubation even though it is filtered, fraternally
3 sterilized product.
4 So here is an issue now, and that issue is
5 Dr. Riley presented some rapid methods, sterility
6 testing to obviate that 14-day test, is an ideal
7 opportunity for one of these viable methods that
8 was just presented, so we need to think about that.
9 The other item that I thought was helpful
10 to the industry was the FDA, I think it was Bureau
11 of Drugs back somewhere in the seventies,
12 introduced a protocol that allowed you to shorten
13 your incubation time for biological indicators that
14 are used to monitor sterilization processes,
15 providing statistically your data fell into the
16 mode presented in that protocol, and that was very
17 helpful because in many cases, that shortened
18 process time testing from, in some cases, 7 days to
19 5 or 4.
20 I have gone through the role of the FDA as
21 an advocate of some of the methods.
23 On thing I might mention in terms of
24 microbiology, rapid methods in microbiology, one of
25 the rapid methods that does exist is the
1 identification of microorganisms. You used to have
2 to go through laborious test tube reaction types of
3 tests. There is now identification equipment where
4 you can inoculate cards or wells, and actually have
5 a much faster readout.
6 So that has been fairly widely accepted in
7 industry, and that does exist as a rapid method.
9 Some of the important aspects of rapid
10 methods you have heard, you have heard a lot of
11 this, but it is real-time analysis, process
12 real-time analysis. We are getting close to it in
13 microbiology because sometimes you still need a
14 dwell time, you need some type of incubation time,
15 but you could minimize corrective action time,
16 which is very important.
17 You might be processing something and we
18 find the water supply is over action level, you
19 didn't wait days to find that out, perhaps you
20 could find that out that very day, stop the batch,
21 make the improvements.
22 Again, you are going to increase assay
23 sensitivity in many cases. That was already
24 described. Therein lies a problem, but I think, as
25 scientists, you have to deal with the data.
1 So if technology moves you forward and you
2 now have a more sensitive test, you have to figure
3 out basically how to do that. You know, maybe in
4 some cases you are going to have to modify your
5 alert and action levels, but you can't hide from
6 the facts, and the new procedures will be more
7 sensitive in many cases.
8 Of course, it is going to remove some of
9 the operator performance, and we hope to see more
10 improved reproducibility. I think there will be a
11 more efficient utilization of personnel, and that
12 is why I say efficiency and productivity, because
13 now you can take those people who were spending too
14 much time on some of the longer assays and have
15 them doing other things basically.
16 I think there is an opportunity for cost
17 reduction after the initial capital investment.
18 Many of these rapid methods have equipment that you
19 have to purchase basically and then once you
20 establish and have that equipment, you have to buy
21 the commodities to keep it going.
22 So it is that initial capital investment
23 that is going to cost, and I think to have an
24 appeal to the industry, you probably need a payback
25 of, you know, maybe in a five-year period.
1 What does all this mean? It means
2 potentially, reduction of product release time.
3 Now, maybe not all companies have this, but, you
4 know, there is an element that is moving towards,
5 and it is already there, just-in-time
6 manufacturing, reduce your inventories, manufacture
7 to the orders, so therefore, you are trying to
8 remove all the lag times and delays out of your
9 processing, and shorten that product release time,
10 and these micromethods have that potential.
12 Dr. Riley already went over several
13 methods, but just to categorize these for you,
14 there are about four basic methods, growth based,
15 and I might say for every one of these methods,
16 there are about three to four rapid methods that
17 can support those four entities.
18 So if you have a growth-based assay, you
19 could perhaps utilize ATP bioluminescence, maybe
20 reduction of CO 2,
maybe head space pressure in a
21 container, and, of course, under growth-based
22 technologies, one would find the various
23 biochemical ID assays that I talked about.
24 Then, I am going to show a slide on
25 viability-based studies, which I think have
1 probably a fairly wide application and utilize some
2 very sophisticated instrumentation that is
3 appearing out there, and also has some costs
4 associated with it.
5 The next technology would be cellular
6 component. This would trying to look for entities
7 associated with a cell, so you could have fatty
8 acid detection, you could have mass spectroscopy
9 that kind of gives a fingerprint. You talked about
10 signature. Well, it sort of gives a signature of
11 your different genus, maybe species, of
13 You could have enzyme-linked immunosorbent
14 assay that looks for antigens or antibodies
15 associated with a cell, and also you could have,
16 under cellular component, I just talked about LAL,
17 that is a rapid method in a sense because it takes
18 just a couple of hours and you can determine
19 whether you have an endotoxin of LPS concentration
21 The next item would be the nucleic acid
22 technology, and there we are talking about DNA
23 probes, ribosomal tying, and PCR, polymerase chain
24 reaction. So you can see there are technologies
25 out there, there are methodologies out there that
1 could begin to fit these required technologies.
3 I am not going to talk about this to any
4 great length, but example of rapid viability
5 methods. It is using again perhaps you filter the
6 solution, you bring the cells in contact with a
7 dye. Internal esterase enzyme within the cell
8 cleaves that, it becomes fluorescent. You either
9 look at it via a microscope or it goes through a
10 photomultiplier tube, put that information in the
11 computer. Basically, you have counted cells.
12 These methods are turning out to be quite
13 sensitive. I believe the fluorescence flow
14 cytometry, we are measuring, looking at
15 microorganisms in flowing solution. I think that
16 requires somewhat of a higher count, but at least
17 on the filter scanning types, you can detect down
18 to 1 to 10 cells.
19 The literature is in your booklets, right?
20 So it is there. I think these perhaps have lots of
21 promise, could be quite sensitive.
23 I put together some thoughts on what might
24 be ideal attributes of a rapid viable microbial
25 quantitative method, and could process variable
1 sample sizes. You want it to detect more microbes
2 than general plate counting. You want to detect
3 low levels of viable cells, and there is an issue
4 going on, on unculturable cells. We never heard
5 this, you know, 10 years ago, that word wasn't
7 We are finding in certain systems where
8 the microbes are stressed and just about able to
9 survive. They are there, and when you use
10 conventional culture media, you can't recover them,
11 because the media is too enriched for the
12 environment that they were used to.
13 This method should probably have that
14 capability, and it has to be able to differentiate
15 between artifact and actual cells. Sometimes you
16 may stain, in your staining procedures, some type
17 of debris, may stain and it is not a cell. You
18 have to be able to differentiate that in these
20 In industry, it is very important for us
21 to have portable systems, your environmental
22 monitoring, you are going from aseptic suite to
23 aseptic suite, you need something portable. So
24 this system should be portable.
25 Very important, you should be able to
1 corroborate the data by some other method, and that
2 is going to lead us into validation. Then, you
3 want to see a return on the capital equipment.
5 Now, pharmaceutical acceptance, you know,
6 where is the USP on these issues? Maybe my
7 colleague, Dr. Scott Sutton, may have something to
8 say about that, but I am mainly using an example a
9 little bit of sterility testing here in that there
10 is some polymerization trying to occur between USP
11 and EP.
12 Relative to sterility testing, it is still
13 the accepted, you know, it's a 14-day test even if
14 you are filtering the product. As I said, it may
15 get to get 14 days for products that are
16 aseptically filled, and yet there is no -- the USP
17 will talk about the possibility of available
18 methods, but there is no rapid method mentioned in
19 USP or EPA that basically addresses, say, sterility
21 So my opinion is -- just anecdotally, I do
22 sit on a USP committee -- but my interpretation is
23 it is rather slow or nonexistent, and what I mean
24 by that, is the encourage of new rapid microbial
25 methods, and kind of why.
1 I think the reason for it is there is
2 really no provision for the validation of these
3 methods, and there is an uncertainty of how do you
4 validate some of these new rapid methods and by
5 whom, you know, in order to get a reasonable cogent
6 interpretation of that data. You can't have the
7 supplier just presenting their validation data. It
8 has to be done by some type of outside peer group.
10 I might add, though, the USP, when I said
11 slow to move, does recognize, in some of the
12 chapters they recognize that alternatives can
13 exist, and such methods should be validated if they
14 are used, and, of course, you should have
15 equivalent reliability and when dispute arises, the
16 compendial method is conclusive. So while it is
17 recognized, there are no specific examples of
18 alternative rapid methods.
20 I might add that, if you are interested, a
21 very good resource document is the PDA Technical
22 Report 33 that addresses evaluation of validation
23 of rapid microbial methods. It basically lists
24 these items, it defines them, gives them
25 definitions, but it is a fairly demanding and
1 arduous task to validate a new microbial method, it
2 will be.
4 Now, if we look for guidance, you know,
5 how can we validate these methods. Some of you are
6 probably aware of more of these, but there are two
7 guidelines for validation of chemical methods, and
8 one is USP Chapter 1225, Validation of Compendial
9 Methods; ICH, Validation of Analytical Methods.
10 However, some of us just off-line had a
11 conversation. I am not so sure how often we can
12 take chemical validation procedures and apply them
13 to the microbial method scenario. I don't know how
14 much we can draw upon that.
15 In terms of the microbial methods
16 validation, I think it is fairly weak. We have an
17 ASM verification and validation of procedures in
18 the clinical micro lab. That is good, but in
19 industry, we are not in a clinical micro lab, not
20 in the manufacturing environment.
21 The other item is USP Chapter 1227,
22 Validation of Microbial Recovery for Pharmaceutical
23 Articles. Good, but it doesn't directly apply to
24 some of the rapid methods that we are considering.
1 Now, I have a proposal for validation and
2 review, because I think that is one of the keys in
3 the system of these rapid methods.
5 This is my own viewpoint, so no one in any
6 group or agency advocated this, but it just seems
7 to me if we can only go back and look at what it
8 took to implement the LAL method in industry, that
9 could serve as an ideal model, and I think we can
10 establish a protocol for evaluation of microbial
12 We should involve industry in generating
13 the data and then we can covalidate perhaps --
14 perhaps at an FDA laboratory and/or USP labs, and
15 as I said, use the LAL test method as acceptance,
16 and have a joint peer review by the FDA, USP, and
17 industry scientists.
18 Now, I thought about this. This sounds
19 nice, but there is going to be a challenge in there
20 in that every company that supplies a rapid method
21 or makes rapid method equipment are going to line
22 up and say, you know, are you putting my method in
23 queue for validation testing.
24 So you are going to have to deal with
25 those issues, and if you selected one viable
1 method, why didn't you select the viable method
2 manufactured by another company basically. So
3 those are the challenge would lie ahead.
5 So, in total, if we look at an initiative,
6 and I think this initiative is very compatible with
7 what I heard this morning relative to the chemical
8 side, and that is to facilitate the technical
9 transfer of valid rapid microbial methods to the
10 pharmaceutical industry, resulting in the use of
11 consistent and accurate assay methods that will
12 expedite corrective action, reduce manufacturing
13 time, increase productivity, and, of course, reduce
14 expenses, and hopefully, those will be passed along
15 to the consumer.
16 Thanks for your time.
17 DR. LEE: Thank you very much.
18 I will now open the floor for questions.
20 DR. HUSSONG: I think one omission on my
21 part, I forgot to introduce Peter Cooney. Peter
22 Cooney heads the Microbiology Group in the Office
23 of Pharmaceutical Science, and this group has just
24 moved to direct under the Office of Pharmaceutical
25 Science, as I mentioned yesterday. He will
1 participate in this discussion.
2 DR. LEE: Peter, would you have any
3 comments to make?
4 DR. COONEY: I just want to say that the
5 Microbiology Group in OPS is on board with Process
6 Analytical Technologies. We look forward to
7 cooperating with the industry, and we encourage you
8 to make submissions because we are not opposed to
9 approval of these methods.
10 DR. LEE: Great. I think that is one
11 question posed to the committee - is the PAT's
12 program sufficiently broad to address the general
13 issues related to the introduction of rapid
14 microbial testing. So that is the question. We do
15 have representation by Dr. Riley, and do you have
16 any specific questions for him or for Dr.
17 Korczynski. Yes.
18 DR. SHARGEL: I would like to bring up
19 another issue that occurred to me, and it probably
20 impacts on PAT, as well. This is a case where, in
21 many cases, there is an older product with low
22 sales volume, say, $10 to $20 million, that a large
23 company may feel for business purposes that we
24 drop, and this is happening right now.
25 A smaller company may feel it wants to
1 pick up the product, but accordingly, and let's say
2 it's an antibiotic product, that the NDA is pretty
3 old, it's safe, it's efficacious, it's a low cost
4 product, in order for a small company to pick it
5 up, they would have to do, say, a fair amount of
6 analytical testing and validation, whereas, the
7 original antibiotic NDA may not even have had a
8 chemical assay. It could have had an antibiotic
9 assay, which was total actives by some approach.
10 How will this impact, this new technology,
11 on old products and particularly the fact that
12 right now we are losing some very good products
13 just currently because of business decisions, and
14 smaller companies cannot sell these products
15 because of the economic costs of validation and
16 development are too high?
17 DR. HUSSAIN: I was hoping, in a sense,
18 that what we are talking about is not a
19 requirement, and so forth, so I think it gives a
20 company a choice to use whatever approach is
21 appropriate, so that is a reason I felt that the
22 issue was sort of addressing that.
23 DR. SHARGEL: I would just like to follow
24 up. Currently, using the state of art now, there is
25 a requirement to have stability indicating assays,
1 chemical methods, and all of that, so we are losing
2 products right now currently as the regulations
3 occur. So we are adding now more methodology.
4 DR. HUSSAIN: Leon, I think -- I haven't
5 given thought to exactly the issue you just raised
6 -- but I didn't see that as a sort of PAT issue per
7 se, but let me go back and think about that. I am
8 not sure I have the answer for you today.
9 DR. LEE: Tom.
10 DR. LAYLOFF: I think the one he just
11 mentioned is the one where the technology changes
12 and the bar raised, so when the chemical assays
13 came in, they were more sensitive to some of the
14 product quality dimensions, and the bar actually
15 raised on the products.
16 Going back to one of Mike's comments, I
17 don't think there is going to be a change in the
18 base legal status, you know, legal definition of
19 what is a sterile product. These will probably be
20 validated replacements which are open in USP, that
21 you can cross-validate that there will still be a
22 legal bar, and that is probably not going to change
23 unless there is something really extreme happening,
24 but I think setting up validation criteria to bring
25 in new test methods is a very reasonable thing to
2 DR. KORCZYNSKI: Regardless of whether you
3 use the rapid method or conventional method, the
4 conventional method for a small company may be less
5 expensive at the beginning basically.
6 The final result is the final product.
7 The final product is sterile whether they use the
8 conventional method or someone used a rapid method,
9 but the person that used the rapid method enjoyed
10 some efficiencies and productivity perhaps that the
11 smaller company didn't use. I think that's the way
12 maybe the outset, the way it is going to be.
13 In other words, you could take an analogy
14 to that. Aseptically filled product is sterile,
15 and some companies will fill in an isolator, some
16 companies will fill in a sterile suite, and you
17 still have some hand-filling going on, but that end
18 product is still sterile.
19 So I think, at least maybe in this next
20 decade, there is some larger core for variability
21 in how we do these tests. Does that make sense?
22 DR. COONEY: Let me just make a statement
23 about sensitivity levels, because that is what
24 everybody is concerned about. In other words, you
25 know, in chemistry, sometimes when the ASA
1 sensitivity got better and better, the limits got
2 tighter and tighter.
3 I personally do not intend to do that in
4 microbiology, and the reason for that is we will
5 only do it if there is an associated increased
6 risk, and it has to be risk based, so that if you
7 have one of these methods that have been talked
8 about, and let's say you detect in terms of
9 microbial limits, not sterile products, but
10 microbial limits, let's say you detect 10 times the
11 number of organisms in the sample that you would
12 have detected using compendial methods, using
13 trypticase-soy agar.
14 Well, that doesn't mean the product is 10
15 times worse than it ever used to be. An example of
16 that is, for example, if you use trypticase-soy
17 agar and do bioburden assessments or assay to
18 water, you know, people accept a limit of 10
19 colony-forming units per 100 ml, and I think that
20 is even mentioned in USP, if I am not mistaken, but
21 if you use a different agar and different kind of
22 culture conditions, you can get 10 to 100 times
23 more colony-forming units in the same sample. That
24 is in the literature, and it is seen a lot of
1 We expect that to happen with these new
2 methods, as well, and this is what Bryan and Mike
3 were alluding to, what that means is you have a
4 different measure. You have X number of ATPase
5 units, or you have X number of esterase units, and
6 how does that correlate to what you see in old
8 It doesn't mean that now the limit of
9 acceptability will be 10 or 100 times less just
10 because you can detect 10 or 100 times more,
11 because like I said, it's a risk-based assessment.
12 DR. LEE: Peter, let me ask you a
13 question. It might be a silly question. Would you
14 envision that we would expect to identify the
15 bacterium? I think soon the genome would be
16 sequenced, but that's overkill.
17 DR. COONEY: Well, in the manufacturing
18 environment, when they establish microbiological
19 control of a manufacturing process for a certain
20 product, identification of the microorganisms is
21 part and parcel of that. Some people do more, some
22 people do less, but it is important to know what
23 kinds of organisms are associated with the
24 environment, with the product, so that if there is
25 a change, you will know that something is
2 There are a lot of rapid microbial ID
3 methods, as well, that Mike spoke to. One thing to
4 think about for the Advisory Committee and the
5 subcommittees, or any future subcommittees, is
6 there is a difference between microbial limits and
7 sensitivity in microbial limits where something is
8 supposed to be there, and sterility testing where
9 something is not supposed to be there.
10 The question one might ask from a
11 technical standpoint is what happens if 50 percent
12 of samples tested using the technologies turn out
13 to have something in them that you never saw before
14 using USP sterility tests, what do we do then? So
15 that would be an interesting question for the
17 DR. LEE: Yes, Tom.
18 DR. LAYLOFF: That is what I was
19 interested in because USP, in the General Notice,
20 it says that you can do all type methods, but there
21 is one definitive legal standard. Now, if you
22 stick with that, then, you don't raise the bar.
23 You can change the technology, but the
24 legal standard platform is still there, and I
25 thought that is what I heard you say you wanted to
1 do with microbiological analyses, and if you went
2 with modern technology, you were going to keep the
3 legal platform where it is, which is an alternate
4 method approach.
5 DR. COONEY: Well, it is an interesting
6 statement, and maybe we could talk later, but the
7 USP sterility test doesn't say that a product is
8 sterile. All it says is it meets the requirements
9 of the test.
10 DR. LAYLOFF: That's correct, but in the
11 General Notice section, there is a statement on
12 alternate methods, that you can use alternate
13 methods for sensitivity, speed, whatever, but that
14 the legal platform is that one that is defined.
15 DR. LEE: Let's hear from the other
16 members of the committee. Any comments, Judy?
18 DR. BOEHLERT: I definitely think this is
19 a topic that falls under the umbrella of PAT,
20 however, there are specific differences, and those
21 have been mentioned by Tom and Mike and Peter.
22 In this case, we are talking about a new
23 rapid technique where a referee method already
24 exists, and it is not brand-new. That referee
25 method has legal consequences. You are talking
1 about a number of different techniques which would
2 need validation perhaps to show that they are
3 equivalent or better than that referee technique.
4 You might want to give consideration to
5 working with USP to see whether that is the
6 appropriate referee technique going forward because
7 if indeed a manufacturer uses one of these rapid
8 techniques, their product gets out in the field and
9 it is challenged for whatever reason, and they
10 haven't used the referee method, you know, then,
11 they are in trouble, and there is some risk
12 involved there.
13 So that area needs to be addressed
15 DR. COONEY: You know, I mean these are
16 really interesting issues and we have thought about
17 them for a long time. One example of a process
18 analytical technology and microbiology, maybe it
19 was stated before by somebody else, maybe it should
20 be called process assessment technology, is
21 parametric release, that is releasing products
22 without a sterility test.
23 Now, we first approved that in 1985, and
24 since that time, I made the statement once before,
25 just a gross estimate is over 5 billion individual
1 product units have been released without a
2 sterility test with no problems in 17 years.
3 Yes, the USP sterility test is the referee
4 test, and I suppose if you took one of those
5 products and you tested it and it failed, you would
6 be in trouble, but as far as in terms of product
7 release, I mean there isn't any microbiologist in
8 the world who now believes that test is worth
10 So working with the USP might be a good
11 idea to change the referee test. In fact, the
12 question is, is there, in fact, an end product test
13 that can detect nonsterility and at what level.
14 In sterility, we know you insist the
15 probability that any one unit is nonsterile, is
16 about 1 in a million, and the sensitivity of a USP
17 sterility test is about 1 in 14, 1 in 10, so you
18 are talking about a 100,000-fold difference in
20 There, you run into what Mike was
21 referring to, is how do you validate the methods,
22 and do you validate the new method against the old
23 method if the old method is 100,000-fold less
24 sensitive than the new method.
25 So all those are interesting things that
1 need to be discussed in the future.
2 DR. LEE: John, you are shaking your head.
3 DR. DOULL: Well, I am a little concerned.
4 The focus that you have given us this morning is
5 really on diagnosis, and you have showed that you
6 can improve diagnostic methods a lot and do it a
7 lot faster, and so on, but the real issue, and I am
8 glad you brought up risk, because that is the real
9 issue, what you want to do is predict risk, and we
10 are focusing on developing methods and we are not
11 asking at the same time the question we should be
12 asking, is how do we improve our ability to predict
13 risk from these microbiological exposures.
14 It seems to me that somehow we need to
15 figure out how we can pay a little more attention
16 to predicting risk than simply developing new
17 methodology. You talked about chemical comparisons
18 and the fact they don't really go, and I agree, but
19 a lot of microbiologists are looking at that issue
20 of how really do you predict risk from
21 microbiological exposures.
22 I think there are some developments, and
23 there are particular molecular biological
24 developments that would give you a way to begin to
25 get ahold of that issue of predicting risk. I
1 guess what I would say is hopefully, that would --
2 I don't know whether that fits into PAT or not, but
3 somehow it ought to at least fit into what we are
4 doing in microbiology.
5 DR. HUSSAIN: In terms of PAT, I think the
6 risk can be looked at from two different
7 perspectives. One is risk assessment or risk
8 management for existing products that have proven
9 and have a track record in terms of when you find
10 something new, which had already been there, I
11 mean, but since you are using new tools, how do you
12 manage. That's one perspective on risk.
13 But on the other hand, I think I would
14 like to look at risk management, the PAT is a tool
15 for minimizing risk, because essentially you are
16 controlling every process, every step much, much
17 more carefully, and because of the availability of
18 new technology, you are preventing the bad product
19 to be manufactured in the first place, so it is a
20 prevention mentality. So it is a risk minimization
21 approach that I think PAT brings.
22 DR. DOULL: Ajaz, that is only half of it.
23 The risk assessment is the other half of it, and
24 you could develop some new procedures in risk
25 assessment which would help you before you get to
1 the management stage.
2 DR. HUSSAIN: I totally agree with that.
3 I think the aspect which I think I sort of
4 underscored in one of my slides was understanding,
5 process understanding, and prevention and
6 identifying risk factors, I think if you want to
7 look at it from that point.
8 If we do a good job in identifying all the
9 critical variables that affect quality and
10 performance, then, that is one assessment of risk
11 factors and how we control that, so that will go in
12 that direction.
13 DR. LAYLOFF: I have one question for
14 Peter again. I think the surrogate testing for
15 sterility, the target is 1 in a million, and I was
16 wondering what failure rate might be required to
17 find it out in a population where it is being used.
18 In other words, is the epidemiology sufficient that
19 you could pick up 1 nonsterility in 100,000?
20 DR. COONEY: Not on a bet.
21 DR. LAYLOFF: You said not on a bet?
22 DR. COONEY: Not on a bet. The false
23 positive rate, even in a well-constructed sterility
24 testing facility, and Mike can chime in here,
25 ranges in the area of about 0.1 percent, 1 in
1 1,000, and you are looking for an event that is as
2 infrequent as 1 in a million, so it kind of doesn't
4 We actually in the beginning, you know,
5 you talk about conservatism in the agency and in
6 the industry, in the beginning, when we first
7 approved parametric release for terminally
8 sterilized products, we asked the company to do
9 sterility testing along with parametric release for
10 two years, and they accumulated all this data, and
11 we didn't learn anything.
12 So that kind of a validation isn't really
13 right. We have to think about a better scientific
14 way to do that, and there will be cases. I am sure
15 there will even be cases in chemistry -- and Ajaz
16 can attest to that -- I mean you are talking about
17 content uniformity, and stuff, and you do 10
18 tablets versus checking every one, so it is kind of
19 like apples and oranges.
20 DR. LAYLOFF: But you do a surrogate model
21 to validate the system, the sterility process, but
22 there is no way to tell if it meets 1 in a million
23 or not, even in population use.
24 DR. COONEY: That is part of the
25 validation process.
1 DR. KORCZYNSKI: I just want to make a
2 comment in terms of the current compendial USP
3 sterility test, if I recall, my probability tables,
4 you could have 5 percent contamination, and you
5 would only recover that about 64 percent of the
6 time. There is room for improvement.
7 DR. LEE: I think we are getting into very
8 technical issues. Let's hear from Pat.
9 DR. DeLUCA: I just wanted to comment on
10 the sterility test. I know Peter implied it is not
11 an effective test. It is a very good test, it is
12 effective. The problem is the sampling plan and
13 the fact, I think that Mike just brought out,
14 actually, to be assured of 95 percent sterility,
15 you have to have about 15 percent contamination in
16 the batch.
17 I think you were saying 5 percent, 64
18 percent of the time. If you want to really be 95
19 percent sure, you have got to have 15 percent
20 contamination in order to get that.
21 I guess the on-line, I think it would be
22 good to have some rapid tests certainly to make
23 decisions with regards to release, I think that
24 would be very, very beneficial, and there certainly
25 are DNA probes that would allow rapid testing, as
1 Mike I think pointed out, within a 24-hour period.
2 I think the other area, too, is with
3 regards to assessing bioburdens. I think this is
4 very important in an operation, if these rapid
5 methods, and I don't know how the PAT could be
6 adapted to this, to be able to monitor bioburdens
7 in a manufacturing operation. I think this would
8 be very valuable.
9 DR. LEE: Is Pat speaking the sentiment of
10 the committee? Should we put this on the plate of
11 the PAT group, to identify what are some of the
12 hurdles, what is to be done?
13 Well, hearing no objections, Pat, you have
14 another assignment.
15 DR. LAYLOFF: Great.
16 DR. LEE: One more horse.
17 So that concludes the agenda item on rapid
18 microbial testing. Thank you very much for all the
19 presentations and discussion.
20 We are now into the open public hearing.
21 We have two volunteers. Their names were mentioned
22 already. That is Jeanne Moldenhauer from Vectech
23 Pharmaceutical Consultants, and Dr. Scott Sutton.
24 They each have been told that they have 10 minutes
1 Open Public Hearing
2 MS. MOLDENHAUER: Currently, if you look
3 at the microbiology testing lab, this is the
4 typical testing performed for each product.
6 Depending on your product, some tests may
7 not apply but this is the typical kind of
8 microbiology testing. The majority of it is
9 retroactive testing where it is performed after the
10 fact, and so improving all these things to the PAT
11 is great and wonderful, but you won't be releasing
12 product any quicker unless we also apply rapid
13 methods to microbiology.
15 Within these methods, there is three basic
16 types of tests that are performed.
17 Presence/Absence tests, is there positive sterility
18 tests, is there not? Is there a specific organism
19 present, is there not?
20 Enumeration tests where you are actually
21 looking for counts of organisms, and
22 identification/characterization tests, what
23 organism is it that is present?
25 When we talk about rapid microbiology
1 technologies, Dr. Korczynski gave a general
2 overview of the technologies that are available,
3 but within the growth-based and viability-based
4 technologies, you would find methods to do -
5 presence/absence tests, enumeration tests.
6 If we go on the additional methods that
7 are available, there is methods to do presence of
8 organisms. There are additional items to identify
9 and characterize organisms. These methods, in
10 general, are superior to the methods that exist
11 today, and as a industry person, the difficulty
12 arises, then, the USP method allows me to provide
13 equivalence, but these methods are superior.
14 The technologies may not even be remotely
15 similar, and the ability to appropriately show
16 equivalence is extremely difficult. In addition,
17 the problem that one faces is training your local
18 investigators to understand that these new
19 technologies are different and how you are going to
20 address the fact that we are not raising the bar,
21 but this sterility test is positive, and this one
22 is negative, and the risk to the product, and
23 that's not an easy thing to address or resolve as
24 an industry person.
1 So we run into some difficulties. I would
2 like to say publicly that CDER's microbiologists
3 are probably the best in the agency as far as
4 resolving or providing guidance on rapid micro
5 methods. I work with several different divisions
6 of the agency, and they are the most responsive and
7 knowledgeable in helping us in trying to get these
8 things approved through industry.
10 But the technology currently is available.
11 There is over 300 companies that are in some degree
12 of commercialization of rapid microbiology
13 technologies of as last degree.
14 It is available for all the types of tests
15 that we need to do. They are generally superior,
16 but the other thing is no one system is going to
17 handle all our problems. You may find that in the
18 typical pharmaceutical company, when these methods
19 are employed, that they may end up with four, six,
20 or eight different technologies to accomplish all
21 the tests that they need to do, and that is one of
22 the problems that people face in looking at it, is
23 looking for one system that is going to solve
24 everything or the fact that one system is validated
25 or approved will solve all their needs. It just
1 will not do that.
2 They allow decisions to be made in a more
3 timely fashion. It is a very difficult, as a user,
4 to say that I am going to find out three days from
5 now that I probably should have shut down
6 production three days ago because I have a problem.
7 It doesn't help, it is very difficult in resolving
8 the cost of the batch, how much additional cost you
9 placed into it which results in end product that is
10 more expensive for the end user.
11 In addition, it is harder to convince
12 people why you have to throw away product on the
13 possibility that it might have maybe been
14 contaminated. Those things are difficult in
15 resolving and addressing.
16 In addition, most of these things will
17 reduce batch release time. Dr. Cooney gave an
18 example of parametric release. I can tell you that
19 eliminating the sterility testing, going to
20 parametric release, realized a more than $3 million
21 annualized savings.
22 That same savings is available, if not
23 more, to go to a rapid sterility test because again
24 you reduce the inventory hold time by that same
25 amount. In the case of aseptically filled drugs,
1 there is no parametric release allowed, so
2 eliminating a 14-day inventory hold time realizes a
3 very significant financial savings to the user and
4 the end consumer and makes it worthwhile.
5 I do have one caution that wasn't on my
6 conclusions before, but it is my concern as of this
7 morning. I am very concerned as an industry person
8 about issuing a guidance document by chemists, for
9 chemists, that is going to be applied to
10 microbiologists without sufficient microbiology
11 review and input because there are many of these
12 documents that get out there, and it makes it
13 extremely difficult for microbiologists to get
14 resolved both in their company, how to get these
15 methods approved and provide appropriate guidance,
16 and there are significant differences between rapid
17 chemical systems and microbiology systems
18 specifically dealing with differences in
19 sensitivity and counts, and how you are going to do
20 these things.
21 Thank you.
22 DR. LEE: Thank you very much. Are there
24 If not, Dr. Sutton.
25 DR. SUTTON: I appreciate the opportunity
1 to address the Advisory Panel.
3 The issue that I would like to talk about
4 is the existence currently of documents that bear
5 on this process, rapid microbiology methods. There
6 are four of them I am going to talk about. There
7 are others I could talk about. Dr. Korczynski
8 talked about the ASM document. I am not going to
9 mention that.
10 There are also a couple of ICH documents
11 dealing with validation of new chemical methods. I
12 am not going to talk about that. I am going to
13 talk about the domestic documents primarily in this
15 The first one, of course, is Chapter 1225
16 in the USP, which everyone is fairly familiar with,
17 and Chapter 1223, which is a new chapter,
18 Pharmacopeial Preview Stage, that just appeared in
19 the January-February Pharmacopeial Forum.
20 I also want to talk a little bit in depth
21 about PDA Technical Report 33 and USP Chapter 1227.
23 I am going to go over this quickly. I am
24 sure most people in the room are far more familiar
25 with this chapter than I am. It was designed by
1 USP to help the USP staff in analyzing incoming
2 methods from industry and from other sources on
3 chemical assays.
4 After they developed this analysis scheme,
5 they realized it would make a very good general
6 information chapter, and so published it as such.
7 It is from here we get the different terms,
8 accuracy, precision, specificity, detection limit,
9 and so on.
11 There are also in this chemical analysis
12 of a new method or an analysis of a new chemical
13 method, certain data elements that are required.
14 These are broken down into different categories
15 depending on the use that this chemical assay is to
16 be set to.
18 These data elements then are further
19 broken down into performance characteristics, and
20 depending on the category, certain characteristics
21 are needed or were not needed.
23 That is basically where we stand as far as
24 the chemical assays, but what became clearer to
25 many of us who were looking at how to handle
1 microbiological assays, it's that that system
2 doesn't work for microbiology. It just flat-out
3 does not work.
4 There are three kinds of micro assays that
5 we are talking about, and these have been alluded
6 to by other speakers. First, there is qualitative,
7 is there something there, are there viable
8 organisms present, and a quantitative, and the
9 topic of this morning's discussion, by my
10 understanding was plate counts, so I have kind of
11 highlighted that one, how many microorganisms are
12 present, and then there is identification, if there
13 is something there, what is it.
14 Now, one thing on the quantitative that I
15 did want to mention. Dr. Riley mentioned that
16 there is going to be changes in the counts that you
17 get from some of these methods. He used the
18 esterase method as an example. That is a very good
20 If you grow cells up on TSA,
21 trypticase-soy agar, or on R2A agar, if you are
22 doing water testing, you are going to get a certain
23 number of organisms that grow. If, however, you
24 change the definition of viability from "ability to
25 grow and form a visible colony" to "does it have
1 esterase activity and an integral cell membrane,"
2 that is a completely different definition of
3 viability, you are going to get a completely
4 different response from that test.
5 In fact, I will share with you that I have
6 been playing with some of the city water down in
7 Fort Worth, Texas in R2A agar. It's good stuff,
8 less than 10 colony-forming units per ml. However,
9 if you move over to this esterase activity,
10 question, you get several thousand viable cells per
12 Now, this is kind of, of academic interest
13 at this point, and it is really not that important
14 as far as the pharmaceutical process, because as it
15 passes through the water treatment, these counts go
16 way down inside the plant. However, it does
17 underscore the problem of how do you set specs when
18 your method changes. The other main question is
19 how to demonstrate equivalence to a compendial
22 There are, as we have mentioned, several
23 different types of alternate methods out there. I
24 have broken them down by slightly different scheme
25 as I want to approach this topic from the proposed
1 USP Chapter on Validation of Alternative Methods.
2 I have broken them down on the basis of qualitative
3 tests, are there something there, quantitative
4 tests, and identification.
5 I have heard a lot of talk this morning
6 about an alternate sterility test. None of these
7 methods is going to provide an alternate sterility
8 test. That is not the correct way to think. With
9 apologies to everyone present, that is not the
10 correct way to think of this problem.
11 What we are doing is we are taking a
12 certain subset of the sterility test, that portion
13 of the sterility test where you take a membrane
14 filter and ask are there viable cells on that
15 membrane filter, and we are changing that part. We
16 are asking the viability question differently.
17 That is all we are doing, we are still
18 sampling 20 units, we are not improving the
19 sensitivity of the sterility test, we are not
20 changing anything about that test except the
21 recognition of viable microorganisms, are they
22 there or not, and by changing that, we can recover
23 14 days in process time and perhaps increase the
24 sensitivity of the test, but not changed the test
25 in any fundamental way.
2 Okay. We have talked about 1225, the
3 chemical assays. A companion to 1225 in USP is a
4 brand-new chapter I mentioned, 1223, Validation of
5 Alternative Micro Methods, which is a close
6 companion to the PDA Technical Report 33, which has
7 been discussed at some length already.
9 Now, similar to the Chapter 1225 in
10 Chemistry, there are different components depending
11 upon the type of test you are looking at, whether
12 it be an identification test for microbiology or a
13 qualitative type of test for microbiology or, in
14 this case, a quantitative test that would apply.
16 However, when we talk about accuracy in a
17 micro test, perhaps we are talking about something
18 slightly different than we are talking about for a
19 chemistry assay. These changes in definitions -- I
20 apologize, I am going to breeze right through
21 these, but they are available in the press -- these
22 changes in definitions are out there both in the
23 PDA Technical Report and in this proposed USP
1 They need to have some attention paid to
2 them, are we looking at the correct way of
3 analyzing a micro assay. The changes that we have
4 made from Chapter 1225, are these changes
5 appropriate, and we need input, and I am hoping
6 that that is one thing that the Advisory Panel can
7 help out with here.
9 They range in ruggedness, and so on.
13 The final one has been mentioned briefly,
14 1227, Validation of Microbial Recovery from
15 Pharmaceutical Articles, and this one is very
16 different from the chemical questions.
18 On this one, the question really is can
19 you recover viable microorganisms in the presence
20 of compounds that are inhospitable to microbial
21 growth, can you neutralize preservatives, can you
22 neutralize the antibiotics.
23 Secondly, micro assays are notoriously
24 variable. The accuracy of the plate count is a
25 serious question. One of the problem with the
1 out-of-spec results when you are looking at
2 something like the esterase activity model is that
3 when you ask for a colony-forming unit, everyone
4 assumes that a colony-forming unit is a cell.
5 Well, it is not a cell. In diplococci, it
6 is two cells. In most of the strep, it could be a
7 string of anywhere from 5 to 50 individual cells.
8 For many of the staph, those clusters can get into
9 the hundreds of cells, all of which yield 1
10 colony-forming unit, but on the esterase activity,
11 they would lead to 2, or to 5, or to 10, or to 50,
12 or to hundreds of counts, a very, very different
13 way of looking at the same question.
15 So plate counts are going to be a very
16 real problem here.
18 I am going to move through here. I am
19 running out of time, I apologize.
20 One thing I do want to spend time on,
21 though, is validation of the recovery, as described
22 in 1227. There are three different types of
23 recovery strategies that are used in traditional
24 methods, recovery in agar, recovery in liquid, and
25 recovery in membrane filtration.
1 Sterility tests, which you talked about a
2 lot this morning, doesn't use recovery in agar. It
3 does for a direct transfer use recovery in liquid.
4 You directly inoculate your sample into a liquid
5 and ask does the liquid turn turbid after 14 days.
6 Cells in liquid grow very, very
7 differently than cells on agar. Membrane
8 filtration is yet a third way, and this is the
9 other main way that the sterility test is used.
10 These three main types all have different concerns
11 that need to be addressed.
12 The final issue in this validation is the
13 recovery of injured organisms, which Dr. Korczynski
14 talked about earlier.
16 The other question on plate counts is that
17 you have a very narrow range. If you have much
18 more than 300 colonies, these are very small
19 colonies on a plate, you start seeing crowding
20 effects, you start seeing competition for
21 resources, you start seeing a depression in the
22 number of cells that you should see.
23 So you really can't count more than 300
24 colonies of very small, well-defined colonies on a
25 plate, and you can't really count much fewer than
1 30 because you start getting errors on the other
2 side, so you have to do dilutions.
4 In summary, technologies for these
5 alternative methods are not new. Everything we
6 have talked about this morning, esterase activity,
7 bioluminescence, these have all been in the
8 research labs and in academia for decades. This is
9 not new stuff. This is stuff that we are trying to
10 get into the pharmaceutical industry.
11 Guidance documents exist or are under
12 development to help us do that. We need some help
13 in developing these, and we need some guidance.
14 Hopefully, this Advisory Panel will help us out
15 with this.
16 Finally, microbiology validation studies
17 are very different than chemistry validation
18 studies, and I would have to echo Ms. Moldenhauer's
19 concern that what would be really bad at this point
20 -- I would have to phrase it that way -- would be
21 to have yet another chemistry assay that is forced
22 to apply into a microbiology laboratory, because
23 they just don't fit, they are different beasts.
24 Thank you very much.
25 DR. LEE: Thank you. Any questions?
1 DR. HUSSAIN: Just one sort of observation
2 for the committee. I think that the proposal that
3 we presented to you was to address the general
4 issues, not the technical issues, so I think the
5 concerns expressed here are not really the issue
6 from my perspective, because the regulatory process
7 and the Safe Harbor concept, and so forth, I think
8 are the general philosophy that the guidance would
9 go, and I think will be followed by technical
11 I just wanted to clarify that for the
13 DR. LEE: Thank you.
15 DR. SHARGEL: Nothing to say.
16 DR. LEE: John?
17 DR. DOULL: I do have one comment. I
18 appreciate what you are saying about chemical and
19 microbiological. You ask three questions - is it
20 there, how many, what is it. I would add a fourth
21 question, will it hurt me, and I would like you to
22 answer that question with science, and not with
24 In order to answer that question with
25 science, we have got to explore somewhat how we are
1 going to answer that question with science. All I
2 am saying is we are grateful because on detection,
3 we don't have much focus on prediction. Somehow we
4 need to get that in there, at least that concept.
5 DR. LEE: Okay. We have a volunteer.
6 DR. HUSSAIN: I think that is an excellent
7 suggestion and I think in the framework of risk
8 management and how we link quality issues to
9 safety, efficacy, and risk, I think we probably
10 should consider bringing that as a topic for
11 discussion later on.
12 I don't have an idea exactly how we will
13 do that, but I think it's an excellent suggestion.
14 DR. LEE: There are several observations
15 that I made along those lines. Number one is that
16 science moving forward, are the tests moving along
17 with it. We have an opportunity of expanding to
18 implement the database informatics. Are we in a
19 better position to assess risk?
20 Obviously, there are technical issues,
21 there are philosophical issues, and I think what
22 this subcommittee is going to be asked to do is to
23 think about the philosophical issues, and if the
24 philosophical issue is given the green light, then,
25 the technical issues will be addressed in due
1 course, I would hope.
2 Tom, you are chair of the PAT
3 Subcommittee. Do you want to say anything?
4 DR. LAYLOFF: I was just going to comment
5 on John's comment or Ajaz. The question is how
6 many organisms, which ones, who is exposed, and
8 DR. LEE: On that note, I am going to
9 conclude this morning's session. We are doing very
10 well on time. Lunch is here. We will continue at
11 12:30. Thank you.
12 [Whereupon, at 11:30 a.m., the proceedings
13 were recessed, to be resumed at 12:30 p.m.]
1 AFTERNOON PROCEEDINGS
2 [12:30 p.m.]
3 DR. LEE: The afternoon is going to be on
4 two issues - blend uniformity, this is an issue
5 that was discussed last time, and with an update.
6 Ajaz, would you like to introduce the
8 Blend Uniformity
9 Introduction and Overview
10 DR. HUSSAIN: In some ways, we probably
11 will look back at this meeting as sort of a
12 historic meeting, and this is the first
13 recommendation of PQRI, and I really thank Tom,
14 Toby, Sid, and others of PQRI, who have really
15 worked hard over the last two years to build
16 consensus in this proposal.
17 As Helen mentioned in her opening remarks,
18 we have already started the process of withdrawing
19 the drug guidance in anticipation of incorporating
20 the recommendations of this PQRI recommendations
21 into our next draft guidance that will be issued
22 again as draft for public comment.
23 Today is the opportunity to sort of have a
24 public discussion on the recommendations itself.
25 Within the agency, we have formed a separate group
1 to look at this and adopt this as it goes along.
2 This group is different from the group which worked
3 on the blend uniformity proposal that is coming
4 from PQRI. So this is sort of a separation as a
5 peer review process.
6 My own role sort of changed when PQRI was
7 started. I served as the technical director, and I
8 think Tom's working group was essentially getting
9 started, make sure true scientific dialog starts
10 between FDA folks on the committee, as well as the
11 industry members.
12 From that point, I sort of moved away from
13 PQRI process in terms of creating a distance for a
14 rational evaluation process.
16 Let me give you a background information
17 on blend uniformity. Many of the slides you have
18 already seen in the previous meeting, but I think
19 it helps to bring that into focus. The slides you
20 see, again, you have seen before.
21 Blend uniformity analysis is an in-process
22 test we do today. It has been the subject of
23 intense debate for about 10 years, and I have sort
24 of criticized the whole processing that we have
25 talked about, but haven't found a solution.
1 I think we have a solution at hand now to
2 deal with it. The controversies and the debate
3 have focused on sample size, sampling errors,
4 segregation following blending operations, lack of
5 correlation with content uniformity, and so forth.
6 Also, I think the issue has been whether
7 it is a cGMP issue or a review issue. Clearly, we
8 had at the Blend Uniformity Workshop, complaints,
9 and so forth, that there has been inconsistent
10 enforcement, some do, some don't, and so forth.
11 The draft ANDA guidance was issued in
12 1999. I will share with you the motivation behind
13 that, and then the PQRI came about to solve some of
14 these issues.
16 If I look at the draft Blend Uniformity
17 Guidance, the motivations for these were to sort of
18 improve the consistency in the review process
19 itself. Clearly, when we issue a guidance, we
20 highlight some concerns reviewers have, and the
21 reviewers, from my way of looking at that guidance,
22 raised the issue of some concern that the content
23 uniformity needs to be emphasized.
24 Why would that be, I think in the generic
25 applications one could look at and say there is
1 insufficient information to assure the quality was
2 by design, but that is not a generic issue. I
3 think that issue is a general issue for new drugs,
4 as well as ANDAs from my perspective.
5 Why would one say that? If you look at
6 the submissions, how do we define blending, define
7 the blender type, capacity, operating speed, and so
8 forth. Again, a lot of these issues I think are
9 issues of disconnect between how we operate between
10 the field and review. I think a lot of this
11 information that is already generated are with
12 companies, so in many ways, some of these issues
13 are communication issues rather than science issues
14 per se.
15 The draft guidance recommended for which
16 products blend uniformity testing is needed and
17 how, to some degree, you have to do this, some
18 indication of sampling size and criteria was
19 incorporated into this draft guidance.
21 From a science perspective, I think these
22 are sort of my thoughts, which again I have shared
23 with you before, is from a pharmaceutical science
24 perspective, what is the science issue. I think
25 blending is a process which is quite complex when
1 it comes to physical process itself, and
2 performance of a physical unit, performance of a
3 unit operation depends on material characteristics,
4 particle attributes, equipment design, operating
6 I think we address all of these through
7 our validation in different ways, but I think we
8 lack clear way of making a case that this was by
10 This is how an engineer might look at that
11 to optimize the performance of a blender or any
12 other physical unit operation. That is from AICHE
13 Journal in 2001.
15 If you continue to argue that today, trial
16 and error is the norm, and have done that on many
17 occasions, the question from a reviewer perspective
18 is do SOPs reflect established heuristics at least.
19 Here are some of the heuristics that we have
20 learned over the years. Again, this is from the
21 same article that the previous slide was from.
22 Here, you look at attributes of material
23 that result in segregation problem either during
24 blending, after blending, and so forth, and many of
25 these are at least not apparent in the SOPs that
1 are practiced today, and the general assumption is
2 the validation process would have addressed this.
4 Limitations of current approach, I think
5 unit operations are intended to produce in-process
6 materials that possess optimal attributes for
7 subsequent manufacturing steps.
8 In general, I think the testing mentality
9 instead of control mentality, I would say that the
10 current controls always ensure consistent quality
11 of in-process material. I think one way we do that
12 is to reject through testing.
13 But I think the point again, I keep
14 harping on this, but it's an important point, the
15 physical attributes of pharmaceutical raw materials
16 can be highly variable, and that is one
17 contributing factor to the concern that we tend to
18 express with some of our guidances.
20 Again, from a review perspective,
21 limitations of process validation leads to such
22 concerns. Again, a quote from a published paper,
23 "In the spirit of cGMP and how we practice, there
24 may be a disconnect." In some cases, I think,
25 again, this is not a general observation, but
1 illustrates what can happen when quality was not
2 built in.
3 So validation in many ways, some people at
4 least would view that has become a well-rehearsed
5 demonstration that manufacturing formula can work
6 three successive times.
7 That is not the true intent. A lot of the
8 development efforts go towards the whole validation
9 process, but again, it is a perception leading to a
11 In their experience, Harwood and Molnar,
12 "validation exercise precedes a trouble-free time
13 period in the manufacturing area only to be
14 followed by many hours, possibly days or weeks, of
15 troubleshooting and experimental work after a batch
16 or two of product fails to meet specification.
17 This becomes a never-ending task."
18 There is, if you recall, data, that G.K.
19 Raj presented points to some of that thought
22 With respect to blend uniformity, reliance
23 on end product testing, I think the whole issue
24 here is a question of representative sample. Here
25 is an example where I think the stratified sampling
1 will really help.
2 This is a case study that was sent to me
3 and Helen by a company, an individual in a company
4 who had done this work for PQRI, but I looked
5 through the database, I couldn't find this in the
6 database example, so this probably never got
8 Here is an example of a validated product
9 which has been on the market, blend sample
10 analysis, I think wonderful results, percent RSD of
11 less than 1, it passed. USP content uniformity
12 Stage I passes. But when you do stratified
13 sampling, you see a trend, in this case, towards
14 the end of the production run, where you have a
16 So the stratified sampling in this case
17 picks it up, whereas, the blend sample, how the USP
18 sample did not.
20 So the draft BUA Guidance that we have,
21 and I think this is what Tom pointed out, changing
22 the focus a bit right now, I think the questions
23 that we asked in the draft guidance and our
24 regulations, and what we have practiced for years
25 and years and years have been focused on drug
1 substance alone, and we assume that demonstration
2 of adequacy of mix with respect to drug alone is
4 Is this generally a reasonable assumption
5 with a few exceptions, I think that question comes
6 up, but I think it is, because the manufacturing
7 history, the recall, and so forth, the small
8 numbers would bear that. In a sense, I think it's
9 a reasonable assumption.
11 But with respect to PAT, we can ask that
12 question and actually build quality in upfront, and
13 here is an example from Steve Hammond at Pfizer,
14 how he can even look at magnesium stearate in his
15 distribution whether it's homogeneous or not.
16 Currently, we don't. Currently, we look at
17 dissolution as a surrogate for some of these
20 But I just want to sort of put this on the
21 radar screen, is homogeneity with respect to drug
22 substance alone sufficient? In some cases, if the
23 development efforts are not there, it may not be
24 the case.
25 Here is an example of a drug product which
1 does not need blend uniformity testing, does not
2 need content uniformity testing because the drug is
3 95 percent of the product, but homogeneity of
4 magnesium stearate became an issue, and you can see
5 stratified sampling in this case picks up even
6 dissolution failures at the beginning and the end
7 of the run.
8 So the point I am making is I think the
9 stratified sampling brings more rationality to the
10 issue of representative sample and can help improve
11 the whole process of quality assessment, and so
14 So, in summary, the PQRI recommendations
15 on blend uniformity analysis, I think analysis of
16 in-process dosage units , collected using the
17 proposed stratified sampling plan, may be used as
18 an alternate to routine blend sample analysis to
19 satisfy the requirements of 21 CFR 211.110(a)(3).
20 That is essentially the letter Toby Massa
21 sent to Janet Woodcock. That is essentially the
22 summary of the recommendation.
24 In your handout, I will not read through
25 all of this here for 211.110, but I just provided
1 you the entire section for which this guidance
2 applies. Instead of reading it, I am just going to
3 skip and, for the sake of time, have Tom and others
4 to come and speak to the proposal itself.
6 The other issue simply here is it goes to
7 (3), adequacy of mixing to assure uniformity and
8 homogeneity, but the whole section applies to
9 dissolution, disintegration, weight variation, and
10 so forth, also.
12 I am going to skip that. This was just
13 for you to have it available to the discussion. I
14 hope you can read it. I think the copies were made
15 on a smaller print.
17 The questions that we pose to you, and I
18 hoping that as Toby Massa and Tom Garcia walk
19 through that, they will address that and the
20 committee could discuss and give their
21 recommendations on this.
22 The same questions that we posed before, I
23 am just refining, adding a few clarification points
25 PQRI proposes that blend uniformity
1 analysis may not be necessary following development
2 and validation studies. During routine production,
3 dosage unit testing, going back to 10 and 20, are
4 sufficient to document "adequacy of mix," based on
5 a study about sampling plan now.
6 The proposal utilizes a criteria or a
7 classification system which says some products
8 readily comply when the RSD is less than or equal
9 to 4 percent. Some "marginally comply" when the
10 RSD is still less than 6, but greater than 4, but
11 for those, you do additional five consecutive lots
12 before you can sunset the blend uniformity testing.
13 For "readily comply," you sunset routine blend
14 uniformity testing almost immediately.
16 So the questions to you are: Do you
17 consider the PQRI proposal appropriate for
18 inclusion in a planned revised FDA guidance? You
19 may consider the following point.
20 Supporting simulation studies assume a
21 normal distribution, is this a reasonable
23 Was the retrospective data mining
24 sufficient to conclude that "blend uniformity
25 testing in routine in routine manufacture is not
1 predictive of the uniformity of dosage units"?
2 Is this conclusion a necessary condition
3 for regulatory application of the PQRI proposal?
5 If the proposed stratified sampling and
6 analysis plan is limited only to bioequivalence and
7 validation batches, how should adequacy of mix be
8 ensured for routine production batches?
9 In a sense, this question goes to the
10 point is the classification, that is,
11 "readily"/"marginally" comply, and proposed
12 additional assessment to justify deleting routine
13 blend uniformity analysis justified?
14 In the absence of blend uniformity
15 analysis, is stratified sampling plus limited, that
16 is, going back to 10 or 20 depending on how many
17 products you test, product testing sufficient to
18 assure content uniformity of the entire batch?
20 In some ways, I think the letter Dr. Massa
21 wrote, and I think the recommendation applying to
22 CFR 211, probably has already addressed this, but I
23 just want to be clear that our thinking here is:
24 Should the planned revised FDA guidance only focus
25 on generic drugs or should it be a general
1 guidance, that is, for both new and generic drugs?
2 Our thinking is it is a science issue, and
3 it is not an ANDA versus new drug issue, and it
4 should apply equally on both sides. When we do
5 that, I think we will have to rethink, since the
6 recommendation is only focused on ANDA
7 bioequivalence and validation batches, we will have
8 to go back and see what would be an appropriate
9 counterpart of that in the drug development.
10 With that, I will stop and invite Toby to
11 give the opening remarks followed by Tom Garcia.
12 Tobias Massa, Ph.D.
13 DR. MASSA: Thanks, Ajaz. It is a
14 pleasure to be here today. As Ajaz said, this is a
15 special day for us because this is the first of
16 what we hope will be many recommendations from PQRI
17 for the agency to consider.
18 Although I work at Eli Lilly, I am here
19 today really as the chair of the PQRI Scientific
20 Steering Committee, and as a member of the board.
22 If you are not familiar with PQRI, we were
23 formed three years ago, and our charter is to serve
24 as a neutral forum for academia, industry, and the
25 agency to conduct pharmaceutical product quality
1 research and to develop recommendations that lead
2 to public standards.
4 I think that the real benefit that PQRI
5 brings is that we are fostering good science to
6 good regulation. I think we have heard variations
7 on that theme this morning, and certainly we have
8 heard people like Jane Haney, the former
9 Commissioner, as well as Janet Woodcock, the
10 current Center Director, talk about the need to
11 emphasize that regulation has to come from good
13 We hope that our research will serve as
14 the basis for reducing burden, not only for the
15 industry, but also for the agency, so that our
16 resources can be used more efficiently and used in
17 places where they really do need to be used, and at
18 the same time, we want to either maintain or
19 increase product quality. Reduction in burden
20 doesn't mean reduction in product quality.
22 The advantage we have is that we have
23 industry, FDA, and academia cooperating on
24 identifying what the specific product quality issue
25 is, helping design a protocol that addresses that
1 problem, analyzing the data, writing the
2 recommendation, all together and all agreeing that
3 yes, this is indeed the way we need to be going.
4 Additionally, although we don't write the
5 final guidance, guidance is openly discussed in the
6 PQRI forum, and unlike many other instances where
7 there is FDA-industry cooperation, this is one of
8 the few, if not the only, place where guidance will
9 be discussed, and that was by design.
10 I think you have heard earlier, in some of
11 our discussions this morning, that when we are
12 talking about PAT, that the subcommittee is not
13 going to be the place where guidance gets written.
14 It is going to be written within FDA without the
15 industry present.
16 This is a case where we are openly
17 cooperating on guidance. Ultimately, the agency
18 independently has to assess that recommendation.
19 We don't obviously write the final guidance. We
20 might like to write the final guidance, but it
21 doesn't work that way.
23 I put this chart of the organization up,
24 not to discuss the organization, but to demonstrate
25 for you the rigor of the PQRI process. If you look
1 at the part here, the working groups, that is where
2 all of the hard work occurs, and all of the PQRI
3 organizations, as well as academics who are
4 appointed from AAPS, work to develop the issue,
5 develop the protocols, review data, and actually
6 write the recommendation.
7 Those recommendations are then reviewed by
8 the Technical Committees. There are three
9 Technical Committees within PQRI, and Blend
10 Uniformity was part of the Drug Product Technical
13 Each of the member organizations has a
14 representative on this Technical Committee. They
15 review the recommendation, as well as disseminate
16 that document within their own member organization,
17 so all the member companies at PhRMA, for example,
18 were asked to comment on this.
19 Any comments that came back that warranted
20 being addressed had to be addressed by that working
21 group, so it is a pretty rigorous process.
22 Ultimately, the recommendation will go to the
23 Steering Committee, and the Steering Committee role
24 is really to manage the research portfolio and deal
25 with the policy issues of the institute, not really
1 the scientific aspects of it, but we ultimately
2 will send the recommendation to FDA for their
5 These are the members of the group and you
6 can see that it reflects the diversity of PQRI.
7 There are generic company members on there,
8 innovators, as well as a number of people from FDA
9 representing new drugs, generics, as well as
12 Now, the charter, as Ajaz has mentioned,
13 of the Blend Uniformity Group was to address the
14 specific part of the guidance that said blend
15 sampling is required to demonstrate adequacy of
16 mixing, and they specifically referenced Part 211.
17 They undertook a rather long process, and
18 this was our first project within PQRI. We learned
19 a lot about how to do things and quite a few things
20 about how not to do things, as Tom can attest, in
21 the PQRI process, but they basically looked at the
22 gaps between where the regulation was and where we
23 thought current science was, and to come up with
24 alternative approaches.
1 Tom will go into the nitty-gritty of the
2 recommendation, but basically, we came away saying
3 that blend uniformity is not always predictive of
4 mixing and that stratified sampling and testing of
5 in-process dosage units is a viable alternative to
6 the use of blend uniformity analysis.
8 Now, these study results, as I had
9 indicated before, go through a review process
10 within the institute, and ultimately get submitted
11 to FDA. As per the bylaws of PQRI, there are two
12 options that the agency has. They can either
13 accept our recommendation and change the guidance
14 or regulation as appropriate, or they will reject
15 our conclusion, and if they do, they will respond
16 to us in writing indicating where the faults were
17 in the data and the recommendation that we made, so
18 that we can address this and hopefully come back
19 with a recommendation that is acceptable.
20 Again, that is one of the beauties of
21 PQRI, because that doesn't happen anywhere else.
23 Now for us, obviously, success is that the
24 agency will accept the recommendation. We think
25 that we are well on the way for that to happen. To
1 address one of Ajaz's questions, although this
2 guidance was specifically dealing with ANDAs or
3 generic products, we feel that this applies to new
4 drug chemistry situations, as well as the Office of
5 Generic Drugs, as well as the GMP part that would
6 be dealt with, with the Office of Compliance.
7 We think this recommendation ought to be
8 applied wherever blend uniformity is an issue.
9 With that, I will turn it over to Tom
10 Garcia from Pfizer, who chaired the Blend
11 Uniformity Group, and he is the guy who will answer
12 all your questions about the science stuff.
13 DR. HUSSAIN: Vince, may I make a comment?
14 Something Toby said, I just want to make sure I
15 clarify that for the record.
16 Good guidance practices would not allow us
17 to even share a draft guidance that we are working
18 with PQRI, so that doesn't apply. I think we
19 discussed a published draft guidance, so that was a
20 different scenario. We have to follow the good
21 guidance practices, and that would also apply.
22 DR. LEE: Thank you.
23 Thomas P. Garcia, Ph.D.
24 DR. GARCIA: Today, I want to address two
25 things, just to briefly go over the recommendation
1 that PQRI came up with. It is very similar to what
2 I presented back in November of last year, so my
3 apologies for those that are going to hear it
4 again, but for those of you that weren't here in
5 November, you get a shot to see it.
6 The second thing will be the results of
7 the data mining effort that PQRI conducted to
8 support the recommendation.
10 The recommendation that we are proposing
11 does a number of means. First of all, it
12 collectively considers the uniformity of the powder
13 blends and the dosage units that are manufactured
14 from them.
15 We really believe that you couldn't look
16 at the two kinds of uniformities in a silo, they
17 are interrelated.
18 The second thing, it acknowledges the best
19 way to assess blend uniformity may be indirectly
20 through analysis of the subsequent dosage units
21 coming out of that batch. Mainly what we are
22 talking about here is a sample bias issues that
23 arise when we try to take blend samples.
24 The test is very simple to use. It
25 maximizes use of all the data and acceptance
1 criteria that we are presenting are very easy to
2 interpret. They don't involve detailed statistical
3 analysis or anything like that, very basic
5 Finally, this recommendation is very, very
6 discriminating when you have a poor quality batch.
7 If you have some segregation that occurs during the
8 dosage unit manufacture, it will pick it up, and
9 there is a good chance that you will end up
10 rejecting that batch.
12 The first part of the recommendation
13 starts out with process validation for the blend.
14 Basically, what you do is you have to take at least
15 10 locations out of the blender, take triplicate
16 samples from each of those locations. You test one
17 sample from each location. Your acceptance
18 criteria is the RSD is less than or equal to 5
19 percent, and all individuals are within plus or
20 minus 10 percent of the mean absolute.
21 This is different than 90 to 110 percent
22 because there were a lot of instances that the
23 working group members cited where you would have a
24 very consistent bias in the sampling technique
25 where you either preferentially sampled the drug or
1 the excipients. In other words, you may have a
2 mean of 110 percent, but an RSD of 2 percent. That
3 is all due to sampling bias albeit it in a very
4 consistent manner.
5 So, hence, we incorporated it's all based
6 on the mean.
7 If you pass, congratulations, the blend is
8 done. If the 10 samples initially tested fail, you
9 assay the second and the third day sample from each
10 one of those locations. Basically, what we are
11 doing now is perform some sort of investigation
12 into the cause of the failure of the first 10
14 If that cause is related to mixing, then,
15 you failed that validation batch. You have got a
16 problem, you need to go back to development and
17 figure out how to address that.
18 If the problem is determined to be
19 something attributed to non-mixing, a problem, for
20 example, may be an analytical error or sampling
21 bias, then, you proceed to Stage 2 testing of the
22 dosage units.
24 This is the second half of the validation
25 approach, and this is addressing the dosage units.
1 What you do is during your compression or your
2 filling operation, you take at least 7 dosage units
3 from at least 20 locations during the filling or
4 compression operation.
5 Stage 1 testing is examining at least 3 of
6 those dosage units. Your acceptance criteria are
7 the RSD of all the individual tablets or capsules,
8 whatever, is less than 6 percent. Here is the
9 critical one. Each location mean of these 20
10 locations up here, the mean has to be between 90
11 and 110 percent of label claim. That is the most
12 discriminating part of this approach.
13 Finally, all individuals have to be within
14 75 to 125, and what we are looking for in this last
15 point is just if by some remote chance, happen to
16 get a tablet at 126 or 130 percent, but passed
17 everything else, that batch should be rejected. We
18 are looking for superpotent or subpotent tablets.
19 If you find those, you should stop.
20 If you pass this, the process is
21 validated. If you fail, you progress to Stage 2
22 testing where you analyze at least four more
23 tablets or capsules, so a total of 7 dosage units
24 are now tested in combination with Stage 1 and
25 Stage 2.
1 The acceptance criteria are the same.
2 Obviously, if you pass, you are done; if not, the
3 batch fails. Really, Stage 2, all it does is it
4 gives you a second chance, if you have got a mean
5 value of, say, at 89 1/2, to bump that up. It gives
6 you one more chance to pass it.
8 Now, for routine manufacture, once again
9 we are advocating the use of stratified sampling.
10 The first question you have to ask -- and Ajaz
11 alluded to this in his presentation -- is do you
12 readily comply or does your product not readily
14 "Readily comply" is described in the box
15 up on the top. During your exhibit or validation
16 batches, all of the dosage unit RSDs were less than
17 or equal to 4 percent, all your means results were
18 within 90 to 110, and the 75 to 125 percent for
19 individual dosage units that applies.
20 If you meet this criteria, then, you
21 readily comply. What you do is you go during your
22 filling operations or compression operation, you
23 take at least 3 tables or capsules, dosage units
24 from at least 10 locations. What we are doing here
25 is we are trying to get 30 dosage unit per USP
1 testing, so 10 locations, 3 dosage units.
2 The acceptance criteria here is the mean
3 is between 90 to 110 percent, and that is weight
4 corrected, and the RSD is less than or equal to 5
6 If you meet that criteria for the first of
7 the dosage units from each of the locations, then,
8 you have passed, you have demonstrated adequacy of
10 If you don't, progress to Stage 2 and test
11 the remaining 2 dosage units from each of the
12 sample locations, and in this particular instance,
13 once again you rate and corrected all your results,
14 mean between 90 and 110 for all 30 now, and your
15 RSD less than 6 percent, so you get another 1
16 percent for that.
17 If you do not readily comply, you are
18 going to come right down into Stage 2, so you have
19 got to test 30 dosage units rather than being given
20 the opportunity to go to 10 plus 20.
21 If you come down this path, you don't
22 readily comply, and you meet the acceptance
23 criteria, up here, 5 batches in a row, then, in the
24 future, you can come down this level, the go to
25 Stage 1 test. So, just because you don't readily
1 comply at the first few batches after validation
2 doesn't mean you are locked in there forever. You
3 do have to prove, though, that you have made some
4 changes to your process and it's under control.
6 That is a very brief tour of the
7 recommendation. By the way, the recommendation and
8 the datamining report are located on the PQRI web
9 site, PQRI.org, going to Blend Uniformity Working
10 Group, I think, or something like that, and there
11 is a nice icon. You can click on it, and you can
12 get both of these documents there.
13 So the second part I want to talk about is
14 the results of our datamining effort.
16 These tables on the slide summarize the
17 data that was submitted. We got 149 batches
18 submitted from 8 companies, and the distribution of
19 how many batches each company submitted is on the
20 bottom plot here.
21 Of the batches, about half or over half of
22 them were less than 5 percent active ingredient,
23 which is what we wanted, because typically, your
24 more dilute blends are going to give you more
25 problems than when you have higher concentrations
1 of active, so that was good.
2 We did get a nice distribution between 5
3 and 15, 15 to 25, and greater than 25 for the
4 remainder of the batches, but really here is where
5 we were interested in, but we also wanted to make
6 sure that it served the purpose up there.
7 We had 12 direct compression products or
8 batches, 67 wet granulation, and 70 dry
9 granulation, so we had all three of those
10 manufacturing processes covered. We only had
11 tablet data submitted. We didn't get any capsules,
12 sachet powder packets, and I will address that in
13 the next slide.
14 Our batch sizes had quite a range. I
15 believe the less than 100 kilos, the smallest batch
16 was something like 25 or 30 kilos, I can't remember
17 exactly, but it was in that range. Then, the
18 greater than 400, I think this was up around 1,200,
19 1,300 kilos, so we had a very wide range when it
20 came to batch sizes.
22 Now, the big question there we wrestled
23 with -- is capsule data essential to apply this
25 There was a lot of discussion with the
1 working group about this, and what we decided, you
2 know, the scientific explanation we came up with is
3 general processes that you use to produce a blend,
4 whether it be for tableting or encapsulation or
5 powder filling, is the same.
6 The processes to make that blend do not
7 differ significantly. Thief sampling error is just
8 as likely if you have a capsule or a tablet blend,
9 and that is another thing we were addressing with
10 this recommendation.
11 The key thing is the capsule weights,
12 although they may be skewed, all the data that we
13 analyze in our recommendation is weight corrected,
14 so that takes care of that problem.
15 So our conclusion was, yeah, we would have
16 loved to have had some capsule data to test it, but
17 we don't feel that is necessary just because the
18 processes up to encapsulation or compression are
19 basically the same.
21 The acceptance criteria that I presented
22 in the previous slides were all generated using
23 computer simulation, Monte Carlo simulations. The
24 way we did this is we had a number of operation
25 characteristic curves that we generated, and each
1 one of those curves had a number of points on it,
2 probably about 25 or 30 points. Each point had
3 5,000 simulations, so we used extensive use of
4 Monte Carlo simulation to come up with these
6 The one thing about the computer
7 simulation is it assumes that the data was normally
8 distributed, so one of the things we wanted to look
9 at is all the data we had submitted, how was that
11 Eighty-five and 89 percent of the batches
12 were normally distributed, and what these two
13 numbers refer to is within a location and between
14 locations, we look at the distributions of both of
15 those. So you are looking at micromixing and
17 So, for the most part, there was normally
18 distributed. The instances where it wasn't
19 normally distributed was due to outliers.
20 Remember, we asked industry to submit us data to
21 challenge our proposal.
22 They send us some good data, but as
23 expected, they sent us some data they had problems
24 with, and that was exactly what we wanted to do,
25 how would this proposal perform.
1 If you sent us your best data, well, then,
2 anything will pass the good criteria, so we wanted
3 a challenge, and that is probably the cause of
4 seeing up to 15 percent non-normality, those
5 particular batches.
6 The other thing is even if you are in a
7 non-normal situation, the acceptance criteria in
8 our recommendation becomes much more discriminating
9 and restricted. You are going to fail more
10 batches, batches are not going to slide through.
11 So if it is not normal, it is harder to pass.
12 So the conclusion that we came up with,
13 our assumption is justified.
15 The second part of the datamining effort
16 was to test the hypothesis that blend uniformity
17 testing during routine manufacture is not always
18 predictive of the uniformity of dosage units.
20 This slide right here I put up back in
21 November, and it pretty much sums it up. What it
22 is, is the dosage unit uniformity is a function of
23 the blend RSD. If you had a 1 to 1 correlation,
24 the blend and the dosage unit RSDs will perfectly
25 correlate. You have this 45-degree line going up
1 here sort of in red.
2 From the points of the data, you can see
3 that correlation is lost. What we did is we
4 divided it up into three sections. That particular
5 part, RSD of the blend is between zero and 3
6 percent. We then looked at between 3 and 5
7 percent, and then greater than 5 percent.
9 What we found, and you actually cheat
10 ahead here and go to the next conclusion slide, if
11 the blend RSD is less than 3 percent, and we had
12 pretty good correlation between blend and dosage
13 unit uniformity, and, in fact, in some instance,
14 you could see that the dosage unit uniformity is
15 higher than the blends.
16 Potential causes of this, it could be
17 weight variability, the dosage unit, another
18 component are there. Also, what is just as likely
19 is you may have a uniform blend or a blend in the
20 mixer, as soon as you start transferring it to the
21 tablet press or capsule-filling machine, you are
22 getting segregation. As a result, your RSD goes
24 So, in this region, it is of use. As you
25 start going up to the 3 to 5 percent range, though,
1 you start losing that correlation, you see a couple
2 points on the line, but down here, you are seeing
3 higher blend RSDs and low dosage unit RSDs. So
4 here is where you are losing your correlation.
5 By the time you get to the situation where
6 your blend RSD is greater than 5, there is no
7 correlation between blend and dosage unit
9 So that is the first conclusion that we
10 came out with, you know, whether or not the
11 hypothesis held.
13 We do believe, though, that there are many
14 instances where blend uniformity is value added.
15 For example, during process development, one of the
16 things we wanted to stress is our recommendation is
17 not a substitute to go out and do poor process
18 development and blend mixing development. You
19 still have to do that, and as you saw, the number
20 of tablets that you have to test in Stage 1 and
21 Stage 2 testing is significantly different, so it
22 is in your best interests to make sure you get a
23 uniform blend and one that you can sample.
24 Other instances where it is warranted is
25 in validation. The one exception that we
1 highlighted is if you have toxic products where you
2 have contained processes, it may not be in your
3 operator's or safety's best interests to break
4 those containers. We feel that stratified sampling
5 approach is still very discriminating to indirectly
6 measure the uniformity of the mix.
7 Finally, during investigations, blend
8 uniformity data is always valuable information to
10 We also came to the conclusion that blend
11 uniformity testing is not necessarily the best
12 choice during routine manufacturing to demonstrate
13 adequacy in mix. The stratified sampling approach
14 is superior, we feel, to it for a number of
15 reasons. You eliminate all the sampling bias that
16 you potentially have.
17 The other thing is it picks up if you have
18 that segregation between the blending operation and
19 filling operation, it will detect that. The blend
20 can be perfect in the mixer, but what happens to it
21 when you transfer it to the press or the
22 capsule-filling machine. If you get segregation,
23 it's all for naught.
24 Another thing is regardless of how the
25 blend data looks, you are always going to go and
1 test the dosage units. If the blend data is good,
2 you are still going to have to test the dosage
3 units because you have got to make sure you don't
4 have segregation during transfer. If the blend
5 data is bad, you are going to test the dosage units
6 to see whether or not it is sampling error, so it
7 all comes down to the dosage units.
9 The final conclusions that we have or one
10 thing we want to emphasize is this approach is only
11 one of many ways that you could assess blend and
12 dosage unit uniformity. There is other ones out
14 GMP should be flexible and allow a number
15 of different techniques to be used. For example,
16 if you want to go with some sort of process
17 analytical technology, such as NIR, that is
18 perfectly acceptable, as well. If you want go
19 continue going with traditional blend sampling and
20 dosage unit testing, that is fine, as well.
21 This is one way, but one technique that we
22 feel is very, very discriminating.
23 That concludes my presentation.
24 DR. LEE: Thank you very much.
25 Committee Discussion
1 DR. HUSSAIN: Just to sort of summarize
2 the process that we plan to use, as I said, we have
3 a separate group which is going through these
4 recommendations carefully and get back to PQRI if
5 we have any disagreements, and so forth.
6 We have also requested a statistical
7 consult on the statistical analysis. The
8 preliminary findings I think from the statisticians
9 have been that I think in terms of the
10 retrospective data analysis really can't conclude
11 the hypothesis holds. I think that is the initial
12 part that has come back to us from the statistical
13 group, so that is one of the issues, the questions
14 I pose to you.
15 In addition, so what we would like to do
16 is have you discuss the issues, and we will take
17 back this discussion and recommendations, and
18 re-discuss that and get back to PQRI and provide a
19 process for revising the draft guidance.
20 DR. LEE: Art.
21 DR. KIBBE: First, I would like to say
22 that I strongly support eliminating of a test which
23 not only doesn't predict, but might mislead.
24 I have some questions about some of the
25 recommendations and a couple of other little
1 things, so, first, when you decided on the number
2 of tablets to take at each stage during your
3 testing, did you take into account the batch size
4 when you decided that you were going to use those
6 DR. GARCIA: No. We debated this issue.
7 We had Jerry Planchard, who was on the committee,
8 who is PhRMA statistician, and we said, you know,
9 we are saying you take 20 locations, 140 tablet, 7
10 per location, whether it's a 20-kilo batch or a
11 2,000-kilo batch, and do we want to look at that.
12 We decided not to because the number of
13 locations and the number of replicates in the
14 locations were all determined through Monte Carlo
15 simulations, and the statistical power behind those
16 numbers was established and one that the group felt
17 comfortable with.
18 DR. KIBBE: I understand you gave the
19 value of the batch based on the weight, but for me,
20 I sit here thinking is this a 2 million tablet
21 batch or is it a 25 million tablet batch, and now I
22 am thinking of are we taking 20 times 3, 60 tablets
23 to characterize a 2 million tablet batch and to
24 characterize a 25 million tablet batch, and that is
25 where I am coming from.
1 I mean I am sure your statistician is
2 doing something, but if you make 150-mg tablets,
3 and you make a 4-kilo batch, and you make 500-mg
4 tablets and you make a 4-kilo batch, you have got
5 completely things.
6 I just wonder if it's worth looking at it
7 in terms of number of tablets in the process. I
8 don't have any real basis for arguing four more,
9 but I wonder if it's overkill on a small batch and
10 underkill on the big batch.
11 DR. GARCIA: Right now we are looking at
12 30 per USP. So we are way beyond that. This is a
13 question, though, that we could get back and get a
14 formal response.
15 DR. KIBBE: When you didn't have any
16 capsules at all, and you said, well, okay, we
17 blend, but I don't know how many capsules you used,
18 what granulation before you blend, and what
19 granulation changes the ability of actives to
20 stratify the changes the way those blends are
21 re-mixed when you actually go to tablet. It
22 changes segregation patterns. Even dry granulation
23 can't, because when you start to bind up the active
24 with some of the inactives, then, they move in the
25 blender differently. You don't do that with
2 I am not as comfortable as you seem to be
3 that only tablet data lets you make the connection
4 to capsule data. I don't know whether anybody else
5 feels that way.
6 DR. LEE: Art, are you proposing that this
7 proposal is not complete?
8 DR. KIBBE: I am asking questions. I hope
9 somebody has better answers than I have.
10 DR. GARCIA: Back to your previous
11 question, direct compression is covered in the
12 tablets, though, the data that we had. So direct
13 compression is probably your more common capsule
14 doing mix and process.
15 DR. KIBBE: Well, yes and no. I wouldn't
16 use freeze-dried lactose in a capsule necessarily,
17 and that has different stratification
18 characteristics, and also some of your directly
19 compressible excipients have an ability to absorb
20 active ingredient. I am not saying you are wrong,
21 but I am not yet convinced that using only tablets
22 is a guaranteed extrapolation to capsules.
23 I think those are the two things that I
24 was most interested in. I have got a couple other
25 little notes, but I can come back to it.
1 DR. LEE: Let's hold it for now. Let me
2 read the two questions.
3 DR. DeLUCA: Can I comment on what you
4 just said?
5 DR. LEE: I would like to read the
6 questions first.
7 The committee is asked to address two
9 1. Do you consider this proposal
10 appropriate for inclusion in a planned revised FDA
11 guidance? If no, there are a couple of things that
12 we need to consider. That is Question No. 1.
13 2. Should this planned revised FDA
14 guidance only focus on generic drugs or should it
15 be a general guidance?
16 Those are the two questions.
17 DR. HUSSAIN: The questions I posed, if I
18 could put them back on.
19 DR. LEE: Am I reading the wrong one?
20 DR. HUSSAIN: If you look at my
21 presentation, there are three set of slides for the
22 questions, the last three. They are essentially
23 the same, I have sort of refined that a bit more.
24 DR. LEE: Would you please read it.
25 DR. HUSSAIN: Question 1. Do you consider
1 the PQRI proposal appropriate for inclusion in a
2 planned revised FDA guidance?
3 Within that, sort of a question I am
4 asking: Supporting simulation studies assume a
5 normal distribution, is this a reasonable
7 Was the retrospective data mining
8 sufficient to conclude that blend uniformity
9 testing in routine manufacture is not predictive of
10 the uniformity of dosage units?
11 Related to that, is the above conclusion a
12 necessary condition for the regulatory application
13 of the PQRI proposal?
14 Question 2. If the proposed stratified
15 sampling and analysis plan is limited only to
16 bioequivalence and validation batches, how should
17 adequacy of mix be ensured for routine production
19 In relation to that question is: Is the
20 classification "Readily" and "Marginally" comply
21 and proposed additional assessment to justify
22 deleting routine BUA justified?
23 In absence of BUA, is stratified sampling
24 plus going back to the 10/20 limited product
25 testing sufficient to assure content uniformity of
1 the entire batch?
2 Those are the two questions related to
4 The third question was generic ANDA for
5 all. That has already been addressed, so we don't
6 have to go to the third question.
7 DR. LEE: Let's focus on the first two
8 questions. I have asked Pat to give lots of
9 thought to those questions and apparently he is
10 ready to address those questions.
11 DR. DeLUCA: I just want to compliment the
12 committee. It certainly was a thorough study
13 albeit just focused on tablets.
14 I guess in answer to Art's question with
15 regards to capsules, I think if the recommendation,
16 in my mind, if the recommendation was that blend
17 uniformity was predictive, and based on just the
18 tablets, I agree with you, I would say that I think
19 that you needed to include capsules in here also to
20 make that recommendation.
21 I think because the recommendation is that
22 it is focusing in on stratified sampling analysis,
23 and of the dosage units, then, I think that
24 precludes that possibility, that there is a
25 problem, and capsules need to be included in here.
1 I guess in going directly, and we haven't
2 had really a chance to I think dialogue with the
3 committee members, I just very briefly talked with
4 them, I guess to answer the questions that are
5 here, do you consider the proposal appropriate for
6 inclusion in a planned revised FDA guidance, I
7 would have to say yes, and I think Ajaz has
8 indicated that that is something you are going to
9 be dealing with.
10 So it looks like that question there is
11 answered. I had a couple of questions with regards
12 to the -- when you say, in the dosage units,
13 locations, what do you mean by a location? I
14 understand it from taking a blend sample with the
15 thief, where the location is in the blender, but
16 when you are on a compression, when you are
17 compressing, what do you mean by a location?
18 DR. GARCIA: It's a sampling time during
19 that run, anywhere from T equals zero, start out at
20 the end.
21 DR. DeLUCA: I thought it was that, but it
22 wasn't clear and I wanted to make sure that you
23 weren't taking some blend locations and then
24 compressing those separately.
25 DR. GARCIA: It's a function of the
1 percentage of the batch that a dosage unit is made.
2 DR. DeLUCA: Would that answer Art's
3 question with regards to size of the batch, the
5 DR. GARCIA: No, he is questioning the
6 number of locations.
7 DR. KIBBE: No, I am questioning as far as
8 number of dosage units.
9 If you have a 25 million batch, and you
10 take it during 20 times, then, you are taking 10
11 or 7 tablets out of a million.
12 DR. GARCIA: No. Oh, wait, a 25 million
13 batch, okay.
14 DR. KIBBE: Right? If you have got a 2
15 million batch, you are taking 7 sample out of
16 100,000, and the question is, in my mind,
17 especially after this morning's microbiology thing
18 about how well we can predict anything from that,
19 you know, 10 out of 100,000 is a much bigger
20 percent sample out of the population than 10 out of
21 a million, and why don't we adjust for that.
22 I am not a statistician, so I don't know
23 how much power we are gaining or losing in the
24 process. That was my question.
25 DR. GARCIA: I am going to defer that
1 question. We will give you answer from the PhRMA
2 statistician on the group, but my guess, and this
3 is just an opinion, is when you get to a certain
4 point, your statistical power, the gains you
5 achieve after you get to a certain level diminish,
6 and I believe that is where he was coming from on
7 this. But let's let the statistician answer that.
8 I am confident that they will be able to provide
9 you a suitable answer.
10 DR. LEE: I wish that our statistician was
11 here, but he is in Houston today.
12 Let me also at this time introduce two
13 guests, Ken Morris from Purdue and Gary Hollenbeck
14 from Maryland. Please feel free to contribute your
16 DR. HOLLENBECK: Would now be a good time?
17 DR. LEE: Please.
18 DR. HOLLENBECK: I would just like to ask
19 a question. Is there any reason why you could
20 speculate there were no capsules submitted as part
21 of the dataset?
22 DR. GARCIA: I don't have any idea.
23 DR. MASSA: Even with the data we had, we
24 had to work very hard to get data from our industry
25 colleagues. This is not an easy process at all.
1 DR. HOLLENBECK: No, and you should be
2 commended for that. For those of us who were
3 around when PQRI started, this is a special moment
4 I think when we look at what you have accomplished.
5 Tom, in your slide on routine manufacture,
6 I am not sure I understood what happens after five
7 consecutive batches have been successful. What
8 happens at that point?
9 DR. GARCIA: This is for those products
10 that did not readily comply. You have to go down
11 to testing 30 dosage units immediately, right off.
12 If after five consecutive batches you meet the
13 "readily comply" criteria, then, for the sixth
14 batch, you do down testing 10 plus 20.
15 DR. MORRIS: Tom, I had one question, and
16 we sort of touched on this at the meeting, whenever
17 it was, a year ago, but I agree that the normal
18 distribution is probably not a valid assumption,
19 it's very often, but as you say, it is the most
20 conservative stance, how concerned is the committee
21 based on the data you have seen that it is going to
22 be too harsh, that is, that you are going to be
23 failing things more often than you expect based on
24 its not being normal?
25 DR. GARCIA: Part of the datamining report
1 that is available on the PQRI web site shows the
2 percentages of batches that passed various
3 criteria, USP, PQRI, PDA criteria. There was, for
4 this subset of data, the PQRI was a little bit more
5 selective than the USP test.
6 The one that was really rejecting the
7 batches was the PDA approach. For the details of
8 that, to answer your question, I refer you to that
9 report on the web site.
10 DR. HUSSAIN: The question, I think Gary
11 raised that in terms of the five. Again, in my way
12 of thinking, in a sense, what is different with the
13 five consecutive batches, and so forth, what
14 happens from a mechanistic perspective, because I
15 think somehow the thought process, the numbers are
16 there, but how do we justify those numbers? I
17 think some discussion on that would be helpful.
18 DR. GARCIA: Ajaz, if I could address
19 where the 4 percent came from, on the operation
20 characteristics curves, for those of you that have
21 the document, I think it is Attachment 2 or 3, if
22 you look at when the dosage unit RSD approaches
23 about 3.8 percent, somewheres in there, you start
24 sliding down, and the number of batches that passed
25 the criteria significantly decreases. This is
1 where you are getting on the steep part of the
2 curve. That is where the 4 percent came from.
3 The five consecutive batches gives the
4 formulators of the process scientists a chance to
5 go and improve the process. We felt if you are
6 passing with an RSD of 5 or 6 percent routinely for
7 dosage units, your product really ought to be
9 So we said if you have made some process
10 improvements post-approval, and you demonstrate
11 that you get that RSD below 4 percent consistently,
12 then, you shouldn't be punished beyond that side of
13 the ladder, and that is where that came from.
14 DR. LEE: Pat has a recommendation for
15 this committee and I am not sure whether the
16 committee feels the same way.
17 DR. RODRIGUEZ-HORNEDO: I just have a
18 comment and a question regarding the first
19 question, and this is to Tom.
20 Regarding the datamining, I find it
21 interesting, and I was present at your seminar here
22 in November where you presented these, probably
23 with more time to present, is there any correlation
24 between the method of whether it's granulation or
25 dry granulation or direct compression, or anything
1 that correlates with a high RSD for the blend?
2 I am certain you thought about that, so
3 that it doesn't correlate with the dose RSD, was
4 there anything?
5 DR. GARCIA: We didn't break it down to
6 that degree. A lot of that would probably be in
7 your formulation and process development.
8 Different companies are going to do different
9 degrees of the science that goes into that.
10 If you do a lousy job of selecting your
11 formulation excipients, particle sizes, grades,
12 things like that, and don't control your drug
13 substance, you are going to have some problems with
14 RSD, but we did not break that out, take the
15 analysis to that degree.
16 DR. LEE: Ken?
17 DR. MORRIS: Just following up on that
18 point actually, in the dataset you have, where you
19 have already analyzed the data in terms of
20 reconciling the unit dose versus the blend
21 uniformity, do you know, can you break those data
22 out by DC versus wet granulation?
23 DR. GARCIA: Not now. I believe it's in
24 an Excel table, if you wanted to go back and look
25 at it.
1 DR. MORRIS: I think that would really be
2 worthwhile doing, I think.
3 DR. LEE: It seems to me, just posing, I
4 am stir the pot or something, it seems to me that
5 maybe this should be put to peer review like
6 journal, conflict of interest.
7 DR. DeLUCA: Let me comment on that now
8 that you have brought that up. That is in the
9 plan. These have been put in the form of
10 publications, both studies, and the recommendation
11 and the datamining.
12 We are going to put it out with a review
13 on this, and I am not finalized on this. I will
14 after hearing some dialogue, I did talk with Tom
15 and with Ajaz on how to proceed with this, but the
16 thought was that we put it out into the journal,
17 and invite comments from the readers on this, that
18 could be fed back to the committee and FDA.
19 DR. HUSSAIN: The thought process, I
20 discussed this, I think it would be a good idea,
21 but I think the timing probably won't work for this
22 case. I think the peer review in a sense would
23 need to occur within the FDA and with this case
24 from that perspective to maintain the timeline that
25 we have.
1 I think for the future projects, I think
2 we could time it in such a way that both could
3 occur. So I had some concern with the timing of
4 that process and how does that link to FDA process.
5 In my mind, I think the FDA process would
6 sort of move on with an internal review,
7 statistical evaluation, and so forth.
8 DR. LEE: I can turn it around in two
10 Yes, Art.
11 DR. KIBBE: Just a couple of more things.
12 First, this report is basically an indictment --
13 that is a bad word -- of the traditional blend
14 uniformity methodologies, so that your conclusions
15 that blend uniformity should be waived in place of
16 stratified sampling might not necessarily be true
17 if we were using an in-process uniformity system
18 that could do a good job of making sure the blends
19 stay uniform, and if that process then was
20 reapplied to, or the same sensing system was
21 applied to the fill line, so that we knew that the
22 fill process was going in, and that I think is the
23 direction that PAT would like to see go.
24 Blend uniformity, the way it is being done
25 is what is not predictive, not necessarily that we
1 couldn't come up with a new methodology that would
2 be predictive.
3 DR. GARCIA: Go back to the last slide I
4 had. We said this is just one of many ways to do
5 it. GMP should be flexible.
6 DR. KIBBE: And I agree with that.
7 DR. GARCIA: We had to come up with a
8 recommendation that could be applied across
9 industry. A lot of companies probably don't have
10 that technology in-house, but, yes, I agree with
11 you, that PAT is a separate issue that could be
12 used in lieu of this approach, which could be used
13 in lieu of current approaches.
14 DR. MASSA: There is one other thing to
15 add, is that even if you had an in-process
16 analytical method that would measure the blend,
17 that wouldn't account for post-blend segregation at
18 the time of compression.
19 DR. KIBBE: No, but you can imagine the
20 same sensing system on a fill line to monitor
21 post-blend segregation as the tablets were being
22 filled and how close to the final compression would
23 you have to be.
24 I mean I can imagine the system doing away
25 with a whole bunch of unit dose assays, but a
1 second small thing is because of the way you
2 sample in your stratified sampling system, it is
3 possible to determine that in a given batch with a
4 given product, that 80 or 90 percent of the
5 products that is manufactured are within compliance
6 because they are right up there, and the last 10
7 percent of the batch falls out, and would that be
8 grounds for a company just separating as the
9 material came off, and sub-lotting, and then
10 getting rid of the last?
11 DR. MASSA: Unfortunately, that is not
12 consistent with cGMPs. It might be if we got to
13 PAT later on and had a way to do that, but right
14 now you can't do that.
15 DR. GARCIA: If that's the case, I think
16 you need to take a look at that formulation and
18 MR. BUHAY: But if there is data which
19 supports that approach, that shows the processes so
20 consistent, and that variation begins at a
21 measurable point, it is consistent with GMP.
22 DR. HUSSAIN: One point I wanted to make
23 for the record in the sense I think the survey that
24 was done by PQRI, and the discussion at the
25 workshop, and even the data, blend sampling is in
1 thieves, I think can pose a problem, does pose a
2 problem in about 10 percent of the cases. In a
3 large percent of the cases, it works very well. I
4 just wanted to make that perspective is also.
5 DR. MORRIS: Can I just add to that in a
6 sense, and somebody had said it earlier, and I
7 apologize for not remembering who, but the idea
8 that you use, whether it is PAT, but particularly
9 for PAT-type approaches, during development is when
10 hopefully you find the sort of systems that you are
11 talking about with PAT, so that when you get it to
12 the floor, you are in the situation where it is not
13 one of the 10 percent. Otherwise, you just are
14 tracking, so you say, yeah, here is where it goes
15 back, but if you can do that every time, it may be
16 accurate, but it doesn't -- what is that?
17 DR. KIBBE: If you can do that every time,
18 you ought to fix it.
19 DR. MORRIS: Exactly, exactly.
20 DR. KIBBE: That's true. I just was being
21 a troublemaker.
22 DR. LEE: So the answer to the first
23 question is okay, looks okay, and the agency is
24 going to do these statistical validation scrutiny,
1 DR. HUSSAIN: The question is I think the
2 preliminary discussion we have had with the
3 Statistical Group essentially, I think I have to go
4 back and carefully read some of this again, but the
5 concern that was raised was the hypothesis at
6 least, the claim of the hypothesis testing that
7 blend uniformity is not a value-added test or
8 predictive, I don't think the initial analysis that
9 this approach can prove or disprove that
11 So that is not the question, and that is
12 reason I raised the question, does that really have
13 to be part of the recommendation at all, because is
14 that necessary for moving forward. That was not
15 the purpose of the recommendation.
16 The point I am making here is essentially
17 in the sense, when you go stratified sampling, you
18 are focusing more on the end product which is given
19 to the patients although I don't like end product
20 testing for the sake of testing, and that goes
21 totally opposite to the PAT, but again we have two
22 systems to consider.
23 So regardless of the old system, testing
24 to document quality, let's keep that system, is
25 when you do blend uniformity, clearly, you have
1 other processes that occur post-blending -
2 discharge, flow, and so forth, that can induce
4 From that perspective, focusing on
5 uniformity does provide relevance from a clinical
6 perspective. It is more relevant from that
8 DR. LEE: Let's move on to the second
10 DR. DeLUCA: This was should the proposed
11 stratified sampling analysis be applicable only for
12 the bioequivalence batch and validation batches, is
13 that right?
14 DR. LEE: Yes.
15 DR. DeLUCA: Okay, because there were a
16 couple of versions here of questions.
17 The recommendation, as I saw it, is that
18 certainly blend uniformity testing is very valuable
19 during the development stage during validation,
20 troubleshooting, and certainly should be continued
21 in those, and the ANDA exhibit batches, but it
22 should be applicable then to not just generic
23 batches, as well. It should be across the board, I
24 think, for ANDA products or not. Wasn't that the
25 intent of the recommendation?
1 DR. MASSA: I think you are addressing the
2 last question, and clearly we said that it ought to
3 apply across the board, it shouldn't just be
4 related to ANDA products.
5 I think what Question 2 is trying to
6 assess is where specifically are we using this
7 stratified randomization. I think what we are
8 trying to say is that it is used in concert with
9 blend uniformity as you are doing development and
10 validation, but once you have established that you
11 are validated, that you do away with blend
12 uniformity, and are only using the stratified
13 sampling on your routine batch release.
14 DR. HOLLENBECK: Can we just clarify that
15 for sure, that you are proposing that you will use
16 the stratified testing on a regular basis for
17 routine release of product?
18 DR. MASSA: Yes. What we are saying is
19 the stratified sampling is to be used for routine
20 release and that the only time you would use blend
21 uniformity analysis is during development and
22 validation, and for troubleshooting should you run
23 into an issue later on.
24 DR. HOLLENBECK: Well, then, to me, that
25 answers your question, Ajaz. That is how adequacy
1 of mix will be ensured doing routine production.
2 DR. VENITZ: It answers the subquestion to
3 your previous one in terms of that the dosage form
4 is more important than the blend uniformity
5 regardless of the datamining.
6 MR. BUHAY: I would just like to comment
7 that I would not want to over-endorse that concept,
8 that if you go to that concept, in-process testing
9 becomes everything, and there is no role at all for
10 in-process testing.
11 DR. MORRIS: I think it makes Art's
12 argument a lot stronger in terms of validating or
13 verifying that the Monte Carlo simulations are good
14 at all scales. If you are really going to do that,
15 I don't even know the algorithms that we use, but
16 it just puts a lot more pressure on that being
18 DR. KIBBE: I am comfortable with the
19 two-step process that I think I hear happening,
20 which is once we have got a process that we have
21 run a few times and we know that we have got
22 consistency, and we have a known problem with the
23 way we sample blend now in some cases, but if they
24 have got a product that has been run a few times,
25 and they have done blend analysis, and they have
1 done tablet analysis, and they seem to be
2 consistent, and the process is holding, producing
3 good batches on a regular basis, then, why do a
4 test that is, at best, redundant?
5 It is a diagnostic test if there is a
6 problem with a tablet, because the tablet is what
7 you have to give to the patient. Now, if the test
8 is truly predictive in that you would do the test
9 and then kill the process completely because that
10 is where your problem is, then, you have to keep it
11 in there. In my estimation, you have got a bad
12 manufacturing process then.
13 DR. HUSSAIN: Art, I think related to your
14 comment right now, I think the question then
15 becomes using stratified sampling, doing the USP 10
16 tablets --
17 DR. KIBBE: That's my real problem.
18 DR. HUSSAIN: That's the question.
19 DR. MORRIS: But there is another exposure
20 issue in the sense that if you have to find an
21 assignable cause, if you have a failure and you are
22 only testing tablets, I mean that is a risk that
23 the companies have to accept then because you are
24 not going to be able track back and find an
25 assignable cause if it happened in the blender, for
1 example. That is a justifiable risk.
2 DR. HUSSAIN: One of the reasons for
3 raising the subquestion, the issue of "readily" and
4 "marginally" comply, the reason I raised that
5 question is I think when we had some internal
6 discussion, two issues had come up. I just want to
7 point out those issues to you.
8 One is many of these decisions are being
9 made on a sample RSD or standard deviation, and its
10 ability to reflect with confidence the population
11 RSD depends on the sample size, and so forth. So,
12 there is that uncertainty. So the population,
13 standard deviation could be smaller or larger, so
14 there is uncertainty there. So that was sort of
15 one concern that was raised internally.
16 The second question was I think in terms
17 of you are classifying "readily" and "marginally"
18 on the basis of those numbers with certain
19 uncertainty, and when you get into routine
20 production, the materials that you have, you have
21 different lots of excipients, and so forth, and
22 there is no sort of linkage between that
23 variability to what the future variability might
25 So those are the sort of underlying
1 concerns that we had discussed internally.
2 DR. DeLUCA: I would like to also share
3 what Ajaz was saying about the way the
4 recommendation was worded. Certainly, I don't feel
5 that the blend uniformity is not a good predictor,
6 I mean it certainly is not a good predictor of the
7 end product, the quality, as doing the dosage
9 But it seems in the validation procedure,
10 you are going to be correlating the blend
11 uniformity with the end product, the dosage units,
12 so as long as that is done and followed, it seems
13 then one could rely then on the dosage units as the
14 end test rather than doing blend uniformity.
15 It seems to me that, one, we shouldn't
16 overlook the importance of putting the blend
17 uniformity testing into the PAT, but that would not
18 be a sampling of the blend, but it would be an
19 in-process type of test with some sensor.
20 I think the problem with the blend
21 uniformity is the sampling itself and any
22 segregation that occurs after the sample is taken
23 and analyzed that's the problem here.
24 DR. LEE: Thank you.
1 DR. BOEHLERT: The thought just occurs to
2 me in looking at this RSD of 4 percent, to what
3 extent did you consider the precision of the
4 analytical method when you are looking at an RSD of
5 4 percent? Some analytical methods are better than
6 others. That might not give you much room for
7 error in your product if the method is variable.
8 DR. GARCIA: In one of the OC curves in
9 the recommendation, I believe we included a 1.5
10 percent analytical error, so we did play around
11 with that a little bit, but that is something else
12 that the company has to address. Your analytical
13 method has a wide variability, that's the price you
15 DR. BOEHLERT: And that might be an area
16 where the FDA will get comments when this gets into
17 revised guidance when people begin to take a look
18 at this and say, well, wait a minute, my precision
19 is 2 percent or 2.5 or 3, and what does that mean
20 therefore, you know, I am never going to pass that.
21 DR. LEE: Other members of the committee
22 wish to express an opinion?
23 DR. HUSSAIN: Everything has been said,
24 Gloria said.
25 DR. LEE: Okay. Pat, will you please for
1 the record the answer to the three questions?
2 DR. DeLUCA: Well, do you consider the
3 PQRI proposal appropriate for inclusion in a
4 planned revised FDA guidance? Yes.
5 If yes, should the proposed stratified
6 sampling analysis be applicable only for
7 bioequivalence and validation, the answer is no on
9 What else do we have? Then, should it be
10 applied to -- I think there was a third question
11 with regards to go beyond the generic products, and
12 the answer to that was yes.
13 DR. LEE: Okay.
14 DR. HUSSAIN: Just to clarify, the answer
15 to the second question you said was no. In
16 essence, the proposal is that for a low variable
17 product, which readily complies, we will sunset
18 that, and for one which has a bit higher
19 variability, you do additional testing for at least
20 five, and then based on that, decide. So, could he
21 just clarify that?
22 DR. DeLUCA: I guess maybe this is worded
23 in a way that -- I think what we are saying here
24 that we are going to use the blend uniformity
25 testing for validation ANDA exhibit batches to
1 bioequivalence batches and troubleshooting. I
2 guess that is what we talked about here, that blend
3 uniformity testing would apply to that.
4 DR. HUSSAIN: In essence, the committee
5 feels that the PQRI recommendation to sunset for
6 routine production, blend sample collection and
7 analysis, and rely on stratified sampling is
9 DR. LEE: John?
10 DR. DOULL: Sounds good to me.
11 DR. LEE: Let me say that as a scientist,
12 I would like to see this work be put through peer
13 review, and I think this is a very feasibility
14 study. I don't think that we tried to address all
15 these situations that might encounter, but I think
16 we have a good starting point and let's see how
17 things evolve.
18 DR. HUSSAIN: To sort of summarize the
19 next steps from FDA perspective, I think we will
20 take your discussion and recommendations, and as I
21 said, we have a separate group, we will work on
22 that, and I think, in my mind, I think we have to
23 have peer review, and peer review that will occur
24 through the internal process and the statistical
1 Then, I think as we go through that
2 process, we will provide information to the PQRI
3 with respect to all concerns if there are, and then
4 we will start working on the draft guidance, so
5 that is essentially the steps we will have.
6 DR. LEE: For the record, we do have an
7 expert in statistics on the committee, but he
8 happened not to be able to be here, so there is no
9 redundancy in this committee.
10 DR. KIBBE: We are going to get some
11 statistical understanding of whether we need to
12 have a different number of tablets for different
13 batch sizes, right?
14 DR. HUSSAIN: We will have our
15 statisticians, we will work with our statistician
16 to focus on that question as we go through our
18 Also, as I had mentioned this morning, I
19 think the draft guidance that will come out, we
20 probably will include a section on on-line
21 planning. Again, those are two different issues,
22 the current system and the future systems, because
23 I did not overlap the PAT with this discussion.
24 Those are two separate issues.
25 So we will go back and proceed in that
2 DR. LEE: Okay. Leon.
3 DR. SHARGEL: I just wanted to comment on
4 the last question. Just as a general concept, my
5 own feeling is that for the NDA and the ANDA-CMC
6 Section, they both should have the same quality
7 standards, so as we move forward on this issue, as
8 well as other areas, I was quite concerned when the
9 guidance came out and said blend uniformity for
11 I think in general terms, we should look
12 at quality standards for both general, for both
13 ANDAs and NDA.
14 DR. LEE: We are kind of on schedule, so
15 let's take a 10-minute break.
17 DR. LEE: First of all, I have to watch my
18 time, as well, because I was told that my cab would
19 be here at 4:15. I thought I had about 5:15 to
20 enjoy the facilities. Therefore, I am going to use
21 my electronic gavel for the first time.
22 The last session is on polymorphism/
23 We have Dr. Chiu to introduce the topic,
24 and we have two presentations. This is an
25 awareness session.
1 Regulatory Issues Related to Crystal Habits -
3 Introduction and Overview
4 Yuan-yuan Chiu, Ph.D.
5 DR. CHIU: Good afternoon. We are going
6 to introduce a new topic - polymorphism to the
7 committee. Today, we would like the committee to
8 make a general discussion. We are not going to
9 have, you know, issues on specific products. We
10 are not having any questions for the committee to
11 address. However, I would want to bring this topic
12 to the committee in preparation of future
14 We do plan to come back to the committee
15 on this topic with specific questions after the
16 agency does a little more work, because we are in
17 the process to draft a guidance document to address
18 a lot of challenges, regulatory and also legal
19 challenges for generic drugs.
21 As you can see, polymorphism has a
22 scientific definition. The scientific definition
23 is the ability of a substance to exist in two or
24 more crystalline forms that differ in the
25 arrangement of the molecules and/or confirmation of
1 the molecules.
2 So this is what we are talking about is
3 the crystallines as habits or crystalline lattice
4 of a substance. However, there is a broad
5 definition under ICH Q6A, which is the certain
6 specification for chemical substances.
7 This definition then actually encompass
8 solid state forms in addition to crystalline forms.
9 So it is stated the occurrence of different
10 crystalline forms of the same drug substance, and
11 this may include solvation or hydration products,
12 also known as pseudopolymorphs, and amorphous
13 forms, because amorphous forms are not really
14 crystalline lattice.
16 The polymorphism is very important to
17 final product quality. I am going to give you a
18 few examples to illustrate the different physical
19 properties exhibited by different polymorphs.
20 The packaging properties of the substance
21 can be different, which includes molecular volume,
22 density, refractive index, hygroscopicity, and the
24 The thermodynamic properties can also be
25 different. They can include melting point,
1 solubility, heat capacity, potential energy.
2 The third one would be the kinetic
3 properties of the crystalline forms. Different
4 crystalline form may have different dissolution
5 rate, and the rates are solid-state reactions, as
6 well as the stability.
8 In addition, the surface properties of
9 polymorphs can be different, the shape of the
10 crystals, and the surface free energy, and
11 interfacial tensions.
12 The last, and not the least, is the
13 mechanical properties, which includes hardness,
14 tensile strength, compactibility, which is the
15 tableting property, as well as handling of the
16 substance including flow and blending.
18 Because of the differences of those
19 properties will affect the product qualities,
20 therefore, for the patients we usually, you know,
21 have information on the polymorphism of the
23 So today we are going to have Steve Miller
24 to present to you how we handle the information for
25 new drugs. Then, Richard Adams will talk about the
1 regulatory and legal challenges of generic drugs.
2 Originally, we planned to invite Dr.
3 Brittain to present experts' views, but he could
4 not attend, so therefore, we will have two talks.
5 Without further ado, I ask Steve to come
6 to give his presentation.
7 ONDC Issues
8 Steve Miller, Ph.D.
9 DR. MILLER: Thank you. Good afternoon.
11 I am the team leader in the Antiviral Drug
12 Division of CDER. I will be presenting an overview
13 of polymorphism, the regulatory aspects of
14 polymorphism from the perspective of the new drugs.
15 Most of what I talk about today will be an
16 overview of a workshop that was organized by the
17 American Association of Pharmaceutical Sciences two
18 months ago. I will talk about that workshop a
19 little specifically in a moment.
21 When the 1987 Drug Substance Guideline was
22 written, it was recognized that for some drug
23 substances and for some drugs, the solid-state form
24 of the drug substance or active ingredient can have
25 an important effect on drug release and on
2 As a consequence, during the development
3 of most solid oral dosage forms, suspensions, many
4 other drugs, there will be a dialogue during the
5 IND phase between the review chemist and the
6 pharmaceutical sponsor to discuss what is known
7 about the solid-state form of this particular drug
8 and what impact it may have on dosage form
11 A second guidance that deals with
12 solid-state form is the BACPAC I Guidance, which
13 was issued more recently. This is the Bulk Actives
14 Postapproval Changes Guidance, which is used when a
15 change is made to an approved product in the
16 manufacturing steps of a synthetic compound, a
17 synthetic drug substance.
18 Essentially, the BACPAC I Guidance is a
19 change control protocol that outlines for many
20 different changes, for example, change to a new
21 solvent in some portion of the synthesis, or change
22 in the synthesis itself with new intermediates, for
23 those changes, what data would be expected to
24 demonstrate equivalence post-change to pre-change.
25 It is recognized that when it is the drug
1 substance that is being measured to look at
2 equivalence, the two important solid-state
3 parameters are polymorphism in its broadest sense
4 and particle size.
5 Here, you will note in this guidance the
6 definition of morphic form is the broad definition
7 that Yuan-yuan mentioned, which is also in Q6A. It
8 encompasses hydrates, solvates, and well as
9 non-crystalline amorphous forms.
11 Now, the guidance that covers polymorphism
12 in greatest detail is the ICH Q6A Guidance
13 developed under the International Conference of
14 Harmonization, and it provides guidance to U.S.,
15 European, and Japanese regulators and
16 pharmaceutical sponsors regarding setting
17 specifications for the active ingredients and for
18 the dosage forms.
19 By setting specifications, we are
20 referring to the tests that will be performed on
21 each batch. For example, a drug substance, each
22 batch before the drug substance is used to make
23 drug product, must be tested according to the
24 specification, and the Q6A guidance outlines how we
25 will go through and determine which tests are
1 appropriate, and when a test is determined to be
2 appropriate for the specification, what the
3 acceptance criteria should be, acceptance criteria
4 formerly widely called the limits, the numerical
5 limits, frequently numerical.
6 The same set of questions occur for the
7 dosage form, for the drug product, and Q6A
8 encompasses both forms.
10 I wanted to show some typical
11 specifications or some of the attributes that might
12 be part of typical specifications. You will see
13 that in some cases, there are what are essentially
14 universal tests that would be present in all cases,
15 identity and assay would be typical.
16 Then, there are other tests that may be
17 appropriate for a particular drug. Morphic form
18 tested in the drug substance, and more rarely in
19 the drug product, is one of the optional attributes
20 that could be appropriate for some drugs, may not
21 be necessary for other drugs.
22 The Q6A guidance goes into quite a bit of
23 detail about morphic form and polymorphism in the
24 form of some decision trees.
1 The decision trees themselves are broken
2 up into three parts for polymorphism. The first
3 part deals with whether multiple polymorphic forms
4 exist. The second part deals with whether a
5 regulatory specification in the drug substance is
6 appropriate. The third part of this decision tree
7 relates to whether a regulatory specification in
8 the drug product is appropriate.
9 Now, even with this amount of detail,
10 there is still quite a bit of gray areas, and the
11 recent AAPS Workshop was an attempt to formulate
12 unified understandings of the Q6A document as a
14 I was one of the four breakout moderators
15 for a session that dealt with solid-state forms.
17 I will now go into the three decision
18 trees that are part of Q6A. I will try to focus on
19 the questions that we brought forward at the AAPS
20 Workshop and the conclusions that came back from
21 the discussion groups that formed to discuss these
23 The first part of the decision tree
24 relates to whether there are multiple polymorphic
25 forms possible. Essentially, it instructs that
1 screening should be done in all cases to look for
2 the possibility of multiple polymorphic forms.
3 If there is an absence of any evidence of
4 multiple solid-state forms, then, essentially, you
5 move to the first NO, and that's the end of the
7 In many cases, there will be several
8 morphic forms available, and in that case, the
9 latter part of this flow chart shows that those
10 forms should be characterized. It outlines some
11 representative tests that could be performed, some
12 X-ray techniques very commonly applied.
13 The second set relates to melting point or
14 DSC, differential scanning calorimetry, some
15 thermal methods that can be used. There are also
16 spectral methods that frequently can assess whether
17 a particular morphic form is present or measure its
18 levels in many cases.
19 Infrared spectroscopy in many cases may be
20 appropriate to differentiate between known
21 polymorphs, solid-state and MARS, another emerging
23 When we brought this forward to the AAPS
24 Workshop, one main question was what is a
25 reasonable polymorph screen for different
1 situations, different drug substances, different
2 dosage forms.
3 On the next slide, I will show some of the
4 results that came out of our discussions.
6 I would have to say that there was a
7 diversity of opinion among the participants. Some
8 people felt that really the screen should be
9 limited, should focus on the solvents that are used
10 in the drug substance manufacturing process.
11 Other participants felt that there was
12 value to be gained in exploring more broadly many
13 different solvents of different polarities,
14 hydrogen bonding propensities.
15 I would say there was quite a universal
16 agreement that when a particular condition could be
17 relevant to the drug product manufacturing
18 situation, for example, if the drug product is
19 formulated through a wet granulation process, then
20 aqueous solvents should be explored in the
21 screening for polymorphic forms because clearly,
22 formation of a hydrate would be something that
23 could occur during the drug product formulation.
24 One general concept was that reviewers at
25 FDA generally want to see some evidence of what was
1 carried out during the polymorphic screen in the
3 After the second bullet, you will note
4 that there is a note GRP document. I have tried to
5 mark up on a number of these slides where we, in
6 CDER, hope to record some of these recommendations
7 and hopefully, some future recommendations, as
8 well, about polymorphism.
9 We are in the process of formulating a
10 good review practices document for the chemistry
11 manufacturing and controls aspect of a drug
12 application. We feel that some of this could be
13 incorporated into that document.
14 The third bullet relates to a separate
15 topic, which deals with solution drug products,
16 where in many situations, there is going to be very
17 few issues about polymorphism related to a true
18 solution, however, it is noted that some
19 information about the concentration of the drug in
20 the drug product solution relative to the limiting
21 solubility, the solubility of the least soluble
23 That can be very valuable. It would
24 essentially tell you what the likelihood that the
25 drug substance could crystallize out of the dosage
1 form. If the drug load is very low relative to
2 saturation, there is essentially no concern there.
3 If it is very close to saturation, there could be a
5 A subpoint under that was the idea that in
6 the situation where you are very close to
7 saturation, it may be relevant to include the
8 dosage form vehicle in the screen for polymorphs to
9 ensure that the form that would crystallize out of
10 the dosage form is a form you have already
11 discovered through other processes, and is not a
12 new form. That is a point that we will try to
13 incorporate into the next drug product guidance,
14 which is currently in internal draft stage.
16 Now, I am going to go on to the second
17 part of the Q6A decision tree, which dealt with
18 whether an acceptance criteria is appropriate in
19 the drug substance.
20 The first decision diamond relates to
21 whether there are different properties of the
22 polymorphs that are known. The second diamonds
23 says if there are different properties, are those
24 properties likely to affect performance of the drug
1 If the answer to either of those is no,
2 the properties are not different, it is unlikely to
3 affect the dosage form, then, essentially, it is
4 the end of story, and the Q6A recommends that no
5 acceptance criteria would be established in the
6 drug substance.
7 If however, yes is the answer to both of
8 those, an acceptance criteria is thought to be
9 appropriate for the drug substance.
10 Now, in terms of the discussion at the
11 AAPS Workshop, there were several points -- I hope
12 this will show up on the slide -- in the first
13 decision tree it says, "Are there different
14 properties," and a main question was, "What is
15 meant there, how different is different?"
16 It was felt that some case studies could
17 be very valuable to try to say how is this being
18 interpreted both in the industrial side and in the
19 review side.
21 A second question related to the second
22 decision point, and it related to the question of
23 when would you make the determination that even
24 though there are different properties, the dosage
25 form performance would not be affected.
1 It was thought that in many cases,
2 solution drug products would fall into this
3 category, but there was some discussion as to
4 whether there would be other categories, as well,
5 and I think that is another area where clearly,
6 some additional discussion could be very useful.
8 Finally, a third question regarding this
9 particular part related to the final diamond. When
10 you have decided that an acceptance criteria is
11 appropriate for measuring polymorphic form in the
12 drug substance, are you thinking in terms of
13 quantitative control, quantitating the amount of
14 the two polymorphic forms, or would there be cases
15 where a qualitative control, verification of
16 identity would be what was needed.
18 With regard to that point, we have some
19 clear decisions brought back from the workshop, a
20 qualitative test was thought to be appropriate when
21 the drug substance manufacturing process controls
22 which polymorphic form is produced, and you have
23 demonstration that morphic form is controlled
24 adequately by the drug substance process.
25 In that case, a qualitative, for example,
1 an identity test, which could be a melting point or
2 an IR test if those have been validated to be able
3 to show the morphic form could be all that is
4 needed in the drug substance specification.
5 There was also discussion about sunsetting
6 these tests when enough manufacturing experience
7 was gained through a certain number of batches or a
8 certain number of years, eliminating this
9 qualitative control.
10 There was also discussion of whether skip
11 testing, testing only one in a certain number of
12 drug substance batches would be appropriate.
13 It was also widely recognized that there
14 are many, much more complicated situations that
15 would need much more control and usually much more
16 information to tell you what type of control is
17 necessary. In many cases, you may need to know how
18 the dosage form will perform using different
19 morphic forms. That is elaborated a little further
20 on the next slide.
22 These complicated situations could involve
23 situations where the drug substance polymorph is
24 changed during the manufacturing process or on
25 stability, where the drug product contains multiple
1 polymorphs and it is known that they do affect
2 bioavailability, or where there is a significant
3 amount of amorphous drug substance intentionally
4 introduced in the drug substance.
5 It was widely recognized that it is
6 important to discuss these issues at the end of
7 Phase II meeting for new drugs, which would
8 typically occur a year or more before the NDA is
9 filed in order to have time to plan what studies
10 are needed, what type of documentation will be
11 available to make these decisions at the time of
12 the review.
14 I am now going to go on to the last part
15 of the flow chart, which unfortunately is the least
16 readable of the sections. This is the section that
17 deals with whether a control in the drug product
18 specification is appropriate.
19 I want to first show a couple of caveats
20 that are brought forth in the text of the Q6A
21 document. The first says that you would really
22 only be dealing with this part of the flow chart
23 when you have already established that there are
24 multiple polymorphic forms of the drug substance
25 and that they are likely to affect the performance
1 of the drug product.
2 Another caveat states that it is
3 frequently very difficult to measure a polymorphic
4 form in the dosage form, and if it is possible to
5 obtain equivalent quality control through other
6 testing, for example, dissolution testing, that
7 that is the preferred approach, and testing of
8 morphic form in the dosage form is more or less a
9 method of last resort if that does not apply.
10 The first decision diamond really relates
11 to this latter point. It asks whether other
12 performance tests, for example, dissolution
13 testing, provide adequate control when the morphic
14 form ratio changes, and if dissolution testing or
15 another performance criteria provide adequate
16 control, then, there would generally not be a need
17 to look at the polymorphic form in the drug
19 However, if it is determined that no
20 performance testing of the drug product will serve
21 that role, then, the decision tree recommends
22 developing a method to look at morphic form in the
23 drug product and measuring it on stability.
24 The second decision diamond, halfway down,
25 says, "Has there been a change in the morphic form,
1 and if there has been a change, it instructs then
2 that in that situation, a control in the drug
3 product specification is appropriate.
5 Now, there is one specific question that
6 we brought forward in the AAPS Workshop, and that
7 related to the word "change" in this second
8 decision diamond, because it is written in the
9 context of stability testing, and it implies that
10 the change would be on stability, but the question
11 that was discussed was does this change also
12 encompass changes during manufacture of the drug
14 I felt that we had a clear decision from
15 the AAPS discussions that yes, this change would
16 encompass change during manufacture of the drug
17 product or change on stability.
18 It is kind of a complicated situation, but
19 an example might be if you had a wet granulation
20 solid oral dosage form, you knew that there was a
21 change to the hydrate during the wet granulation,
22 and you also knew that the ratio of the hydrate to
23 the anhydrous form was critical to performance, was
24 critical, say, to bioavailability, but
25 unfortunately, it was not possible to develop a
1 dissolution test that would be sensitive to that
3 In that case, the decision tree would say
4 there has been a change during drug product
5 manufacture, and you would measure the amount of
6 the hydrate and the anhydrous form in the drug
7 product even if there was no change on stability.
8 That ends the overview of the decision
9 trees. I have one final slide in which I have
10 tried to sum up how the workshop ended.
12 I think there was a general feeling that
13 we could benefit from some additional discussion,
14 possibly an industry-FDA discussion group to put
15 together some concrete examples, some case studies,
16 and to try to bring forward some of the common
17 understandings then of the polymorphism approach in
19 I think that in particular, we would
20 benefit from some additional work related to when
21 dosage form should intentionally be made with
22 different polymorphic forms of the drug substance.
23 I think in both cases, those could perhaps be
24 incorporated into our ongoing good review practices
1 I would like to summarize by saying I
2 think we made some significant progress in terms of
3 establishing some common understandings about
4 polymorphism in specification setting at the AAPS
5 Workshop. I think there is an opportunity to make
6 even more progress if we continue the dialogue, get
7 some additional feedback.
8 I would like to thank the three other
9 workshop organizers with me - Ivan Santos from
10 Merck, Tim Wozniak from Eli Lilly, and John Clark
11 from CDER, and I would like to thank you all for
12 allowing me to make this presentation today.
13 DR. LEE: Thank you very much.
14 Are there any burning questions for Dr.
16 Yes, Ken.
17 DR. MORRIS: Yes. I have more of a
18 comment. In the screening for polymorphs, there is
19 a big gap there that deals with purity, because in
20 my experience, the biggest variable as you go from
21 the bench to the kilo lab to full scale is the
22 purity of the material you are getting. That will
23 bite you in the rear end faster than most of the
24 other things that are on that list.
25 DR. MILLER: That is a point actually
1 which was not discussed during the workshop.
2 DR. MORRIS: That may be the biggest point
3 really. I mean it is not the biggest point in terms
4 of finding them necessarily when you are screening,
5 although it may be there, as well, but in terms of
6 what changes as the chemists get more and more
7 refined processes and they hopefully increase their
8 yield in purity, they change that a lot, and
9 impurities, and for years and years used to control
10 all sorts of things indirectly by just people
11 skilled in the art at large scale. So I would say
12 that that is something that really has to be
14 DR. MILLER: Very good, and I think that
15 was one point that was brought up during the
16 discussions was that the relevance of the data to
17 the whole life of the product is very important,
18 and I think that aspect would play into it very
20 DR. MORRIS: Absolutely, and it is easy
21 enough to do screens, more focused screens. I mean
22 you can't put full resources against it every week,
23 but, you know, to do a more focused screen as you
24 go up, particularly if you know you have forms of
25 significantly different free energy because that is
1 what you really care about.
2 DR. CHIU: I think we recognize that.
3 That is why in the BACPAC, you make manufacturing
4 changes, it is important that you reestablish
5 whether you have the same polymorphic form, and
6 especially when the impurities change, you have
7 the different new impurities, then, you may
8 influence that because everything is based on the
9 crystalline seeds. You have a different seed, you
10 get different forms.
11 Thanks for pointing it out.
12 DR. RODRIGUEZ-HORNEDO: As I studied the
13 guidance and listened to your very good
14 presentation, it strikes me that we are focusing on
15 detection of polymorphs and that there is very
16 little attention, at least it seems to me, to the
17 kinetic events during screening and
18 transformations, and only time-dependent phenomena
19 I see is too late from my perspective to take
21 It is either during dissolution, which is
22 very relevant, or it's also during stability
23 testing. So I think the solvents are very
24 important, and it is one of the variables that
25 determines the appearance of a polymorph, but doing
1 kinetic studies, they don't need to be very
2 rigorous, but they would be indicating what are the
3 levels of risk of a new form appearing during the
4 parameters of relevance of a given process.
5 I see that lacking. If you identify three
6 polymorphs or two polymorphs to me, and I have to
7 work with them, I would like to know what are the
8 rates, what are the time frames for transformations
9 all the way from the process, you know, all the way
10 from screens, and it is not only solvent.
11 I think this may be one of the unit
12 operations that is very applicable for PAT to
13 consider. I would like your comments on the time
15 DR. MILLER: I would be interested in
16 hearing your thoughts. Are you thinking more
17 towards solid-state kinetics, transformation in the
18 pure drug substance or the dosage form, or are you
19 thinking of as kinetic experiments performed, sort
20 of ripening experiments in solvents?
21 DR. RODRIGUEZ-HORNEDO: I was thinking
22 more of experiments in solvents, so they could be
23 in suspensions, I think the induction times, the
24 presence of one of the polymorphs, how quickly does
25 it transform to the other polymorphs during the
1 conditions that are relevant to the system.
2 I also think that the dissolution is very
3 important. We think of water, for instance, when
4 we are designing on what granulation process in
5 which the solvent is water, but ultimately, all
6 these dosage forms are going to heat water, they
7 are going to be in the water environment, so how
8 quickly does the transformation occur in water, and
9 are our dissolution methods sensitive enough to
10 capture that.
11 We may be considering developing
12 dissolution methods to identify or classify drugs
13 that may be high risk for what we may actually
14 initially perceive as erratic dissolution behavior,
15 but the transformation is occurring so quickly,
16 that miss it. So we may need to be a little bit
17 more creative in designing some dissolution methods
18 that are sensitive to these for screening purposes.
19 In the solid-state, I think it is very
20 important. I think we are already doing some of
21 that. I think that industry is doing some of that,
22 and the agency has focused a lot of solid-state
23 transformations, but I think the screening in
24 solvents needs to consider the kinetic events, as
25 well as the dissolution, because I think that is
1 where with a product or the actual substance, may
2 be very revealing.
3 DR. MILLER: I think the challenge will be
4 in creativity to determine the right type of
5 experiments for each particular case.
6 DR. LEE: Thank you.
7 DR. CHIU: I think that is a very
8 important, you know, good point, you know, the
9 kinetics. We are working, drafting a drug product
10 guidance in line up with the CCDQ. We could
11 consider to put that concept in the Pharmaceutical
12 Development section.
13 DR. LEE: I hope that you include dosage
14 forms beyond tablets and capsules.
15 DR. CHIU: Yes, we will do that.
16 DR. MILLER: I would have one more point
17 to add regarding kinetics. At the workshop, one
18 point was made that one reason for possibly doing a
19 broadly-based screen initially, looking at solvents
20 that might not really be used in the current
21 process, might be that kinetically, a particular
22 polymorph might readily form in one of those
24 It might be the thermodynamically, more
25 stable polymorph in general, but you might have
1 more difficulty getting to it from the smaller
3 DR. LEE: Gloria.
4 DR. ANDERSON: My question is much
5 simpler, but before I ask it, I will say that in
6 terms of the crystal forms that you get, they are
7 certainly solvent-dependent. But my question goes
8 back to the beginning.
9 Why do you include amorphous substances in
10 your definition or polymorphs, when, by definition,
11 your definition, they are crystalline forms?
12 DR. MILLER: I think the next speaker, Dr.
13 Adams, will talk a little bit more on that point,
14 but I would say that because of the important
15 relevance in drug product manufacture, where
16 amorphous forms may offer very different properties
17 to the dosage form.
18 DR. ANDERSON: Absolutely.
19 DR. MILLER: Our intent is to bring it in
20 under that terminology. I think if we wanted to be
21 as correct as possible with current terminology, we
22 would probably just talk about solid-state forms,
23 which would then include hydrates, solvates, as
24 well as non-crystalline amorphous forms.
25 DR. ANDERSON: You can have crystalline
1 hydrates, but you can't have amorphous crystalline.
2 DR. MILLER: Many of you would not include
3 hydrates under the term "polymorph," because the
4 unit cell has different contents.
5 DR. MORRIS: If I can just comment,
6 Gloria, I think part of the reason is there is just
7 no other place to put it. I mean it's a condensed
8 phase, it is not a liquid, I mean it's a solid. I
9 just don't know where else you would put it.
10 DR. ANDERSON: In a separate category.
11 DR. MORRIS: Well, in a separate category,
12 but I mean in terms of this workshop.
13 DR. RODRIGUEZ-HORNEDO: One last comment.
14 You may be aware that there are some companies here
15 in this country, more of them in England, but there
16 are some in this country that have very closed
17 monitoring of their crystallization process by
18 Raman spectroscopy and other spectroscopic
19 techniques, so like what we have been discussing
20 this morning, it is very applicable to this.
21 DR. LEE: I can see that it is a very
22 interesting topic. I hate to cut it off, but in
23 order to give justice, in fairness, not justice, to
24 Dr. Adams.
25 OGD Issues
1 Richard Adams, Ph.D.
2 DR. ADAMS: Good afternoon. I would like
3 to talk about the issue of morphic form or I guess
4 we can call it solid-state or morphic form and its
5 issues that are particularly important in generic
8 We have encountered active pharmaceutical
9 ingredients of different morphic form in the past,
10 but recently, the interest in it is intensified
11 because we have gotten a number of applications
12 which have been contested by the innovator
13 companies as inappropriately 505(j) because they
14 are different morphic form, different polymorphs,
15 and the innovator companies have objected.
16 We have gotten numerous Citizen's
17 Petitions and it has been extremely
18 resource-intensive in the Office of Generic Drugs.
19 Yuan-yuan correctly pointed out, when we were
20 speaking about this meeting, that amorphous forms
21 shouldn't be included, and that is certainly
23 The fact of the matter is that there are
24 many amorphous drug substances for reasons related
25 to the patent litigations and also because, in some
1 cases, crystalline drug substances are deliberately
2 converted to amorphous as in the case of
3 lyophilizations to increase the dissolution rates
4 and for other reasons.
6 In any event, we have gotten very familiar
7 with the issues. I would say that some of the
8 issues in generic drugs that are peculiar to the
9 generic review process have to do with the lack of
10 transparency often between the Drug Master File,
11 the supplier or the vendor of the active
12 pharmaceutical ingredient and the actual drug
13 product manufacturer, so that usually, I think the
14 relationship is different for the innovator
16 On the plus side, usually, there is a fair
17 amount of information known in the literature by
18 the time we get these applications, so in terms of
19 the screening for polymorphs, we certainly require
20 it, but usually, you can simply do a quick search
21 and you can find out a fair amount of information
22 about the morphic forms of the active
23 pharmaceutical ingredient.
25 In terms of our approach to it, the
1 regulations and the codifications of them are
2 fairly straightforward. The drug substance, the
3 active ingredient must be identical to the
4 innovator active ingredient, and in addition to
5 that, it must be the same dosage form, strength,
6 route of administration, and the conditions of use
7 must be identical.
8 If those conditions are met, that
9 satisfies the definition of pharmaceutically
10 equivalent, and then it just depends upon the
11 successful completion of a bioequivalence study to
12 achieve therapeutic equivalence.
13 In addition to that, there are some other
14 constraints. Labeling must be the same although
15 that has been interpreted rather broadly by generic
16 drugs, and depending on who is doing the
17 interpreting, the regulations are many different
20 Review issues. The review of the
21 performance attributes, there are really only two
22 performance attributes that are critically reviewed
23 and felt to be critical to the performance of the
24 drug products and simply bioequivalence within
25 certain specified limits, subject to the ANDA, the
1 drug product must be equivalent to the innovator.
2 Of course, it must possess the stability
3 characteristics to remain bioequivalent over its
4 shelf life.
5 Other issues include the USP monographs.
6 They are relevant to our consideration of ANDA drug
7 products. Certainly, the monographs are the source
8 of specs and the drug product and drug substance to
9 the extent there are monographs, the dissolution,
10 identification, and assay specifications are
11 usually listed.
12 By regulation, USP is recognized as the
13 official compendium. To the extent that the
14 identity of an active pharmaceutical ingredient in
15 an ANDA is different from the monograph
16 description, then, it may not be labeled as such
17 unless it is explicitly disclaimed on the label.
18 Patents are prohibitive, but only in the
19 sense of the legal. They have nothing to do with
20 scientific conclusions.
22 The basis of industry arguments have
23 fundamentally claimed that the active
24 pharmaceutical ingredient that is of a different
25 polymorphics form or a different morphic form than
1 that in the innovator drug product, it doesn't
2 satisfy the legal requirement for identicality or
3 sameness, and furthermore, the point has been made
4 that existing guidances imply at least the lack of
5 equivalence when morphic form is different.
6 ICH Q6A has been cited although that
7 technically doesn't apply. It only applies to new
8 drug products.
9 There was also a final rule which is
10 relevant to this discussion in 1992, published in
11 the Federal Register, and that has been cited as a
12 reason for lack of identicality given the
13 definition of identicality given in that document
14 however, we use the same final rule as
15 justification, so it depends on what section you
17 There was a court decision, Serono
18 Laboratories versus Shalala, which has been cited
19 by petitioners, in which the phrase or the ruling
20 that they cite is the variation of active
21 ingredient in a generic product should be permitted
22 unless, in addition to exhibiting clinical
23 equivalence to the pioneer, the generic must show
24 chemical identity to the extent possible, the last
25 phrase being the key.
1 So again that was a lengthy decision and
2 it depends on what portion you choose to excerpt.
4 An additional part of the argument,
5 although differences in formulation are permitted
6 to be different in the labeling, industry argues
7 that a different physical state or form is a
8 difference in active ingredient rather than just a
9 difference in formulation or any of the other cited
10 allowed differences.
11 Finally, because the generic is of
12 different physical form, it therefore doesn't meet
13 the standard of identity in the USP if it is
14 specified, and therefore, it would have to have a
15 different name, and a different name would
16 constitute different labeling and misbranding.
18 Industry has questioned the OGD process
19 with regard to I guess rigor and demonstrating the
20 lack of presence of all, or ruling out the presence
21 of all polymorphs in the active pharmaceutical
22 ingredient that is the subject of the application,
23 that is in the drug product that is the subject.
24 The acceptance criteria that we use has
25 been criticized for doing essentially only
1 evaluation of the bioequivalence after manufacture
2 of drug product without additional data points of
3 that performance attribute on stability or for
4 future batches.
5 Basically, the benchmarks that we use for
6 ensuring the sameness of the batch going forward,
7 they have been questioned, the process.
9 As I said at the outset, our arguments
10 have been rather simple, simply based upon the
11 belief that the identicality requirements are
12 satisfied by virtue of the same dosage form, the
13 same route of administration, conditions of use, et
14 cetera, and the physical form or the morphic form
15 is considered to be not relevant to the
16 pharmaceutical equivalence.
17 As stated in the Orange Book, the agency
18 considers drug products containing different
19 polymorphs of the same drug substance to be
20 pharmaceutically equivalent. So it only remains to
21 be demonstrated that it is bioequivalent to achieve
22 therapeutic equivalence.
24 Again, as Steve noted, in the 1987 Drug
25 Substance Guidance, although this doesn't speak to
1 solvates, it notes, essentially concludes that
2 although different polymorphs have different
3 thermodynamic energy content, they don't differ in
5 As far as the draft Drug Substance
6 Guidance, which has not been published, but as far
7 as I know, that doesn't specifically address the
8 issue of morphic form. As I said earlier, ICH Q6A,
9 we are not within the scope of that, but eventually
10 will be, so I think that that is a short-lived
13 As far as labeling differences go, the
14 differences in labeling cited in 505 and the
15 subsequent codification of that, may include a
16 number of things. Those are noted on the slide.
17 The FDA feels that those are examples, and other
18 differences are not precluded, those are merely
19 examples of differences that are allowable.
20 Additionally, industry has cited, in Title
21 21, 229.5, wherein it is stated that to the extent
22 there are differences in the drug substance, the
23 pharmaceutical ingredient, it doesn't satisfy the
24 identity requirement, and the labeling must be
1 But that same section goes on in Part C to
2 note that to the extent there are differences, as
3 long as those differences are specifically
4 disclaimed on the label, and the extent of
5 differences, it is allowable, and we have approved
6 applications with active ingredients that are not
7 the same, with disclaimers on the labels.
8 Furthermore, it is clear from the House
9 report on the original Hatch-Waxman Act, that
10 Congress did not intend for generic drugs to be
11 exactly identical in every respect to the innovator
12 drugs, and they included a number of other
13 qualifying differences aside from those noted in
14 the codification of that law including color and a
15 number of other things. Clearly, these were just a
16 non-complete list of things that could be
19 As far as our process or assessment of
20 performance, the bioequivalence determination is
21 straightforward, and we have spent a lot of time
22 trying to ensure that the benchmarks that we have
23 with the pivotal batch or batches, that they are
24 adequate to ensure that the drug product will
25 remain the same from a bioequivalence standpoint
1 going forward.
2 That is not an easy task. Depending on
3 the drug product, there are issues, it is difficult
4 to determine whether or not it is going to be the
5 same with any surrogate test. In particular, often
6 the dissolution methodology or the specifications
7 are tailored to the application. We may have
8 several different sets of specs for dissolution
9 because the requirement is that it be
10 bioequivalent, so if the dissolution
11 characteristics are different, then, the
12 dissolution specs are changed.
13 That is the most critical issue clearly.
15 As far as our view of the USP monographs,
16 we have to certainly be aware of the standards of
17 identity as explicated in the monographs, when
18 there are monographs.
19 I just did a quick search, I guess the
20 results are on the next slide, but there are 97
21 monographs in the USP which have the identity term
22 crystallinity in them. There are 8 monographs with
23 amorphous present.
24 Most of those or 95 of those monographs
25 that have crystallinity in the description are
1 antibiotics curiously, but we have had applications
2 with different morphic form across the board,
3 though, they are not limited to antibiotics.
4 We do require unless in rare cases, we
5 require the applications to contain active
6 pharmaceutical ingredients that conform to the
7 identity description in the USP. What has been
8 done, we require the revision, the monographs to be
9 revised before approval.
10 The applicant contacts the USP and makes
11 the case for revising it, and it may be revised to
12 include inclusive of a different polymorph or
13 inclusive of amorphous, and, of course, since that
14 is an open process, the innovator companies
15 participate in the commenting during that revision
16 process, and it is lengthy usually.
18 So, in summary, 21 CFR 314.92 provides the
19 regulatory basis for determining the suitability of
20 drug products for filing in an ANDA. It reads in
21 part, Drug products that are the same as a listed
22 drug, and for determining the suitability of an
23 ANDA, the term "same as" means identical in active
24 ingredient, dosage form, strength, route of
25 administration, and conditions of use.
1 The agency considers drug products
2 containing different polymorphs of the same drug
3 substance to be pharmaceutically equivalent.
4 Additionally, in order to be therapeutically
5 equivalent, the drug product must be shown to be
6 bioequivalent to the listed drug upon which it is
7 based, and it must possess requisite stability
8 characteristics to retain that bioequivalence
9 within a reasonable shelf life.
10 It also should contain the same labeling
11 and it should conform to the identity and specs and
12 tests listed in the compendium if it is concluded.
14 The achievement of those requirements, the
15 critical questions are has the applicant
16 demonstrated diligence in screening for possible
17 polymorphs or hydrates or solvates. There have
18 been some rather practical solutions to some of
19 these problems.
20 In one case, the drug product was known to
21 be plagued with I believe seven different hydrates
22 and of differing solubilities and differing
23 bioavailabilities, so the solution was simply to
24 use a wet granulation, literally wet, and
25 overhydrate it, maximally hydrate it, and then dry
1 it down to a speck of less than a half a percent
2 water, and there were no further questions about
3 the hydrates.
4 As it happened, that anhydrous form was
5 acceptably bioequivalent and acceptably stable.
6 That begs the question of the potential for
7 interconversion on shelf life.
8 We have seen two applications that very
9 successfully used Raman spectroscopy for monitoring
10 of the drug product on shelf life, calibrated with
11 X-ray powder diffraction studies, which was very
12 good work
13 So, bioequivalence having been established
14 and shelf life, adequate shelf life satisfies our
17 There are complicated situations, such as
18 ANDAs, as I mentioned, with mixture of polymorphs,
19 and the formulation process may result in
20 interconversion during formulation requires an
21 assay which will work to discriminate among the
22 various morphic forms.
23 Generic Drugs gets a lot of change of
24 source of drug substance, so this is an ongoing
25 issue. In the previous slide, the first question,
1 this diligence, the screening for possible
2 polymorphs, this is something that we have been
3 much more attentive to recently. I think it is
4 going to become a routine process.
5 DR. LEE: Thank you very much.
6 Are there questions for Dr. Adams? Leon.
7 DR. SHARGEL: I want to thank you for a
8 difficult area, in the generic industry, the
9 concept of sameness is a major issue. In fact, I
10 think in terms of the generic manufacturer, if he
11 is not being sued by an innovator, he is not
13 It stands to reason that an API
14 manufacturer for a generic firm is going to use a
15 different synthetic pathway or approach that
16 doesn't infringe on patents of the innovator, so
17 therefore, the API manufacturer is more than likely
18 going to be somewhat different in terms of
19 polymorph or anhydrous or what is the hydration,
20 and things of that sort.
21 I think the main thing to consider is the
22 dissolution in vitro and bioequivalence in vivo,
23 that we are talking about the same molecular
24 entity, that once it is in solution or in the body,
25 that we really have a medical product. There is
1 much to-do about whether anhydrous and crystalline
2 form are different. I realizes in Chemistry 101 in
3 high school that they are different and have
4 different properties.
5 I think in my mind as we do stability, we
6 do dissolution, we do in vivo bioequivalence, how
7 much are these differences in crystalline
8 properties going to be different in terms of what
9 we expect in a therapeutically equivalent generic
10 drug product.
11 DR. LEE: Thank you.
12 DR. ADAMS: One more point I forgot to
13 make. I guess that one of the reasons why Raman
14 spectroscopy is particularly easy to implement in
15 the cases we have seen is because they have been
16 antibiotics, and they are largely drug substance,
17 which makes it a lot easier.
18 DR. LEE: Joe.
19 DR. BLOOM: If you have a product that has
20 many polymorphs, do you consider it to have just
21 one active ingredient?
22 DR. ADAMS: Yes.
23 DR. BLOOM: If the product becomes
24 bioequivalent, so that if an ANDA has polymorphs in
25 it, becomes bioequivalent, it should pass your
2 DR. ADAMS: Yes, if it's bioequivalent and
3 it's physically acceptable from an elegant
4 standpoint and stability, that is all that is
5 required. In other words, polymorphism or morphic
6 form differences do not preclude the conclusion of
7 sameness as far as composition goes.
8 That satisfies our requirement for
9 pharmaceutical equivalence.
10 DR. BLOOM: Then, a question is hydrates
11 or polymorphs are considered the same as the active
12 ingredient or is it in another category?
13 DR. ADAMS: No, they are considered the
14 same as.
15 DR. BLOOM: The hydrates or polymorphs are
16 considered the same?
17 DR. ADAMS: Yes.
18 DR. MORRIS: And amorphous.
19 DR. ADAMS: And amorphous, yes. OGD
20 regards morphic form, maybe the performance
21 characteristics may be different, and that, of
22 course, is another question, an independent
23 question, but as far as satisfying the regulation
24 and the law under 505(j), that the active
25 ingredient be identical, we have stated in the
1 Orange Book, in the preface, it states that
2 polymorphs and hydrates and amorphous forms, the
3 drug substance are considered to be
4 pharmaceutically equivalent.
5 DR. HUSSAIN: Let me sort of address that.
6 I think with respect to different polymorphs,
7 amorphous, and so forth, I think the key is
8 designing your products to meet the performance
9 attributes. I think you could start with different
10 polymorphic form, chemically identical one, in
11 solution, and essentially how you design your
12 process and how you design your product in terms of
13 bioequivalence and other attributes which link to
14 clinical safety and efficacy essentially is the way
15 we move forward on that.
16 That is how we handle that.
17 DR. MORRIS: A couple of points. I don't
18 think there is any real question that if you have
19 the drug molecule and you change its forms, that
20 it's the same drug molecule, the integrity of the
22 Strictly from the technical and regulatory
23 and leaving the legal out of it because I don't
24 pretend to know anything about that, but there are
25 a couple of issues that are different when you go
1 to a generic, and I think you have hit on a couple
2 of them.
3 The first is the idea of what constitutes
4 a screen, an appropriate or a sufficient screen,
5 and it is different because of all the reasons that
6 we had talked about earlier with respect to
7 screens, and that is, that you have different
8 impurities, you have different solvents, you have
9 changes in vendors, and I can tell you that that is
10 one of the biggest problems that I have run into,
11 so that you really do have to do as good or more
12 broad a screen as the innovator does. Every time
13 you change a vendor, you are really safest to redo
14 a screen and considering the resources that it
15 takes, it is a no-starter to not do it, I mean you
16 just expect to do it.
17 The other thing is, is that I disagree a
18 little bit with what you are saying, Ajaz, and that
19 is because if I have a given form or let me use the
20 example of amorphous form since it is in this
21 category, if you look a work by Zagraffi [ph] and
22 others, you don't always get the same polymorph
23 depending on the conditions under which they
24 recrystallize, so if I start with a different form,
25 you may think, well, everything is fine and I will
1 monitor it through development, and then, you know,
2 sunset it, but if when it converts it converts to
3 an unknown but more stable form -- and this has
4 happened, not necessarily in solid dosage form --
5 then, you are not within the purview of the
6 stability and safety histories that the innovator
7 generated, so the generic is now putting a new set
8 of conditions on.
9 So, I agree that the molecule is the
10 molecule, but I disagree --
11 DR. HUSSAIN: You raised a good issue, but
12 I think in absence of any of the tests you have,
13 that becomes correct, and what you are saying is
14 right, but now I think the question I would sort of
15 rephrase that and say isn't the dissolution test
16 that we have set up - those are the questions.
17 DR. MORRIS: But the question really is --
18 when I pass my bioequivalence, am I passing it at
19 the margin or am I passing it well in the zone? If
20 I am passing it at the margin, then, I think you go
21 into your other point, which I was going to raise,
22 was with time, I think that is where this becomes
23 an issue, Ajaz, is with time to be able to make
24 sure --
25 DR. HUSSAIN: With time, I think the
1 monitoring of the dissolution, the stability
2 program essentially, then, the question becomes is
3 the stability program that we have protecting
4 against that.
5 DR. MORRIS: I fully agree that is the
6 issue. I am not sure that there is a good answer
7 to that question, though, is the problem, because
8 depending on where you live in that zone, there are
9 various differences.
10 To be frank, I think that formulation
11 differences make more of a difference typically
12 than crystal form if it's a polymorph you are
13 talking about, but if you are talking about going
14 from amorphous to crystalline, or anhydrous to
15 hydrated, the free energy differences are not
16 negligible, in fact, I would argue that the hydrate
17 formation and amorphous crystalline formation far
18 outweighs the typical differences you see in
19 polymorphic interconversion and are much more
21 It is much more common in water,
22 everything gets exposed to some level, moisture,
23 you know, you put the cans in it, but it is in a
24 bathroom, so, you know, this is the old story.
25 DR. LEE: I want to save some time for
1 some philosophical discussions. I will now take
2 three more questions - Judy, Leon, and Mary.
4 DR. BOEHLERT: Mine is a fast question.
5 Is OGD now using the ICH Q6A decision trees for
6 deciding when tests are done for polymorphs on
7 active ingredients?
8 DR. ADAMS: No.
9 DR. BOEHLERT: Has that been considered
10 because the issues may be the same, particularly
11 when you are talking about those critical
12 substances that are mixtures, and things of this
13 sort. While I grant that the solution will very
14 often pick up differences, you don't want to find
15 out that you have got an incoming material that is
16 different after you have made the dosage form.
17 DR. ADAMS: Well, again, I would point
18 out, first of all, much is known about the drug
19 substances, which are the subject of ANDAs, either
20 in the literature or -- so the problems are
21 somewhat different, and I would say one thing, that
22 as a result of that difference, I think that the
23 ICH Q6A decision tree No. 4 would be somewhat
24 different if it were inclusive of ANDAs, but that
25 is not an issue that I can really speak to
2 DR. CHIU: However, we do have our
3 internal drug substance, drug product guidances
4 right now under development. Those guidances will
5 follow ICH CDDQ format, so therefore it will
6 include a Pharmaceutical Device section. These
7 guidances apply to generic drugs as well as new
8 drugs, so therefore, the same standard will be used
9 with regard to polymorph.
10 DR. LEE: Leon.
11 DR. SHARGEL: I think the innovator also
12 has similar issues as a generic and API. Very
13 often the API is changed, and that is why the
14 BACPAC guidance go back to the postapproval
15 changes. Both the innovator and the generic has to
16 requalify the API or the API manufacture.
17 The second issue is this idea of
18 marginally bioequivalent just hit me that whether
19 it's an innovator changing formulation or a
20 generic, I think we have a yes/no answer on
21 bioequivalence. We are either there or we are not
22 there. I don't know where we talk about marginally
24 DR. ADAMS: That is a difficult concept
25 actually to accept the statement or the truth that
1 anywhere within the window of acceptable
2 bioequivalence that the clinical endpoints are the
3 same, so would say "marginal" is a term that it is
4 not used.
5 DR. SHARGEL: It applies to both sides of
6 the industry.
7 DR. ADAMS: Yes.
8 DR. LEE: Mary.
9 DR. BERG: Just one further point for
10 clarification. In other words, you are saying if
11 your product conforms to the regulation by being
12 pharmaceutically equivalent, in other words, it
13 meets the standard as such, but then literally,
14 though, the product can be bio-inequivalent as
16 That is what you are saying. So I think
17 that second question becomes important in different
18 ways that people are saying here, that one must
19 really look at that question of bioequivalence
20 because obviously, you are then affecting further
21 down the chain as such what is happening
22 pharmacodynamically as such.
23 That obviously gets into the safety
24 toxicity issue or efficacy issue, so that second
25 question really becomes very important even though
1 you have stated upfront, well, it's met the
2 regulation as such, but that second question is a
3 very good question that you have formulated to look
5 DR. ADAMS: Of course those are the two
6 independent legs of the requirements, and it can't
7 get in the door unless it satisfies the number one,
8 and then once it's in, it must be bioequivalent to
9 be therapeutically equivalent, and therefore
10 approvable as a 505(j).
11 DR. LEE: Are there any other comments? I
12 think certainly you have heightened awareness of
13 this topic on both sides. Now, maybe I should get
14 some guidance or education about where the agency
15 is going from here.
16 DR. HUSSAIN: I think we just wanted to
17 bring this as an awareness topic from a very
18 different perspective. If you look at the previous
19 discussion we had with Christopher Rhodes, it
20 focused on physical steps, and so forth. I think
21 we want to come back. I just want to mention we
22 have a one-day symposium, internal symposium on
23 this topic in June, I believe June 6th.
24 We will go through an extensive look at
25 polymorphism from a science perspective, and so
1 forth, and eventually bring back a topic for
2 discussion, which will focus on physical stability.
3 I think that has not received the attention.
4 Again, when we do that and how we do that,
5 I think we will flesh it out as things go by. In a
6 sense, I think the draft guidances that we are
7 working on, and we will go through the process of
8 finalizing the drug substance, drug product, and
9 even BACPAC II as that comes along. Other
10 guidances that we have under work that will be the
11 focus of the discussion in terms of the physical
12 stability, and so forth.
13 DR. LEE: Are we all invited to that
15 DR. HUSSAIN: Some of you are, and I think
16 if you are in town, you are more than welcome.
17 DR. LEE: This is a half-serious question.
18 Perhaps you know if the committee members who might
19 be providing some advice on this issue, then
20 perhaps I think ought to be there.
21 Nair will be. Are you speaking?
22 DR. RODRIGUEZ-HORNEDO: Yes, I am.
23 DR. MEYER: Let me just ask one question
24 in the context of waiving in vivo bioequivalence as
25 we are going to do for Class I drugs or are doing.
1 Is there anything peculiar about
2 polymorphism that would cause a difference in the
3 polymorphic composition of two products to show up
4 in vivo, but not show up in vitro? Can you
5 hypothesize a situation where that might occur?
6 DR. MORRIS: Are you asking me, Marv?
7 DR. MEYER: Anyone.
8 DR. MORRIS: I think Nair actually, you
9 spoke to that earlier, it's the kinetic question, I
11 DR. RODRIGUEZ-HORNEDO: I understand that
12 but I think your question is more regarding could
13 we see polymorphs in vivo that we don't see in
15 DR. MEYER: Yes.
16 DR. RODRIGUEZ-HORNEDO: I think we can see
17 crystallizations in vivo particularly with drugs
18 that are weekly basic, and I am not prepared to
19 talk about that, but we have seen in my lab some
20 investigations we have done, precipitation of drugs
21 by changing pH in aqueous systems that actually
22 create new solid faces that we have not seen
24 This is an in vitro method generally, but
25 it is not a method that would be used in chemical
1 development, so to address your question, yes, I
2 think there is a possibility for precipitation or
3 crystallization phenomena in vivo, at least in the
4 GI tract with weekly basic drugs.
5 DR. MEYER: But would you also see that in
6 vitro, and if you would, then we are safe.
7 DR. RODRIGUEZ-HORNEDO: Yes.
8 DR. MEYER: If you would not, then, we are
9 not safe.
10 DR. RODRIGUEZ-HORNEDO: Yes.
11 DR. LEE: To summarize, there are certain
12 words I learned in the last couple days, before I
13 turn it over to Helen or Ajaz on the next topic.
14 Our awareness about risk management resonates
15 throughout the two days, PAT, PCS, I think these
16 are all interconnected, and I am very pleased to
17 see the committee deliberate that we tried to see
18 how they might fit into those frameworks.
19 On that note, I would turn the podium over
20 to the OPS Updates. I am not sure who is going to
21 be on the floor.
22 OPS Updates
23 DR. HUSSAIN: I thank the committee for an
24 excellent deliberation and discussion. I think
25 this has been very useful. Reflecting back to
1 lessons learned from my perspective, I think we
2 could have done better with the agenda and
3 organizing some of that, so we learned a few things
4 we hope to use to improve the next meeting agenda
5 and then the background packet itself.
6 I think we will constantly work on
7 improving our meetings, and so forth, and always,
8 any feedback that you can provide will be very,
9 very helpful. I think the first day discussion, if
10 we had the BCS first and food effects second it
11 would really help, but I think it came out fine.
12 In terms of OPS update, I think Helen had
13 mentioned, and I will just reemphasize, that I
14 think we have moved the Office of Pharmaceutical
15 Science, and there have been some changes in terms
16 of new additions. One addition is an associate
17 director which would focus on rapid response
18 project, and I think at some point we will bring
19 that to the discussion.
20 In addition, we have several additions.
21 Dr. Sobel has joined us as Associate Director for
22 Medical Affairs, and I mentioned the Microbiology
23 staff moved to OPS, and we hope to have four more
24 individuals for PAT -- three more, we already have
25 one on board.
1 The next meeting would be in October. We
2 will work more diligently to make sure the agenda
3 and the background packet will be much better
4 designed to help you address the questions. Any
5 feedback more than welcome.
6 Thank you and have a safe trip back.
7 DR. LEE: Thank you very much. The
8 meeting is adjourned.
9 [Whereupon, at 3:20 p.m., the meeting was
11 - - -