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                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

             ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

 

 

                              Volume I

 

 

 

 

                          Tuesday, May 3, 2005

 

                               8:30 a.m.

 

 

                CDER Advisory Committee Conference Room

                           5630 Fishers Lane

                          Rockville, Maryland

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                        P A R T I C I P A N T S

 

      Charles Cooney, Ph.D., Chair

 

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

 

      Committee Members:

 

      Patrick P. DeLuca, Ph.D.

      Paul H. Fackler, Ph.D., Industry Representative

      Michael S. Korczynski, Ph.D.

      Gerald P. Migliaccio, Industry Representative

      Kenneth R. Morris, Ph.D.

      Marc Swadener, Ed.D., Consumer Representative

      Cynthia R.D. Selassie, Ph.D.

      Nozer Singpurwalla, Ph.D.

      Jurgen Venitz, M.D., Ph.D.

 

      Special Government Employees:

 

      Carol Gloff, Ph.D.

      Arthur H. Kibbe, Ph.D.

      Thomas P. Layloff, Jr., Ph.D.

      Marvin C. Meyer, Ph.D.

 

      FDA Participants:

 

      Gary Buchler, R.Ph.

      Lucinda Buhse, Ph.D.

      Ajaz Hussain, Ph.D.

      Mehul Mehta, Ph.D.

      Vibhakar Shah, Ph.D.

      Helen Winkle

      Lawrence Yu, Ph.D.

                                                                 3

 

                            C O N T E N T S

                                                              PAGE

 

      Call to Order

                 Charles Cooney, Ph.D., Chair                    5

 

      Conflict of Interest Statement

                Hilda Scharen, M.S., Executive Secretary         5

 

      Introduction to Meeting--OPS Update

                Helen Winkle                                     7

 

      Opening Remarks

                Charles Cooney, Ph.D.                           16

 

      Establishing Drug Release or Dissolution

      Specifications:

 

         Topic Introduction

                Ajaz Hussain, Ph.D.                             18

 

         Dissolution Measurement System: Current State

           and Opportunities for Improvement

                Lucinda Buhse, Ph.D.                            45

 

         Questions by Committee Members                         76

 

         Overview of Guidance Documents

           and Decision Process:

 

         Biopharmaceutics Section

                Mehul Mehta, Ph.D.                              95

 

         Questions by Committee Members                        128

 

         Establishing Dissolution Specifications:

           Current Practice

                Vibhakar Shah, Ph.D.                           138

 

         Questions by Committee Members                        156

 

      Open Public Hearing:

                Will Brown, USP                                162

 

      Questions by Committee Members                           171

                                                                 4

 

                      C O N T E N T S (Continued)

                                                              PAGE

 

      Establishing Drug Release or Dissolution

      Specifications: (Continued)

 

         Factors Impacting Drug Dissolution and

           Absorption:  Current State of Science

                Lawrence Yu, Ph.D.                             179

 

         Questions by Committee Members                        198

 

         Summary of Tactical Plan

                Ajaz Hussain, Ph.D.                            208

 

         Committee Discussion and Recommendations              229

 

      Clinical Pharmacology Subcommittee Report

         (via teleconference)

                Jurgen Venitz, M.D., Ph.D.                     284

 

      Questions by Committee Members                           301

                                                                 5

 

                         P R O C E E D I N G S

 

                             Call to Order

 

                DR. COONEY:  I would like to welcome

 

      everyone to this morning's meeting.  We have an

 

      opportunity for an on-time start.  I am Charles

 

      Cooney, the new chair of this committee.  I am

 

      delighted to welcome everyone here, both the

 

      committee members as well as the guests.  We have,

 

      not surprisingly, a full agenda this morning and we

 

      will begin with addressing the conflict of

 

      interest.

 

                     Conflict of Interest Statement

 

                MS. SCHAREN:  Good morning.  The Food and

 

      Drug Administration has prepared general matters

 

      waivers for the following special government

 

      employees, Charles Cooney, Patrick DeLuca, Carol

 

      Gloff, Arthur Kibbe, Michael Korczynski, Thomas

 

      Layloff, Marvin Meyer, Kenneth Morris, Nozer

 

      Singpurwalla and Jurgen Venitz who are

 

      participating in today's meeting of the

 

      Pharmaceutical Science Advisory Committee to, one,

 

      receive an update from the Clinical Pharmacology

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      Subcommittee and, two, discuss and provide comments

 

      on the general topic of establishing drug release

 

      or dissolution specifications.

 

                This meeting is being held by the Center

 

      for Drug Evaluation and Research.  Unlike issues

 

      before a committee in which a particular product is

 

      discussed, issues of broad applicability, such as

 

      the topic of today's meeting, involve many

 

      industrial sponsors and academic institutions.  The

 

      committee members have been screened for their

 

      financial interests as they may apply to the

 

      general topic at hand.  Because general topics

 

      impact so many institutions, it is not practical to

 

      recite all potential conflicts of interest as they

 

      apply to each member.  FDA acknowledges that there

 

      may be potential conflicts of interest but, because

 

      of the general nature of the discussions before the

 

      committee, these potential conflicts are mitigated.

 

                With respect to FDA's invited industry

 

      representatives, we would like to disclose that Dr.

 

      Paul Fackler and Dr. Gerald Migliaccio are

 

      participating in this meeting as non-voting

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      industry representatives, acting on behalf of

 

      regulated industry.  Dr. Fackler's and Dr.

 

      Migliaccio's role on this committee is to represent

 

      industry interests in general and not any one

 

      particular company.  Dr. Fackler is employed by

 

      Teva Pharmaceuticals and Dr. Migliaccio is employed

 

      by Pfizer.

 

                In the event that the discussions involve

 

      any other products or firms, not already on the

 

      agenda, for which FDA participants have a financial

 

      interest, the participant's involvement and

 

      exclusion will be noted for the record.  With

 

      respect to all other participants, we ask in in the

 

      interest of fairness that they address any current

 

      or previous financial involvement with any firm

 

      whose product they may wish to comment upon.  Thank

 

      you.

 

                DR. COONEY:  Thank you.  Now Helen Winkle

 

      will provide an update.

 

                  Introduction to Meeting--OPS Update

 

                MS. WINKLE:  Good morning, everyone.  I

 

      would like to welcome all the members of the

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      advisory committee and to especially welcome Dr.

 

      Charles Cooney as our new chair of the advisory

 

      committee.  We, at FDA, have worked with Dr. Cooney

 

      as a member of the committee and have really felt

 

      that he has provided a lot of input into the

 

      committee's activities, and feel that working with

 

      him in the next two years as chair is going to be a

 

      very important step for all of us.

 

                Before I talk about the agenda for this

 

      session of the advisory committee, I would like to

 

      talk a little bit about our current focus at the

 

      agency or what we are calling a paradigm shift.  I

 

      think it is important for all of us to understand

 

      clearly the changes that we are making in the

 

      agency and the role of the advisory committee in

 

      assisting us in making these changes.  Based on

 

      recent initiatives in FDA, including the

 

      Pharmaceutical cGMP Initiative for the 21st

 

      Century, the PAT Initiative and the Critical Path

 

      Initiative, you can see the shift in FDA's thinking

 

      about regulating product quality.

 

                Specifically, there is a focus in these

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      initiatives to place more responsibility on

 

      industry to ensure the quality of their

 

      pharmaceutical products rather than rely solely on

 

      regulatory scrutiny to maintain that quality.  This

 

      is really the paradigm shift, a sharing of

 

      responsibility for drug quality with emphasis

 

      placed on industry to understand their processes

 

      and the underlying science of those processes.

 

                Why would we want to make that change?

 

      There is no evidence that the products out there on

 

      the market are bad products.  There is no evidence

 

      that the agency has done a bad job in serving as a

 

      surrogate for ensuring good quality products for

 

      the consumer.  And, there is no evidence that

 

      industry is not focused on quality as an important

 

      attribute to manufacturing products.  However,

 

      times are changing.  As we enter the 21st century

 

      we have an excellent opportunity to begin to

 

      prepare for how we will handle pharmaceutical

 

      regulation in the future.  The time is ripe for us

 

      at FDA to invest in that future and to ensure that

 

      the direction we are going in is adequate to handle

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      the changing world of pharmaceutical development

 

      and manufacturing while we continue to be able to

 

      serve the consumer.  It is the right time too to

 

      ensure that our regulatory involvement does not

 

      hinder the innovation and continuous improvement in

 

      manufacturing and ensuring the quality of

 

      pharmaceutical products.

 

                So, FDA has begun a journey towards this

 

      paradigm shift.  I want to say it is a long

 

      journey.  It started several years ago but we have

 

      a long way to go, and we have numerous challenges

 

      along that way.  However, with these challenges

 

      come opportunities and I think this is the

 

      important thing for us and the advisory committee

 

      to remember, that we need to take advantage of

 

      these opportunities.  It is important not only to

 

      take advantage of the opportunities to help us

 

      improve on how we regulate product quality, but

 

      also to ensure that we provide for modernization

 

      both at FDA and within industry for the 21st

 

      century.

 

                The guiding principles of the

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      Pharmaceutical cGMP for the 21st Century, which

 

      include risk-based orientation, science-based

 

      policies and standards, integrated quality systems

 

      orientation, international cooperation and strong

 

      public health protection, serve to help us in

 

      developing the pathway to restructure the oversight

 

      of the pharmaceutical quality.  As each of you

 

      knows, there are a number of forks in that path and

 

      you, as members of this advisory committee, are

 

      really here to help us determine the right path in

 

      the road to go from a scientific perspective, and

 

      to help and advise us on how to fill the gaps which

 

      exist in the FDA.  These include gaps in

 

      organization, gaps in science and gaps in policy.

 

                The committee has already participated in

 

      discussions on a number of scientific issues which

 

      have helped in formulating a strategy for

 

      addressing many of the questions that have emerged

 

      as a result of this paradigm shift.  We have

 

      already discussed a number of issues which have

 

      significance as we develop our future regulatory

 

      paradigm, including such issues as polymorphism,

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      bio-inequivalence of generic products, and we have

 

      worked together to support such initiatives as the

 

      Process Analytical Technology Initiative.  The

 

      committee has also been extremely helpful in moving

 

      toward this new paradigm with other discussions

 

      that we have had on various topics.  However,

 

      again, the journey has only just begun.

 

                The agenda for the next two days was

 

      developed to provide an opportunity to discuss two

 

      other scientific topics which are important to us

 

      to better understand and manage in order to move us

 

      steadily along the path of change.  The first topic

 

      is on establishing drug release or dissolution

 

      specifications.  Obviously, how we set

 

      specifications is important to the future.  As we

 

      move to the desired state of pharmaceutical quality

 

      we want to ensure that specifications are based on

 

      mechanistic understanding of how product and

 

      process factors impact product performance.  We are

 

      currently in the process of developing a tactical

 

      plan for setting dissolution specifications.  As

 

      you will hear from the presentations today, we have

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      developed the fundamentals for this plan which

 

      include a systems view of setting specifications,

 

      ensuring that all factors which affect dissolution

 

      are considered; basically ensuring that we connect

 

      all the dots in CMC to ensure a more comprehensive

 

      and systematic way of setting specifications.

 

                FDA recently held a specifications

 

      workshop in co-sponsorship with the Product Quality

 

      Research Institute.  The workshop indicated a need

 

      for additional efforts to move toward better

 

      setting of specifications in general.  Some of the

 

      specific points that were brought out at the

 

      workshop included a lack of globalization on how

 

      specifications are set; a need to better define

 

      what we should do versus what we can do; a need to

 

      better define the role of the compendia in the new

 

      paradigm; and a need to revisit the decision trees

 

      in ICH Q6A.

 

                Our discussion at the advisory committee

 

      today is not designed to address all the workshop

 

      issues and concerns on setting specifications.  The

 

      discussion today will, however, help us finalize

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      the tactical plan for setting dissolution

 

      specification and will lay the foundation for our

 

      thinking in setting specifications for CMC and

 

      addressing the specific issues that were identified

 

      at the workshop.

 

                We would appreciate the committee's

 

      comments and suggestions as to what data is needed

 

      to support our plans.  This would include looking

 

      at statistical methodology, etc., and how we might

 

      improve on our thinking in our tactical plan and

 

      specifications setting in general.

 

                At this meeting we will also discuss, as

 

      our second big topic, quality by design and

 

      pharmaceutical equivalence.  As you will remember,

 

      at the last meeting we set the stage in our

 

      discussions on bioinequivalence and bioequivalence

 

      testing of locally acting GI drugs.  At this

 

      meeting our goal is to modernize our general

 

      thinking about pharmaceutical equivalence and to

 

      explore how quality by design can be leveraged to

 

      ensure more rational approaches to decision-making

 

      so that we can move from a reactive environment to

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      a proactive regulatory scheme of assessing

 

      equivalence.

 

                We will discuss a number of relevant

 

      topics, including biopharm. classification system;

 

      using product development information to address

 

      highly variable drugs; and we will revisit the

 

      concept of decision trees for ensuring a rational

 

      approach to determining bioequivalence for topical

 

      drug products.  We look forward to the committee's

 

      feedback on these extremely important topics, and

 

      that discussion is for tomorrow.

 

                There are a number of other topics we will

 

      cover at this meeting, including an update from the

 

      working group on parametric tolerance interval test

 

      for dose content uniformity.  Bob O'Neill will give

 

      that update.  And an update from the Clinical

 

      Pharmacology Subcommittee.  We will also discuss

 

      with the committee our perceived need to establish

 

      a working group for the review and assessment of

 

      OPS' research programs.  Our goal in looking at our

 

      research programs is to ensure a common approach to

 

      all laboratory work and to ensure that our research

                                                                16

 

      aligns with our overall mission.

 

                Now that we have two laboratories in OPS,

 

      a biotech. laboratory and a lab focused on small

 

      molecules, it is extremely important that this

 

      alignment takes place and we really look forward to

 

      your input on how we can better align these two

 

      laboratories.

 

                As you can see, we have a full agenda but

 

      I think the topics to be discussed are really of

 

      great interest to us as we move down the path to

 

      the desired state for pharmaceutical quality, and I

 

      look forward to a very interesting discussion on

 

      each of these topics.  Thank you.

 

                            Opening Remarks

 

                DR. COONEY:  Thank you, Helen.  I would

 

      like to just add a couple of comments, if I may, to

 

      get us started.  I am delighted to have the

 

      opportunity to work with the FDA and to work with

 

      this committee during the coming two years.  It is

 

      a particularly exciting time because as we look

 

      forward, as Helen has indicated, there are very

 

      important new initiatives on the table with the

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      cGMP Initiative and the Critical Path Initiative

 

      and these, indeed, lay a foundation that we all

 

      need to work within.  In fact, it is an exciting

 

      opportunity to work within those initiatives to

 

      look at how we can better address some of the

 

      challenges going forward.

 

                Certainly, as we look forward there are

 

      more challenges than there have been in the past.

 

      We are facing a world of increasing molecular

 

      complexity; a world of increasing demands by

 

      consumers; a world in which we have increasing

 

      complexity not just in the molecules but in the

 

      delivery formats of these products and the role of

 

      this committee is very important in helping to

 

      provide advice to the FDA and to the division to

 

      deal with these problems.  I must say, I applaud

 

      the forward-looking and the proactive stance that

 

      is being taken on these issues.

 

                We have some challenging goals today and

 

      tomorrow, not the least of which, of course, is to

 

      stay on time.  But the reason that the challenge of

 

      staying on time is a challenge is because of the

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      very high content of material that we need to deal

 

      with.  So, I will do my best to try and keep us

 

      within the proper boundaries.

 

                Again, I look forward to working with

 

      everyone.  This will be a very interesting two days

 

      and I see it as an important step in what will be a

 

      continuing series of discussions and activities and

 

      recommendations that we will need to work on with

 

      the FDA.  With that, the first presentation and

 

      discussion this morning will be by Ajaz Hussain,

 

      and we will begin by digging in to establishing

 

      drug release and dissolution specifications.  Ajaz,

 

      please?

 

                Establishing Drug Release or Dissolution

 

                   Specifications Topic Introduction

 

                DR. HUSSAIN:  Thank you, Dr. Cooney.  I

 

      think topic one is entitled quality by design

 

      approach for quality control and assurance of

 

      dissolution rate.  In the background packet, as

 

      well as in the presentations, I have tried to keep

 

      the terminology dissolution rate all along to

 

      illustrate the one challenge which we will not be

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      discussing today, and that is the metrics for

 

      dissolution rate itself.  We express dissolution

 

      rate as a Q factor which tends to be confounded

 

      with the variability of the assay itself.  So, that

 

      is not the topic for discussion today but I just

 

      wanted to alert you on why the word "rate" keeps

 

      coming back and back again.  So.

 

                Topic one:  Our goal is to seek your

 

      recommendations and endorsement of the proposed

 

      regulatory tactical plan.  With this tactical plan

 

      we hope to start moving towards putting together a

 

      set of regulatory tools and policies that will help

 

      us define elements and details of the elements

 

      necessary to realize the goals of quality by

 

      design.

 

                The question that we are posing to you is

 

      are the tactical steps outlined consistent with the

 

      goals that we have shared with you?  What initial

 

      steps and/or changes would you recommend to improve

 

      this plan?  What additional scientific evidence do

 

      you feel would be necessary to support the

 

      development and implementation of this plan? 

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      General considerations for identifying and

 

      developing statistical procedures and, in

 

      particular, I want to emphasize for this discussion

 

      today that we have left out a discussion on

 

      statistical procedures because our experience has

 

      been that if we start with that as a topic it leads

 

      to protracted debate, and you will hear one report

 

      on that debate from Bob O'Neill tomorrow, the

 

      debate on parametric tolerance interval that has

 

      been going on for years and hasn't come to any

 

      resolution.  We feel that if you approach it from

 

      scientific foundations first, statistics is simply

 

      a tool to implement the scientific decision

 

      framework.  So, that is the reason we have kept

 

      that out of discussion for today.  Clearly, we are

 

      seeking your specific recommendations and other

 

      recommendations that you may have including how we

 

      should prioritize our work to develop this tactical

 

      plan to a full proposal, which we hope to bring to

 

      you at a subsequent meeting.

 

                What are the proposed steps?  The proposed

 

      steps are to develop an alternate regulatory

                                                                21

 

      approach to demonstrate the suitability of

 

      dissolution measurements system; introduce and

 

      utilize the concept of reproducibility and

 

      repeatability study using the actual pharmaceutical

 

      product for which we set specification.  Here, the

 

      proposal is to consider using the pivotal clinical

 

      lot or the bio. lot as a basis for identifying how

 

      sensitive, or lack of it, it is to a dissolution

 

      test method and estimate the variability in the

 

      method and, therefore, of the product.

 

                So, the first two steps are sort of

 

      together.  But the next three steps are also sort

 

      of in one clump.  We want to move towards a

 

      system-based decision tree for establishing

 

      dissolution rate specification.  Within that

 

      framework I think we would like to utilize

 

      opportunities to utilize the PAT approach for

 

      controlling dissolution rate and development of

 

      real-time quality assurance strategies.  Also, a

 

      decision tree for design-based concepts articulated

 

      in the draft ICH Q8 guideline, which is in your

 

      background packet.

 

                So, those are the decision trees which we

 

      would like to develop.  At the same time, when we

 

      come back with the full proposal to you, we would

                                                                22

 

      like to bring to you a side-by-side comparison of

 

      new and generic drugs because we think this is an

 

      opportunity for both sides, and some of the

 

      frustrations the generic industry feels can be

 

      addressed with this proposal, and I will explain

 

      that towards the end of the day, and explain why

 

      the level of quality assurance or quality control

 

      confidence in the proposed approach will be higher

 

      than what is achieved in the current system.  There

 

      is no doubt in my mind but, clearly, you have to

 

      agree with that.

 

                We also seek today your recommendations on

 

      how we should approach the statistical aspect of

 

      this and then what will help you to discuss this

 

      proposal when it comes to you.  So please give us

 

      your recommendations on how we should prepare a

 

      detailed proposal for a subsequent ACPS meeting.

 

                The other step that I think is important

 

      and is very timely, because this Friday or this

                                                                23

 

      Saturday I leave for Brussels for our ICH meeting,

 

      is that we do intend to seek the discussion here,

 

      and utilize the discussion here, to seek

 

      harmonization of the approach we are proposing

 

      under the ICH, especially the ICH Q8 Part 2, and we

 

      will start developing that guideline in Brussels

 

      next week.

 

                ICH Q8 draft guideline essentially brought

 

      a basis for getting and considering pharmaceutical

 

      development information in a structured way for

 

      pharmaceutical decision-making in the CMC arena at

 

      FDA.  The guideline was constructed with this

 

      figure, on your right, in mind.  You have to focus

 

      your design efforts on the intended use of the

 

      product, the patient population and so forth, that

 

      leads to a product design and that product design

 

      dictates the design specification, which are

 

      customer requirements, and these requirements, some

 

      of them if they are critical, become regulatory

 

      specifications.  Then the product design and design

 

      specification dictates or leads to design of a

 

      manufacturing process to reliably and predictably

                                                                24

 

      deliver those specifications back to deliver the

 

      intended use.

 

                In a systematic way, if you approach

 

      pharmaceutical development in a structured way, you

 

      get some benefit, we believe.  You achieve a higher

 

      degree of process understanding and give regulators

 

      high confidence of low risk of releasing a poor

 

      quality product; high efficiency through continuous

 

      learning and improvement.  And, I think it helps us

 

      to address some of the gaps we have in the current

 

      system.  I have tried to illustrate the current

 

      process within FDA and the manufacturing and R&D

 

      process within industry.  Research and development

 

      will develop the products, transfer them to

 

      manufacturing and then we have, by law, a separate

 

      quality unit to maintain quality assurance.  You

 

      have all the specification results and you have

 

      products which don't have all the specification

 

      results.

 

                In approaching and assessing the quality

 

      we bring a team approach, a multi-disciplinary team

 

      approach which includes pharmacology, toxicology,

                                                                25

 

      CMC review, clin. pharm., bio. pharm. review and

 

      the clinical assessment.  And the decision

 

      collectively is a risk-benefit decision that leads

 

      to an approval of a product.  The approved product

 

      is then transferred--it is called technology

 

      transfer--and the process is validated.

 

                The validation process includes

 

      qualification criteria and so forth, but there is

 

      an element of that which is process qualification.

 

      Process qualification is essentially, in my

 

      opinion, the interaction between materials and

 

      equipment and environment that you really have to

 

      study.  In the current state that essentially is

 

      judged on your ability to repeat it three times.

 

      Since the pharmaceutical development information is

 

      not available for CMC reviewers, the quality of

 

      that and the understanding containing that is not

 

      well understood in the regulatory sense.  So, we

 

      are losing an opportunity to make more rational

 

      decisions.

 

                Now, we have a divide, an organizational

 

      divide within the agency between, say, review and

                                                                26

 

      GMP inspection.  The cGMP process is helping

 

      bridge.  The PAT is an example of how we have

 

      bridged it.  Our experience or learning from the

 

      initiative clearly identified a need for a quality

 

      system orientation.  I would be wrong if I said

 

      that I really did not understand what this really

 

      meant or really didn't care about what quality

 

      system issues were because I was looking from

 

      several years ago.  But I think I have gained a

 

      much deeper understanding of the importance of the

 

      quality system orientation.

 

                So, here is a representation of that from

 

      a paper that we published on innovation and

 

      continuous improvement in pharmaceutical

 

      manufacturing.  Say what you do, do what you say,

 

      prove it and improve it are the elements that make

 

      up a quality system.  Consider the way what you do

 

      is your application to FDA.  So, that is a CMC

 

      review assessment process.  Now, do what you say

 

      can be considered as are you able to manufacture to

 

      the commitments that you have placed in your

 

      application?  Now, there is a gap since our

                                                                27

 

      reviewers don't have an idea that they really do

 

      what they say.  That is a GMP function so there is

 

      uncertainty there.  And prove it.  How do you prove

 

      it?  I think metrics for proving it could be

 

      process capability and the recalls, and this and

 

      that.  If you are unable to prove it you need to

 

      have a collective action and a preventive action.

 

                Our experience has suggested that in most

 

      cases root cause is unknown or a poor analyst is

 

      blamed.  So, we actually don't get to a root cause

 

      generally.  Does the current system support or

 

      facilitate getting to the root cause?  I think that

 

      is the question.  In many ways I think say what you

 

      do and do what you say, if you take that ratio is

 

      process understanding and your ability to prove.

 

      So, in many ways I think you have to think about

 

      that.

 

                Now, a modern quality system has a

 

      dimension of improvement, continuous improvement

 

      and innovation.  The dotted line simply says that

 

      is an option that should be available for industry

 

      to do.  It is dotted because that is not a

                                                                28

 

      requirement per se, but the rest are all

 

      requirements.  So, I think we are trying to address

 

      some of these gaps along the way.

 

                Now, the definition of continuous

 

      improvement is interesting and it really sets the

 

      stage for this discussion.  I have taken the

 

      definition from QS-9000 to illustrate the challenge

 

      we face for continuous improvement.  For those

 

      product characteristics and process parameters that

 

      can be validated using variable data, that is

 

      continuous data, continuous improvement means

 

      optimizing the characteristics and parameters at a

 

      target value and reducing variation around the

 

      target value.  So, in a sense, you need a target

 

      value and you need to have an estimate of variation

 

      to start thinking of continuous improvement.  In

 

      our specification setting often we don't even have

 

      a target value.  So.  And forget variation.  So.

 

                But the second bullet is more important.

 

      For those product characteristics and process

 

      parameters that can be only evaluated using

 

      attribute data, pass/fail, continuous improvement

                                                                29

 

      is not possible until characteristics are

 

      conforming.  If attribute data results do not equal

 

      zero defect it is by definition a non-conforming

 

      product.  Improvements made in these situations are

 

      by definition corrective actions, not continuous

 

      improvement.  And, we have clearly distinguished

 

      between corrective action, which is a risky

 

      scenario, and continuous improvement, which can be

 

      managed differently.

 

                Continuous improvement in processes that

 

      have demonstrated stability, acceptability,

 

      capability and performance--continuous improvement

 

      really is only possible for those products that

 

      have demonstrated stability.  Process validation

 

      today does not give us the assurance that the

 

      process is stable.  So, that is another element.

 

      Acceptable capability, we don't have an estimate of

 

      the capability value.

 

                Now, the reason for finding this out is

 

      that I think we don't use compendial methods as

 

      release specifications.  Actually, the compendium

 

      approach to specifications is right.  That is the

                                                                30

 

      way they should be.  There is nothing wrong with

 

      this specification criteria for the market

 

      standard.  It is perfectly all right.  But it is,

 

      as Janet Woodcock says in her paper, different from

 

      release specification and that is the

 

      distinguishing feature that I think is the problem

 

      here.  If you use market standard as release

 

      specification, then you have all the elements that

 

      hold back continuous improvement.  So, you really

 

      need to distinguish between standards and

 

      specifications.  Unfortunately, in the current

 

      paradigm specifications equals standard.  So, what

 

      we are moving towards is a control strategy that

 

      will allow you to have your market standard but

 

      then have a control philosophy that allows you a

 

      risk-based decision process.

 

                A recent proposal from USP I think is a

 

      step in the right direction.  It is essentially a

 

      similar proposal to the parametric tolerance

 

      interval test to take dissolution specification

 

      criteria towards more of a tolerance interval

 

      approach.  But as you will hear tomorrow from the

                                                                31

 

      parametric tolerance interval discussion, you

 

      cannot approach it as hypothesis testing for every

 

      product batch, and that is one of the discussions

 

      that we will have.  And, there are many challenges

 

      before we even can get to that, and that is a part

 

      of this discussion.  We believe one has to start

 

      with a pharmaceutical science discussion before

 

      developing appropriate statistical tools.

 

                One other challenge for continuous

 

      improvement is the mind set--and this is a major

 

      challenge not only within the U.S. but

 

      globally--that corrective actions is the only way

 

      to force improvement of quality on industry.  This

 

      is direct current paste from the paper that we

 

      issued.  Some would argue that corrective actions

 

      provide the necessary constancy of purpose for

 

      improvement, necessary since manufacturing is a

 

      stepchild of industry because the difference

 

      between cost of manufacturing and price of drugs is

 

      large.  Keeping the system of corrective action

 

      provides the leverage for ensuring improvement, to

 

      ensure the cGMP.

 

                That is a fundamental challenge.  How do

 

      we achieve that?  If you improve your manufacturing

 

      process by reducing variability your regulatory

                                                                32

 

      acceptance criteria will be narrow.  So, that takes

 

      things into a way for continuous improvement.  So,

 

      that is another challenge that we will start

 

      addressing.

 

                The argument has some validity but it is

 

      based on an assumption that current practices,

 

      including measurement systems and product

 

      specification, provide efficient means for

 

      identifying, understanding and then reducing

 

      variability.  For quality assurance in the 21st

 

      century we need a sound basis to verify such

 

      assumptions in the current system.

 

                To emphasize this point further, we

 

      discussed the case of dissolution and that is what

 

      we present to you today.  Let me illustrate an

 

      example, a real case example.  This is an example

 

      of an approved and validated manufacturing process

 

      at a major pharmaceutical company.  I will read the

 

      middle portion of this.  This is the warning

                                                                33

 

      letter:  There is no assurance that the production

 

      in process control procedures established--this is

 

      controlled-release product--to produce a product

 

      that has the quality it is purported to have or

 

      represented to possess.  How did we approve it?

 

      How was it validated?  So, this is after the fact.

 

      The duration of each coating cycle is determined by

 

      the pan operator but is based on visual

 

      determination that the coating solutions are evenly

 

      distributed before proceeding to the next step.  It

 

      is noted that literally 50 percent of the batches

 

      are thrown out every year because of dissolution

 

      failures, and then you have partial release

 

      occurring too.  Doesn't this undermine the entire

 

      credibility of our system?  And, this was

 

      catastrophic for the company.

 

                Now, inability to resolve our

 

      specification observations I think undermines the

 

      credibility of our decision system.  It raises

 

      questions of adequacy of the current decision

 

      system.  It increases the risk of releasing an

 

      unacceptable quality product to the consumer, and

                                                                34

 

      contributes to low efficiency.

 

                Now, corrective action, preventive

 

      action--there are some challenges.  There are

 

      difficult questions faced by manufacturing groups

 

      and regulators since we have a calibrated system

 

      that we use for dissolution and a calibrated system

 

      is a tablet similar to any other tablet that we

 

      use, and the quality is an issue there.  If you

 

      choose to use a calibrated tablet for gauge R&R

 

      study, reproducibility and repeatability study,

 

      what you see there is that the calibrator

 

      variability and its manufacturing process is

 

      confounded within that system.  I am not going to

 

      go through the equations but it is simple algebra.

 

                In addition, we have another challenge.

 

      The challenge is that the assumption of independent

 

      variable cannot be really verified because the

 

      hydrodynamics of the vessels are such--I see our

 

      colleagues from Health Canada here who have been

 

      criticizing this for a long time.  Thank you for

 

      coming, sir.  So, how representative is the

 

      suitability for that product is an issue.

 

                But the need for improvement is not

 

      limited.  We need to be confident of our analysis,

 

      of surveillance samples, consumer complaints, other

                                                                35

 

      investigations.  One of the frustrating jobs that I

 

      have is where we get consumer complaints; we do

 

      investigations; we do dissolution--no answers.  I

 

      mean, you really don't get to the root cause.

 

                I think the basic philosophy that Walter

 

      Shewhart sort of proclaimed years ago is very

 

      important.  Pure and applied science have gradually

 

      pushed further and further the requirements of

 

      accuracy and precision.  However, applied science,

 

      particularly in the mass production of

 

      interchangeable parts, is even more exacting than

 

      pure science in certain matters of accuracy and

 

      precision.  That is the basis of this discussion.

 

                Is the current approach to calibration

 

      adequate?  Dr. Cindy Buhse will share with you her

 

      challenges--as one of the premier labs, probably

 

      the world standard for dissolution at FDA and

 

      elsewhere, and Tom Layloff had started some of

 

      these processes and he is here too--dissolution

                                                                36

 

      testing of the USP wants to require diligent

 

      attention to details, mechanical and chemical.

 

      Dosage forms can respond definitely to small

 

      variations; large differences in dissolution

 

      results are possible unless all parameters are

 

      carefully controlled.  Differences in

 

      reproducibility can often be traced to improper

 

      mechanical calibration or degassing.  Much of that

 

      is mechanical.  When you only have suitability

 

      criteria just based on a tablet, it hides some of

 

      this variability.

 

                We had a rude awakening to this ourselves.

 

      This is really when I started realizing the

 

      confounding nature of the problem that we have.

 

      Just to illustrate how frustrating this experience

 

      was, our marines were contracting malaria when they

 

      were in Liberia and we were asked to see whether

 

      this was a quality problem.  We faced significant

 

      challenges in analysis because I had insisted that

 

      two labs would do this because this was a grave

 

      situation.  Unexpected inter-laboratory differences

 

      highlighted limitations of current calibration. 

                                                                37

 

      Here is just a quote from our DPA lab:  We are at a

 

      loss to explain the difference between DPA and the

 

      Philadelphia district office initial results.  Then

 

      we started tracing it back.  It had to be

 

      mechanical differences and degassing.

 

                Well, I think that is not the only issue.

 

      I think the bigger issue that we are confronted

 

      with is that we need to better understand the

 

      sources of variability in product performance and

 

      quality so as to establish the most appropriate

 

      design specifications for the product that support

 

      continuous improvement and address the increasing

 

      complexity of product designs.

 

                This is another concern.  We are moving

 

      towards drug eluting, towards nano materials,

 

      towards other complex devices and, yet, we don't

 

      have good measurement systems for these products.

 

      We want measurement systems for products intended

 

      for non-oral administration and non-oral drug

 

      delivery systems; develop and implement globally

 

      harmonized proactive regulatory decision system,

 

      including Q6A and Q8.

 

                I just want to sort of lay the foundation

 

      for other aspects that Mehul and Vibhakar will

 

      share with you.  Pharmaceutical development and

                                                                38

 

      dissolution specification without pharmaceutical

 

      development information creates more challenges.

 

      Decisions focus only on dissolution test data.

 

      Tests are often used for both in-process control

 

      and final product testing.  Decision

 

      characteristics focused only on the mean value will

 

      deal with variability indirectly.  Variability

 

      managed indirectly using "disconnecting test

 

      conditions" and acceptance criteria leads to

 

      deterministic interpretation of specifications and

 

      ignores background variability and, as Dr. Woodcock

 

      has said, we need to move towards a probabilistic

 

      decision system.  Specifications are standards and

 

      standards don't give any room for uncertainty or

 

      risk-based decisions.  If you don't meet the

 

      standards, you are off the market.  It is as simple

 

      as that.  So.  And you have event trees as opposed

 

      to decision trees.  It is difficult to resolve

 

      specification observations which could be related

                                                                39

 

      to how we set specifications, and post-approval

 

      changes and optimization in continuous improvement

 

      is difficult.

 

                This is simply an illustration of the gap

 

      that we base all of our decisions on test-to-test

 

      comparison, in vivo to in vitro, and there is an

 

      opportunity to use the design information to make

 

      rational decisions.  Just to illustrate this, again

 

      this is from Health Canada which has been very

 

      proactive and pushing this agenda and I am sorry we

 

      just didn't react more quickly--here is an

 

      illustration of the false-positive and

 

      false-negatives that you get.  The reference

 

      product dissolves 95 percent in 15 minutes, and the

 

      reference AUC, Cmax.  But if you look at product F,

 

      it dissolves very slowly in vitro but, yet, in vivo

 

      it meets the criteria--it is almost identical to

 

      that.

 

                So, there is a formulation attribute that

 

      does this.  For example, if you have a large amount

 

      of organic or insoluble excipient it is a

 

      hydrodynamic effect.  That doesn't happen in vivo. 

                                                                40

 

      The in vivo media, the surface tension, the

 

      hydrodynamics are completely different.  So, you

 

      tend to see this but you also get false-positives

 

      and false-negatives.  If I look at product C, it

 

      has only 62 percent dissolution compared to product

 

      F and has half the Cmax.

 

                There are other differences in how we

 

      approach specification setting.  The difference

 

      between the U.S. and Japan--we included a paper of

 

      the Japanese perspective on this in your background

 

      packet.  Because of the new restrictions I took the

 

      names off.  I had to go back and erase those.  This

 

      is a published paper so I was surprised that I

 

      needed to take the names off.

 

                The point here is this, all are basic

 

      drugs and this is a rule of thumb that has been

 

      known for 30 years, if you have a drug with PK

 

      between 4-6 the best media to illustrate in vivo

 

      performance is that of the PK value.  That is where

 

      the dissolution is slower.  So, the Japanese have

 

      been in that direction.  All our specifications use

 

      0.1 normal, here.  Is that important?  Well, the

                                                                41

 

      Japanese think so because they are very concerned

 

      with hypoacidity in the subjects.  If I really look

 

      at it, with antacids and H2 blockers most of us are

 

      hypoacidic too.  So, is this a gap that we need to

 

      fill is the question that I think we will address

 

      as we go along.  So, you can see the dramatic

 

      difference in dissolution as pH 1.2 to pH 7.2 and

 

      the resulting blood levels.

 

                So, in a sense, the opportunity we are

 

      trying to realize is ICH Q6A actually had it quite

 

      nicely captured in this quote:  The quality of a

 

      drug substance and drug product is determined by

 

      the design development, in-process controls, GMP

 

      controls, process validation and by specifications

 

      applied throughout development and manufacture.

 

      So, you have the goal; you have the decision

 

      characteristics; and you have the life cycle.  The

 

      design development was the missing element in our

 

      decision characteristics.  Now we have an

 

      opportunity to use it more effectively.

 

                This is how ICH Q8 captured that

 

      opportunity, to bring the development and design

                                                                42

 

      information not only to ask the right question but

 

      also to realize the opportunities of flexibility

 

      that might bring.  So, design and development

 

      should impact positively on how we set

 

      specifications in process controls and have more

 

      confidence in process validation and GMP controls.

 

                With that as a background and the reason

 

      for this topic for discussion, in many ways the

 

      tactical plan is an attempt now to go back ten

 

      years and to see how we can do better with our new

 

      information that could come through the PAT process

 

      and the ICH Q8 process.  In many ways we are

 

      reexamining the SUPAC guideline, the dissolution

 

      guideline for '97, the biopharmaceutics

 

      classification assumed in ICH Q6A.  The vector for

 

      the desired state is that we are adding another

 

      layer of variability assessment, identification

 

      assessment and utilization of variability in our

 

      decision-making.  So, the basic fundamental is that

 

      the quality of decisions can only be better so the

 

      current system is the minimum level of quality that

 

      we achieve.

 

                So, for the discussion today Cindy Buhse

 

      will share with you her proposal on measurement

 

      system, how mechanical calibration will be better

                                                                43

 

      and that is what we want to use.  Mehul Mehta will

 

      share with you the general overview of our decision

 

      process in our guidances.  Lawrence Yu is one of

 

      the leading experts I think in sort of modeling

 

      dissolution and in vivo absorption.  So, I have

 

      asked him to share a perspective on the current

 

      state of science.  Then I will come back and

 

      outline the steps of the proposal.  I have a number

 

      of slides in your packet but I will not be using

 

      those slides.  I will be using only the first 16

 

      slides to give you ample opportunity for

 

      discussion.  Those are backup slides.  If there are

 

      questions I will come back to them.

 

                In your background packet I specifically

 

      identified one person by name for his

 

      contributions, and that is Dr. Vinotcha [ph.].  I

 

      think the work he has done in particular--the

 

      reason I am pointing him out today is because he

 

      has decided to retire and I want to recognize his

                                                                44

 

      contribution to dissolution.  He has brought it to

 

      this level and I think taking it beyond that, and I

 

      thank him for that and he is here today.  A number

 

      of people are there from DPA who are experts in

 

      this and I will recognize them at some other point.

 

                With that, I will stop and invite Cindy to

 

      share her thoughts with you.  Any questions before

 

      I leave?

 

                DR. COONEY:  Thank you, Ajaz.  We will

 

      certainly have time for extensive discussion later

 

      but I think, particularly since we are right on

 

      schedule, if anyone has any questions for Ajaz

 

      right now, particularly for clarification of any of

 

      the points he has made, this would be a very

 

      appropriate time to take a moment for this.  Ken?

 

                DR. MORRIS:  Yes, just one quick point on

 

      an early slide where you were talking about the

 

      development process, it actually goes from the

 

      intended use through to development.  I would just

 

      say for clarification, because this is something

 

      that I get quite a lot, what we really want to get

 

      across I think is the idea that when you have the

                                                                45

 

      intended use and the characteristics you really

 

      select your process first.

 

                DR. HUSSAIN:  Yes.

 

                DR. MORRIS:  And then come back to the

 

      formulation.  So, it doesn't necessarily change the

 

      order but it adds a level because that is a

 

      constant source of confusion, particularly when you

 

      are talking about building in dissolution

 

      characteristics.

 

                    Dissolution Measurement System:

 

            Current State and Opportunities for Improvement

 

                DR. BUHSE:  Thank you, Ajaz.  It is going

 

      to be my job to tell everybody a little bit about

 

      dissolution.  Some of you, I know, are very

 

      familiar with it but some of you may never have

 

      experienced it or seen it done and it is kind of a

 

      very different way of testing so I am going to show

 

      you a little bit about the different apparatus you

 

      can choose to do dissolution testing; talk a little

 

      bit about how we currently determine instrument

 

      suitability in terms of calibration, both

 

      mechanical and chemical; and also validation of

                                                                46

 

      dissolution of test methods and what we typically

 

      see in our lab when we take a look at method

 

      validation packages.  Then I am going to show you

 

      some sources of variability within dissolution,

 

      show you examples of how some formulations are

 

      sensitive to some parameters and some formulations

 

      are sensitive to others and we really need to

 

      understand for your particular formulation where

 

      your sources of variability are coming from.  Then

 

      I will just briefly talk about some opportunities

 

      for improvement, many of which Ajaz already alluded

 

      to in his talk.

 

                If you go to USP, there are seven

 

      different dissolution apparatus listed.  They are

 

      all up here.  You can see that the ones I am going

 

      to talk about today mostly are apparatus 1 and 2

 

      because those are the two that are used the most by

 

      most pharmaceutical companies.  We do see some of

 

      the other apparatus occasionally.  Apparatus 3,

 

      reciprocating cylinder, can also be set up for

 

      apparatus 7 so those are actually the same piece of

 

      equipment.  The flow-through cell is used more in

                                                                47

 

      Europe than it is in the United States.  We don't

 

      see much with that here.  Then, apparatus 5 and 6

 

      are used for transdermal delivery systems and they

 

      are actually a modification of apparatus 1 and 2.

 

                What I am going to talk about most today

 

      is apparatus 1 and 2, which is actually the same

 

      piece of equipment and what you are doing is you

 

      are changing the shaft on the different vessels to

 

      change it from apparatus 1 to apparatus 2.

 

      Actually shown in the picture there is apparatus 2

 

      and you can see there are paddles above each one of

 

      the about 900 ml vessels there.  The way

 

      dissolution works is that you are actually testing

 

      6 tablets at once.  I think Ajaz showed that in the

 

      specifications there usually is a specification

 

      which says 6 tablets have to have a certain

 

      dissolution value and if one of those 6 fails you

 

      go to 12 tablets and then you go to 24.  So, you

 

      start with just 6 and if everything goes right,

 

      then you will be done after the 6 tablets.

 

                So, you essentially have 6 different

 

      pieces of apparatus here because each one of those

                                                                48

 

      vessels acts independently.  You would fill each

 

      one with whatever media it is that you want to test

 

      in, whether it is 0.1 normal HCL or water or

 

      simulated intestinal fluid.  There are all sorts of

 

      ranges of media that people use.  So, you put

 

      500-900 ml in these vessels and then for apparatus

 

      2 you just lower the paddle down and start it going

 

      at whatever rpm you decide.  Certainly, that is

 

      another variable you can manipulate.  Then you drop

 

      your tablet or capsule in and then you take a

 

      sample out of the media at whatever time point your

 

      specification is.  If your specification may be 80

 

      percent dissolved after an hour, then after an hour

 

      you would withdraw a small portion of the media and

 

      then you would determine how much the drug has

 

      dissolved.  Usually the determinative step there is

 

      HPLC.  So, you do that for all 6 of these vessels

 

      and then, hopefully, everything dissolves in the

 

      right amount of time and you will be done.

 

                the basket--similar.  You just change the

 

      shaft and you put a basket on and you actually put

 

      the drug in the basket and then you lower the

                                                                49

 

      basket and start it spinning and you go through the

 

      same procedure.

 

                Just so you can see what it looks like,

 

      this shows you what apparatus 3 looks like, which

 

      you can also turn into apparatus 7 by changing the

 

      holders.  You actually would put the tablet or

 

      capsule inside each one of those up at the top.

 

      What it does, it comes up and down inside each one

 

      of these little vessels down at the bottom.  What

 

      you can do with this apparatus is you can change

 

      the media so in every row you can put a different

 

      medium if you want.  So, if you want to start your

 

      capsule dissolving at 0.1 normal HCL and move it to

 

      simulated intestinal fluid, in the first row you

 

      could put acid.  In the next row you could put

 

      intestinal fluid.  In the next row you could put

 

      whatever you want.  Then you can move this

 

      apparatus up, you know make it go up and down for

 

      an hour in one and then move to the next and go up

 

      and down.  So, that is how you could do it with

 

      apparatus 3.

 

                This is apparatus 4, and I think I

                                                                50

 

      mentioned we don't see a lot of this one.  This is

 

      a flow-through cell.  You can see over there, on

 

      the far side, that is what the actual cell looks

 

      like.  So, if you had a capsule or tablet that

 

      didn't completely disintegrate you could put it in

 

      this cell and actually flow through, somewhat like

 

      actually happens in humans--flow through a media

 

      and change it as you go.  You can either recycle it

 

      around or you can actually have a one pass through

 

      media as well and then analyze the media as it is

 

      coming out to see how much drug is dissolved.  For

 

      this one there is also a bunch of different cells,

 

      different geometries that you could put in this.  I

 

      kind of show examples of that there.

 

                Most of what I am going to talk about

 

      today is apparatus 1 and 2, and that is because

 

      that is the majority of what we see in methods that

 

      are given to us for method validation.  When they

 

      use apparatus 1 or 2 they use the USP criteria for

 

      setting up the equipment and for calibrating the

 

      equipment, and I will go over what those parameters

 

      are.  Then, as I think Ajaz said, most tablets and

                                                                51

 

      capsules have a one point acceptance criteria.  For

 

      immediate-release products we see anywhere from 2

 

      to 4 time points, maybe 1 hour, 4 hours, 8 hours,

 

      24 hours depending on the product.

 

                The first thing you are going to do if you

 

      have one of these apparatus, you are going to run a

 

      test method.  You need to ensure that you have

 

      instrument suitability.  The first point I have up

 

      there is which one of these 7 instruments you are

 

      going to use.  What we find is that most people use

 

      1 and 2.  Most people believe that that is what the

 

      FDA wants to see.  I have been to many different

 

      dissolution conferences and, you know, consultants

 

      and companies will get up there and say if at all

 

      possible use apparatus 1 or 2 because that is what

 

      the FDA wants.  I have heard many people say that

 

      so a lot of people try to use 1 and 2.

 

                Then, once you have chosen your

 

      instrument, you need to make sure it is set up

 

      properly for mechanical calibration.  You can see

 

      by the picture that if your shaft is not quite

 

      centered, or if your vessel is not quite seated

                                                                52

 

      right, your rpm aren't calibrated, etc., you can

 

      imagine that you can get different hydrodynamics

 

      from vessel to vessel or from time to time.  You

 

      need to really carefully make sure that everything

 

      is set up properly.  Then, once you have everything

 

      set up properly, you can then run a calibrator

 

      tablet provided by the USP to see if you get within

 

      the range that the calibrator tablet says you

 

      should get.  Then that gives you some measure of

 

      confidence that perhaps you have set this thing up

 

      properly with mechanical calibration.  I think Ajaz

 

      has mentioned that the calibrator tablets actually

 

      are U.S. phenomena and they are not used either in

 

      the European or Japanese pharmacopeias.

 

                Once you have instruments all set up, then

 

      you can certainly do method development/method

 

      validation, and I will talk a little bit about what

 

      we see and what is actually given to us, as the

 

      agency, when it comes to validating the dissolution

 

      method.

 

                Here is an example of some of the

 

      mechanical calibration parameters out of the USP. 

                                                                53

 

      Some of them have specific values.  For instance,

 

      the shaft has to be 2 mm from the centerline, which

 

      means you actually have a 4 mm spread because you

 

      can have one direction and then it spins around to

 

      the other.  You can see there are other parameters

 

      which don't really have any hard numbers associated

 

      with them, such as the wobble--no significant

 

      wobble and that is kind of nebulous there, or no

 

      significant vibration.  So, those are the some of

 

      the USP criteria for setting up the basket and

 

      paddle methods.

 

                The actual calibrator tablets--actually,

 

      our lab in St. Louis had a lot to do with

 

      calibrator tablets coming into being.  It is

 

      certainly the current 10 mg one that is used today.

 

      But they came around in the 1970s and there are two

 

      different calibrator tablets.  One is

 

      disintegrating and one is non-disintegrating.  So,

 

      one pretty much falls apart when it goes into the

 

      dissolution apparatus; the other stays together as

 

      a tablet throughout the calibration procedure.

 

                In 1997 a 50 mg prednisone tablet, the

                                                                54

 

      disintegrating one, was replaced with a 10 mg

 

      tablet which was manufactured at the University of

 

      Maryland, here, and was based on the formulation of

 

      a product that our lab had found was sensitive to a

 

      lot of the parameters of calibration, including

 

      degassing and mechanical calibration, so we thought

 

      it would be a good calibrator tablet.

 

                Actually, last year the working group at

 

      the USP was actually looking for a replacement for

 

      the 10 mg tablet.  It does have quite a bit of

 

      variability associated with it and some stability

 

      issues so they would like to see if they can find

 

      something else.

 

                So, if you are actually calibrating your

 

      apparatus what you would do, if you use your

 

      equipment for both basket and paddle which is what

 

      we do in our lab--a lot of pharmaceutical companies

 

      will have one that will always stay paddle and

 

      another will always stay basket but we go back and

 

      forth.  If you are using the same instrument for

 

      both paddle and basket, what you would do is you

 

      would do 4 different calibration runs.  You would

                                                                55

 

      do both calibrators with the paddle installed and

 

      then you would turn around and do both calibrators

 

      with the basket installed to make sure that your

 

      instrument is set up properly.

 

                How often do you do these?  In our lab we

 

      do it every 6 months.  We do the calibration using

 

      the prednisone 10 mg tablet.  Here is the actual

 

      data on the current lots of calibrator tablets.

 

      The O lot, which has been in effect now for almost

 

      two years I think--you can see there are different

 

      dissolution criteria depending on whether you are

 

      running it in the basket or the paddle method.  You

 

      see there is a fairly wide range.  You can see that

 

      for the basket as long as you are anywhere between

 

      53-77 percent for each vessel you are going to pass

 

      calibration.  So, you have your 6 vessels and this

 

      one, over here, can be 53 and this one, over here,

 

      could be 77 but you are still going to pass

 

      calibration.  Actually, late last year they changed

 

      the ranges of the prednisone tablet because there

 

      were stability issues and a lot of failures in the

 

      market, and you can see that the range is even

                                                                56

 

      wider now, 51-81 percent.

 

                I have also included up there the values

 

      we get in our lab for at least the prednisone

 

      tablet.  For the basket method we get 72.6.  You

 

      can see we run very much on the high end of that

 

      range.  In fact, we do quite often fall out on the

 

      high end.  You can see we tend to run on the low

 

      end of the range on the paddle method for these

 

      calibrator tablets.

 

                The salicylic acid tablet has a much

 

      narrower range.  It is also much less sensitive to

 

      many of the parameters that you set for dissolution

 

      testing so it is not sensitive to degassing; it is

 

      not sensitive to mechanical calibration setup.

 

                The problem often with running these

 

      calibrator tablets is if you do get an out of

 

      specification value, then what do you do?  You

 

      check your mechanical calibration.  It can be

 

      difficult to decide whether the issue is the actual

 

      calibrator tablet itself or the issue is some way

 

      that you set up the instrumentation.

 

                The other problem with the calibrator

                                                                57

 

      tablet is that you can see it has a fairly wide

 

      range.  It can often interfere with a continuous

 

      improvement process.  If your vessels can be

 

      anywhere from 51-81 percent and you are still

 

      passing, what does that say when you are running

 

      your own product and you want to try to narrow down

 

      the variability of your product?  You don't have

 

      much room here I guess to try to keep everything

 

      consistent.

 

                I am going to talk just a little bit about

 

      development and validation.  We don't see a lot of

 

      development data but we do see the validation data

 

      in our lab.  Obviously, when you are developing a

 

      dissolution method you have to decide about all

 

      these different parameters, a lot of which I have

 

      alluded to, and you want to develop a method that

 

      is going to be discriminatory.  You want to be able

 

      to tell between good product and bad product.  You

 

      want the method to be repeatable.  You would like

 

      the method to give you the same results no matter

 

      which lab you are running it in.  I think Ajaz said

 

      we had some trouble with the malaria drug in trying

                                                                58

 

      to get two different labs get the same results.

 

      You have to decide which instrument to use.  Like I

 

      said, most people try to pick 1 and 2 if at all

 

      possible; then what media to run it in.  A lot of

 

      the test methods we get either are in 0.1 normal or

 

      HCL; a lot of them are just plain water.  Then you

 

      have to decide whether degassing is going to be

 

      important or not for your product; and decide

 

      whether or not you need sinkers.  Some products

 

      don't automatically go to the bottom of the vessel

 

      if you are using the paddle method.  You can buy

 

      commercial sinkers, which are these little devices

 

      that you put the tablet in that will actually make

 

      it fall to the bottom, or you can just wrap a wire

 

      around, which is what is in the USP, to make it go

 

      down to the bottom.

 

                Once you have decided all these

 

      parameters, you still need a determinative step,

 

      and that is what the main focus of validation is

 

      for most companies.  So, when we get validation

 

      packages in from companies on their dissolution

 

      test methods, their validation really focuses on

                                                                59

 

      the determinative step.  They do a lot of work on

 

      varying the parameters on the HPLC method but less

 

      data do we see on varying the parameters on the

 

      actual dissolution method.  So, we see more on the

 

      determinative step and less on the actual

 

      parameters that are associated with the dissolution

 

      apparatus.

 

                You can see that there are a lot of places

 

      here where variability can be introduced, and

 

      certainly when developing a product if you want to

 

      have a test method that is going to allow you to

 

      continuously improve your product you really need

 

      to understand what all the sources of variability

 

      are going to be.

 

                This is one of Ajaz's slides.  I think he

 

      showed a similar one earlier which is basically a

 

      slide just to show you that the total variability

 

      you are going to see in any test method is going to

 

      be the variability that is inherent to your product

 

      and your manufacturing process and the variability

 

      that is inherent to your test method.  For

 

      dissolution the variability inherent to the test

                                                                60

 

      method can be quite large, especially if you don't

 

      understand how all the different parameters can

 

      affect your product.

 

                I am going to just show some examples of

 

      some of the variability.  You can see I have a lot

 

      of information up on this slide, and every single

 

      one of these bullets can be a source of variability

 

      when running a dissolution test method.  You have

 

      to make sure your operators are well trained.  You

 

      have to make sure you have set things up properly.

 

      You have to make sure that you understand how all

 

      the different media and equipment parameters,

 

      sinkers etc., can affect the variability of your

 

      specific product.  So, there are a lot of places in

 

      here where, you know, if you add a tenth or so, or

 

      a percent or two of variability by the end you have

 

      quite a wide range of potential dissolution

 

      parameters you could get even with the same lot of

 

      material.

 

                When it comes to mechanical calibration, I

 

      think I showed some of the USP parameters earlier

 

      and what I want to show you here is actually that

                                                                61

 

      in our lab, DPA, we use more stringent mechanical

 

      calibration than what is listed in the USP.  A lot

 

      of the criteria we use come directly out of the

 

      PhARMA recommendation.  I think that paper is in

 

      your packet.  It came out in the '90s, where they

 

      did a collaborative study to take a look at

 

      mechanical calibration a little more closely to see

 

      if tighter mechanical calibration might reduce

 

      variability when running the calibrator tablet.

 

                Because we run so many products in our lab

 

      and we don't necessarily have the time to stop and

 

      see if this product is really sensitive to

 

      centering or not, etc., we just try to be very

 

      careful about how we set up our equipment.  Some

 

      tools are now available to very easily set these

 

      parameters much tighter than what is currently in

 

      the USP.  So, you can see that for quite a few of

 

      these we are tighter, and for others we have added

 

      criteria that are not actually in the USP as

 

      specific numbers.  For instance for shaft wobble

 

      and vibration, we actually measure those and set

 

      criteria for those.

 

                Degassing is one of the things I think

 

      that really got us into trouble--I don't want to

 

      use that word, but with the malaria drug the

                                                                62

 

      different labs were degassing in different ways and

 

      this drug happened to be very sensitive to

 

      degassing.  So, typically in the past the way you

 

      decided whether your media was well degassed or not

 

      is that you ran the calibrator tablet.  The 10 mg

 

      prednisone is very sensitive to dissolved gasses in

 

      the media so if you weren't sure if you were

 

      degassed or not you could just run that calibrator

 

      tablet to see if you were in range and then decide

 

      if you were degassed properly.

 

                Well, it turns out that there is some

 

      equipment on the market that you can use to

 

      actually measure dissolved gasses so this is

 

      something we have done recently in our lab.  We

 

      have taken this meter, which is actually used in

 

      other industries and not in the pharmaceutical

 

      industry, and used it to try to determine how much

 

      dissolved gases are left after using different

 

      degassing techniques.

 

                There are many different ways in which

 

      people degas their media.  The reason you need to

 

      degas your media is because there are some products

 

      that if you take a vessel and you drop in a tablet

 

      or capsule, what will happen is you have gases in

 

      the media.  The bubbles will form around this

                                                                63

 

      tablet or capsule and oftentimes will prevent it

 

      from dissoluting.  So, you actually need to get the

 

      gases out of there before you start.

 

                Here is a little graph of the different

 

      ways people degas and the results we got with the

 

      total gas meter, measuring both total gas and

 

      oxygen.  You can see that for the first bar over

 

      there that is obviously atmospheric pressure and

 

      atmospheric oxygen in the media.  These are all

 

      done in just plain water.  The next bar is the way

 

      we degas at DPA, which is point of vacuum at less

 

      than 150 ml of mercury with agitation, and you can

 

      see we get rid of about a little more than half of

 

      the total dissolved gases and quite a bit of the

 

      oxygen.

 

                The USP method is also very good.  There

                                                                64

 

      you are heating up to about 41 degrees and

 

      aspirating to remove the dissolved gases.  They

 

      also get half the total gone and about half the

 

      oxygen.

 

                Some people actually helium sparge and you

 

      can see helium sparging and although you do reduce

 

      the oxygen significantly you do not reduce the

 

      total dissolved gases.

 

                So, does this matter or not matter?  You

 

      know, this all depends on the product you are

 

      testing.  So, I just want to show you some examples

 

      here.  These are 3 different products, called

 

      product 1, 2 and 3 so I don't give any product

 

      names.  You can see that for product 1 and product

 

      2 there is a huge difference between non-degassing

 

      and degassing.  For both of those graphs I have

 

      shown two different ways of degassing.  One is the

 

      USP and DPA method, both of which give similar

 

      results.  The other is helium sparging.  You can

 

      see in both cases that the helium sparging does

 

      give slightly higher results than either the USP or

 

      the DPA method.  Certainly, for product 2 helium

                                                                65

 

      sparging gives much more variable results than the

 

      DPA degassing.  You can see that on the helium

 

      sparging line which is kind of the green-yellow

 

      one.

 

                You can see that product 3 doesn't really

 

      care whether you degas or not.  One of those lines

 

      is non-degassed and one is the DPA method which had

 

      the lowest percent of dissolved gases.  You can see

 

      that you get essentially very similar dissolution

 

      whether you degas or not.

 

                Larger than just degassing is the actual

 

      composition of the media.  I think as Ajaz

 

      mentioned, Japan is looking at what type of media

 

      you actually want to be using.  We see a lot of

 

      acid here and some buffers.  Here is a product and

 

      the dissolution method is pH 7.2.  So, 7.2, as you

 

      can see on your left I guess, is the media that is

 

      used in this product.  It also turns out that with

 

      these 6 different tablets there is some variability

 

      between the 6 but they all passed the dissolution

 

      specification for this particular product.

 

                This is a product where we wanted to take

                                                                66

 

      a look at some lower pHs just because there are

 

      some patients who happen to use this drug who may

 

      have lower intestinal pH than 7.2 and so we went

 

      down to 6.8 and, lo and behold, every single tablet

 

      looked different to us and no two tablets were the

 

      same.  We repeated this over and over again, trying

 

      to figure out what is going on.  You can actually

 

      do a lot with dissolution by just watching your

 

      product.  There is nothing like the human eye

 

      sometimes.

 

                If you watch this product in the vessel

 

      what you will see is that it sits there and does

 

      not dissolve and you get no dissolution until you

 

      see the coating split open.  Once the coating

 

      splits open, then it dissolves fairly quickly.  So,

 

      taking a look at that we were trying to figure out

 

      what could be the sources of variability of this

 

      product.  Is it the way we are handling it when we

 

      put it into the dissolution vessel?  Are we

 

      damaging the coating in some way?  Are these tablet

 

      differences real or is this the manufacturing

 

      process itself?  Do we have instrument variation? 

                                                                67

 

      These 6 tablets are in 6 different vessels so is

 

      there some difference in these vessels where maybe

 

      we have improper calibration or something?

 

                Well, after much investigation, what we

 

      found is that this is actually a product problem.

 

      If you cut open these tablets and take a look at

 

      the coating, not all of them have uniform coating.

 

      You can see there, on the left, one of the tablets

 

      that has a very uniform coating thickness.  Then

 

      every once in a while you ran across a tablet that

 

      had a void between the drug and the coating.  The

 

      drug is actually on the left side here; it is kind

 

      of the yellow sparkly stuff and the red is the

 

      coating.  So, some of the tablets had very uniform

 

      coating; some of the tablets had defects.  These

 

      defects were dissolving much faster or were

 

      breaking open, splitting open much faster than the

 

      ones that didn't have defects.  This is a situation

 

      where perhaps dissolution could help this

 

      manufacturer make a more consistent product if they

 

      were doing their dissolution at a slightly

 

      different pH or doing a dissolution test method at

                                                                68

 

      several different pHs to try to make sure they were

 

      making a consistent product.

 

                I was just going to mention sinkers

 

      because I talked about them and also because they

 

      do make a big difference.  The graph up there

 

      actually has nothing to do with the sinkers but it

 

      shows you what happens if you don't get your tablet

 

      at the center of your vessel.  The bottom blue line

 

      is product 1, right down at the bottom of the

 

      vessel, centered completely.  The green-yellow line

 

      is if it is off center by 1 cm.  So, if it is just

 

      off center by a centimeter you can see that it

 

      dissolves much faster.  There are different

 

      hydrodynamics in that area than at the bottom of

 

      the vessel.  So, if you have a tablet that is

 

      fairly light and is not going to stay put, then

 

      often you will put it inside a sinker.

 

                Traditionally, in our lab we have used the

 

      sinker at the top to the right.  That is the one

 

      that we have used in our lab.  It is very easy to

 

      use.  It has a spring load and you just pull back

 

      the spring and drop the capsule or tablet in and it

                                                                69

 

      is, you know, very convenient I guess.  The USP

 

      method is to use a wire and wrap the wire three

 

      times around the tablet or capsule.

 

                Well, we did run across a product--this is

 

      what I talked about, that you have to understand

 

      your product and how it reacts to different

 

      variables--that was sensitive to this actual

 

      commercial sinker.  This is the product we tested

 

      and with the commercial sinker that I just showed

 

      you it failed dissolution.  The specification here

 

      was 80 percent at 30 minutes and you can see that

 

      all 6 tablets failed.  Of course, we thought the

 

      product was perhaps a failure but it actually

 

      turned out that if you visually looked at what was

 

      going on, the product was being trapped.  It was

 

      swelling up and getting trapped inside that

 

      commercial sinker and so it could not essentially

 

      dissolve.

 

                We went back to the USP method with three

 

      wire turns around the tablet, and you can see that

 

      the product passes wonderfully with no problems

 

      whatsoever.  So, we no longer use commercial

                                                                70

 

      sinkers in our lab but a lot of people use them so

 

      I just wanted to make you aware of the fact that

 

      something as simple as a sinker can affect the

 

      individual product that you are looking at.

 

                So, what I have tried to show you is just

 

      some data that illustrates the fact that different

 

      products are sensitive to different parameters when

 

      you are doing dissolution, and there are obviously

 

      a lot of places where you can introduce variability

 

      in your test method.  What we would like to propose

 

      is an alternate approach to calibration and

 

      validation which includes complete understanding of

 

      how dissolution and the measurement system in your

 

      product specific variables affect variability, and

 

      try and understand the relationship between your

 

      product properties and your dissolution results.

 

      This includes understanding the dissolution

 

      apparatus that you are using, why you are choosing

 

      it and why you are choosing the media you are

 

      choosing, and determine, hopefully, the best method

 

      to give you opportunities for improvement and to

 

      ensure that the quality of your product is good.

 

                You can see that because of the way

 

      dissolution is currently set up there are a lot of

 

      things you have to control, and perhaps there are

                                                                71

 

      new approaches we can also use to get the same type

 

      of information that might have inherently less

 

      variability.  Then, obviously, a part of this whole

 

      process needs to be communication and training.  If

 

      people are out there saying that FDA wants us to

 

      use apparatus 1 and 2, then that is what people are

 

      going to do.  So, the FDA is trained in a more

 

      open-minded look at other things.  If people feel

 

      that way at least, then they might be willing to

 

      look at other approaches.

 

                When it comes to alternative approaches to

 

      dissolution calibration validation, I think as I

 

      told you in our lab we do more stringent mechanical

 

      calibration because some products are very

 

      sensitive to how the apparatus is set up and,

 

      certainly, if you set it up properly your

 

      variability will be less than the variability of

 

      the calibrator tablet.  Certainly, when you are

 

      using your specific product itself, you need to ID

                                                                72

 

      and control all the source of variability that you

 

      are going to see.  You need to determine how your

 

      product is sensitive to things like the apparatus

 

      type, the setup parameters and the media, both type

 

      of media and whether it is degassed or not.  There

 

      is an interaction between the instrument you use

 

      and your product, and understanding that is going

 

      to also help you reduce the variability in the

 

      dissolution test method.  People like to use

 

      calibrator tablets.  I think it gives them a

 

      measure of confidence that they set everything up

 

      and their system is suitable.

 

                So, what we are proposing is that

 

      certainly the USP calibrator can be used if

 

      somebody wants to take a look and see that they

 

      have set up properly.  Perhaps it also might be

 

      useful to set up an internal calibrator maybe based

 

      on a bio. batch or clinical batch to make sure of

 

      system suitability.  The calibrators dissolve in a

 

      certain way or are sensitive to certain things and

 

      not sensitive to certain things, the USP ones, and

 

      those parameters may not be the parameters that

                                                                73

 

      your particular product is or is not sensitive to.

 

      So, creating your own internal calibrator and

 

      understanding how your product is sensitive to all

 

      the parameters is going to be perhaps better than

 

      an outside product that may not have the same

 

      sensitivities that yours does.  Obviously, you need

 

      to confirm the suitability of your internal

 

      calibrator using some kind of a gauge R&R study so

 

      you can really understand what the variability is

 

      in your product.

 

                Ajaz mentioned gauge R&R a little bit.  If

 

      you pick a lot of product or a piece of a lot to

 

      maybe set up as an internal calibrator you need to

 

      carefully characterize that and determine what its

 

      variability is.  You want to make sure it is

 

      representative of your manufacturing process.  You

 

      want to make sure that it was manufactured while

 

      your process was under control.  Obviously, when

 

      you are doing a gauge R&R you need to take a look

 

      at what variability is introduced instrument to

 

      instrument, vessel to vessel.  As you can see, each

 

      instrument is like 6 individual little instruments.

                                                                74

 

      And variability from personnel to personnel and,

 

      obviously, media and whether it is degassed or not.

 

                We need to understand the benefits and

 

      limitations of the different dissolution apparatus.

 

      I showed you that there are 7 different ones in the

 

      USP.  We also sometimes get ones that are non-USP

 

      apparatus when people submit test methods.  So,

 

      there are a lot of different things out there to

 

      choose from and, better than just choosing one that

 

      someone thinks maybe the FDA wants to see, maybe

 

      try to understand how the hydrodynamics work; try

 

      to model your system.  Actually, I have been told

 

      by people who do modeling that apparatus 1 and 2

 

      are difficult to model so there may be some better

 

      systems out there where we can do some better

 

      predicting of what is going to happen as we change

 

      physical parameters of our product, and take a look

 

      at some other things we might be able to do.

 

                Of course, what would even be better is

 

      just quit doing dissolution as it is known today

 

      and maybe find some other ways to assess product

 

      quality.  People have done some work in our sister

                                                                75

 

      lab here, in White Oak, to try to correlate

 

      dissolution with NIR.  There is a lot of

 

      spectroscopy out there that can be used online as

 

      part of a PAT feedback loop, and perhaps good

 

      correlations and good models could be developed

 

      between those and quality and in vivo availability

 

      and we can dispense perhaps with the current

 

      dissolution test method, which has all of its

 

      parameters--things that can go wrong and need to be

 

      set very carefully.  Obviously, key to this is

 

      going back to the first principles and modeling and

 

      understanding your formulation, and how each

 

      component of your formulation contributes to the

 

      quality of your product.

 

                So, that is all I had to say and I just

 

      wanted to acknowledge Terry Moore, who is actually

 

      here today, who probably knows more about

 

      dissolution than anybody in the world.  He is

 

      sitting over there, if you want to know more about

 

      dissolution.  Then, Zongming Gao is also in our lab

 

      doing dissolution; and Lawrence who also knows a

 

      lot about dissolution; and Ajaz all helped with

                                                                76

 

      this.  So, thank you.

 

                DR. COONEY:  Thank you very much, Cindy.

 

      There certainly is time for questions.  Gerry?

 

                     Questions by Committee Members

 

                MR. MIGLIACCIO:  Cindy, first I applaud

 

      your last comment about using alternate methods.  I

 

      just want to point out that you made several

 

      comments about the use of apparatus 1 and 2 and,

 

      speaking I think for most companies, we don't use 1

 

      and 2 because we think FDA wants us to use them.

 

      You did a great job of pointing out the variability

 

      of the different parameters that can impact

 

      variability.  It is very important when you are

 

      testing thousands of batches a year that you have a

 

      really well trained work force that knows how to

 

      use this apparatus, and that you have consistency

 

      in the way you test because if you are switching

 

      from one apparatus to another it presents another

 

      level of complexity.  So, it is really the

 

      consistency.  Because of the variability that is

 

      inherent here, it is the consistency that drives us

 

      to apparatus 1 and 2 and not a lack of desire--

 

                DR. BUHSE:  To try something else?

 

                MR. MIGLIACCIO:  --but, you know, it is

 

      complicated enough so it is really consistency that

                                                                77

 

      drives us there.

 

                DR. COONEY:  Marvin?

 

                DR. MEYER:  The data you showed from your

 

      lab versus the specs on prednisone, and you said in

 

      one case you tend to be high and some cases fail,

 

      when you do fail the calibration what do you do

 

      about it?  Is it the calibration that is no good?

 

      Is it the USP specs that is no good?  Is it the lab

 

      that is no good?  Or, do you just keep going until

 

      you have 36 samples?

 

                DR. BUHSE:  Well, historically what we

 

      have done is double check your mechanical

 

      calibration and then you really run the calibrator

 

      tablet.  So, was the original failure the tablet?

 

      Rarely do we find something to adjust when we check

 

      the mechanical calibration.  We do the mechanism

 

      calibration much tighter than the USP anyway so

 

      essentially you rerun.  We actually don't run them

 

      anymore in the lab, the USP calibrator tablets.

 

                DR. MEYER:  That solves that problem!

 

                DR. BUHSE:  That solves that problem!  We

 

      have an internal calibration tablet that we use now

 

      that we have characterized ourselves in our lab

 

      that has lower variability.  We stopped using this

 

      one probably at the end of last year.  The data I

                                                                78

 

      showed was the data from 2004, 2003.

 

                DR. MEYER:  The other question I have or

 

      comment is that on one of the slides you suggest

 

      using perhaps an internal calibrator, a bio. batch

 

      or some known that you have produced.

 

                DR. BUHSE:  Right.

 

                DR. MEYER:  How do you know that that

 

      product, over the lifetime of the product being

 

      manufactured, hasn't changed?  Dissolution doesn't

 

      change, you are satisfied your equipment is in good

 

      order when, in fact, it isn't because you couldn't

 

      pick up the change--

 

                DR. BUHSE:  Stability is a big issue.

 

      Stability is an issue with the current USP

 

      calibrator.  It is known to drift down I believe

 

      with the paddle method over time, or whatever.  Do,

                                                                79

 

      you want to talk about that, Ajaz?

 

                DR. HUSSAIN:  Yes.  Marvin, I am going to

 

      go over that in detail.  The gauge R&R is actually

 

      for three purposes.  It is to establish and

 

      benchmark the variability.  I think the proposal

 

      actually is that mechanism calibration actually is

 

      sufficient.  The gauge R&R is an opportunity to

 

      establish your target.  You benchmark your

 

      variability and then use that variability for

 

      setting specifications, and so forth.  But then you

 

      have that and then you can keep the system stable.

 

      I think stability of the system has to be based on

 

      mechanism calibration.  That is what other

 

      countries do anyway.  So, I will go over that in a

 

      bit more detail.  So, the opportunity is more than

 

      just the internal calibrator.  So.

 

                DR. MEYER:  One follow-up, I kind of joked

 

      that you made the problem go away because you are

 

      not using it anymore.  What if you are a company

 

      and had in your NDA or ANDA that you would

 

      calibrate your dissolution using the prednisone and

 

      USP and you started to fail, your dissolution

                                                                80

 

      couldn't meet the calibration?  They don't have the

 

      luxury of just saying, well, we are going to use

 

      our own now because they are stuck with using what

 

      they said in the NDA, right?  What should a company

 

      do about that?

 

                DR. BUHSE:  You want to talk about that,

 

      Ajaz?

 

                DR. HUSSAIN:  Well, I think this meeting

 

      is step one to start addressing that in a sense.

 

      Here is an alternate procedure.  So, I think if the

 

      advisory committee will sort of endorse this and we

 

      move that way, we will put that in policy and there

 

      are many different ways to implement that.  So.

 

      But from the compendia perspective, I think you

 

      have to comply with the compendia so that is a

 

      different challenge that the industry and companies

 

      have to deal with.  So, all we are doing right now

 

      is creating an alternate regulatory decision

 

      pathway and our enforcement strategy based on that.

 

                DR. COONEY:  Nozer?

 

                DR. SINGPURWALLA:  Slide number 13, I

 

      thought you said it was Ajaz's slide.  Therefore,

                                                                81

 

      it is wrong!

 

                [Laughter]

 

                DR. BUHSE:  Yes, it was Ajaz's slide.

 

                DR. SINGPURWALLA:  Well, how do you

 

      distinguish between repeatability and

 

      reproducibility?

 

                DR. BUHSE:  Well, I was going to say with

 

      a destructive test it is very difficult.

 

                DR. HUSSAIN:  See, this is gauge R&R for a

 

      destructive test.  You really have to have design

 

      experiment and I was going to cover that in my

 

      talk.  What this does is, it actually ensures that

 

      the lot you choose is stable and in a state of

 

      control.  That is the only way you can actually

 

      move in this direction.  So, that achieves that

 

      target.  The destructive gauge R&R is a very formal

 

      experiment and it is a nested design which does get

 

      an estimate of whether a practice or an operator

 

      can repeat it.  That is repeatability.

 

      Reproducibility is the variability associated with

 

      that.

 

                DR. SINGPURWALLA:  So, the repeatability

                                                                82

 

      refers to a physical thing.  The other thing is I

 

      don't know how important it is for you to manage

 

      variability but if it is important to you to manage

 

      variability, then my sense is that as the product

 

      variability increases the measurement variability

 

      will also increase.  Therefore, there will be

 

      correlation and, therefore, the sigma squared total

 

      that you have will be underestimated the way you

 

      have put it down.  If it is of any importance, you

 

      may want--

 

                DR. HUSSAIN:  I think it is.  That is the

 

      reason the leverage--the quality by design having

 

      the pharmaceutical development information starts

 

      to allow us to dilute some of this.  But the

 

      variability that you are observing you are

 

      observing to the eyes of the measurement system so

 

      the measurement system and variability in the

 

      product are together.  I will try to come back and

 

      sort of explain some of that.

 

                DR. DELUCA:  I apologize for my voice.

 

      You very nicely pointed out the multitude of

 

      variables that are involved.  There is instrument

                                                                83

 

      variability as well as product variability so you

 

      have interaction.  You mentioned degassing.  But

 

      you are using a set agitation in your system.  When

 

      you start degassing, are you not sparging?  Now,

 

      you can create agitation or sparging during the

 

      test?

 

                DR. BUHSE:  No, it is done beforehand.

 

      You do it before you start and you put the media in

 

      the different vessels and there is no degassing

 

      during dissolution itself.  Questions come up,

 

      especially for extended-release products, where

 

      actually the dissolution test method lasts for 24

 

      hours per product, and the question then becomes

 

      what happens to the gas level over that time.  We

 

      hope to test that with this meter.  The one I

 

      showed you here is actually one that has a probe

 

      that is, like, 3 inches around so you have to put

 

      it in a giant vessel.  They are making a new probe

 

      that is small and will fit inside the dissolution

 

      vessel so we can see what happens actually in the

 

      dissolution vessel over time.  Like you say, with

 

      some of these test methods at high rpm, 100 rpm, we

                                                                84

 

      are getting a lot of agitation.  So, that is a good

 

      question.

 

                DR. DELUCA:  And I was worried about the

 

      product and how product variation can affect--so,

 

      you have an interaction between the instrument and

 

      the product where particle size might influence,

 

      you might have a set agitation rate.  If the

 

      particle size changes then it is going to change

 

      the result.

 

                DR. BUHSE:  Right, unless you have a

 

      method that can discriminate that if it is

 

      important to the acting of the drug.

 

                DR. DELUCA:  You have talked about

 

      modeling, I mean you mentioned it.  Maybe it is

 

      going to be covered later on, but I wondered if you

 

      include anything here to look at profiles, release

 

      profiles.

 

                DR. BUHSE:  We haven't done a lot of

 

      modeling yet in our lab.  I don't know if we are

 

      going to talk about that specifically later on or

 

      not today.

 

                DR. COONEY:  Ken?

 

                DR. MORRIS:  Just a couple of things.  One

 

      is that given the sort of lag--I guess I just have

 

      a philosophical problem with calibrator tablets in

                                                                85

 

      that if you are looking at a process and want to

 

      independently establish that it is in control or

 

      that it is doing what you think it is doing--we are

 

      producing these the same way we produce the tablets

 

      for testing--

 

                DR. BUHSE:  That are no better.

 

                DR. MORRIS:  What is that?

 

                DR. BUHSE:  That are no better.

 

                DR. MORRIS:  In fact, there are some data

 

      that I think we will see to day that there are some

 

      liabilities.  I think maybe this is something we

 

      will talk a lot more about, I am sure, but I think

 

      one of the things that may come out of this is that

 

      calibrator tablets just don't have a prominent

 

      role.  What I would say is that if you look at an

 

      immediate-release system--and we will also get into

 

      BCS exemptions--then the issues become sort of

 

      treatable in other ways.  If you are looking at

 

      sustained-release or modified-release, such as

                                                                86

 

      enteric or extended, then my argument is that you

 

      ought to be controlling the coating process and

 

      that sort of activity is really much more advanced

 

      than it was.  I mean, you have your example of the

 

      tablet that has the air pocket but probably what

 

      was more important was the difference between the

 

      80 and 50 micron coating thickness.  This is

 

      clearly a failure of reproducibility of coating and

 

      the dissolution may catch it or may not.  I mean,

 

      the statisticians--I don't know, there is the

 

      Bayesian argument but I have talked to Sandy

 

      Bolton, for one so, you know, if you have high

 

      variability dissolution maybe 6 tablets is enough

 

      to pick it up but, depending on what constitutes

 

      high variability, you know, it is in the laps of

 

      the gods whether you get it or not.  So, to the

 

      extent that things are surface-based alternate

 

      methods--I mean, in the first place, you want to be

 

      controlling the coating processes and then, to the

 

      extent they are surface-based, have you considered

 

      things within the group like the combination of

 

      that and, like, IGC to look at surface free

                                                                87

 

      energies or something that is at least a little

 

      less subjective?  I don't know if you have talked

 

      about it because everything else is a correlated

 

      technique.

 

                DR. BUHSE:  Right.

 

                DR. DELUCA:  Whereas, something that

 

      actually measures surface free energy, even though

 

      there is no practical instrument right now, is a

 

      direct measure.

 

                DR. BUHSE:  We haven't done that with that

 

      particular product.  We have tried to do some

 

      spectroscopy correlations.

 

                DR. HUSSAIN:  If I may?

 

                DR. COONEY:  Yes.

 

                DR. HUSSAIN:  I think you make a good

 

      point, and I think the goal that we have, number

 

      two, desired state, specification based on

 

      mechanistic understanding--so, if the mechanism is

 

      controlling the dissolution based on a coating

 

      thickness, if you are able to measure the coating

 

      thickness reliably, and so forth, that should be

 

      sufficient.  So, I think that is the direction we

                                                                88

 

      wish to move in, and some of the new technologies

 

      and science sort of helps that.

 

                There is another point I think which I do

 

      want to make and this is my graduate school

 

      training; this is biopharmaceutics 101.  When we

 

      approach trying to develop a product we first think

 

      about the patient, and so forth.  Prof. Richard

 

      always insisted you don't even think about an in

 

      vitro test.  You first try to get initial

 

      information in humans and then say, all right, what

 

      sort of testing will we need.  So, you establish

 

      your formulation, human connection or patient

 

      connection first before spending time in an

 

      artificial way.  In my consulting role before I

 

      came to FDA, one company I worked for carried out

 

      53 experiments, screening and so forth; they had no

 

      idea whether dissolution was useful or not.  They

 

      spent all this development effort trying to

 

      optimize a hypothetical, what they thought was the

 

      dissolution rate and the first experiment they did

 

      was completely off.  So, all the experiments were

 

      actually off target.

 

                So, there is a tendency within industry to

 

      assume that in vitro dissolution is going to guide

 

      them to a formulation without even understanding

                                                                89

 

      its relevance.  I think Marvin knows that company

 

      very well.  We actually had a paper on that issue

 

      together.  So, there are challenges I think.  So,

 

      quality by design actually forces us to think what

 

      is the patient and then think about the tests so

 

      that is what we are trying to achieve here.

 

                DR. COONEY:  Ajaz, perhaps we can capture

 

      that as a point, that the purpose of formulation

 

      development is to optimize patient care, not

 

      dissolution assay.  We hear you.

 

                DR. FACKLER:  Could I just make a point?

 

      Dissolution can function for a number of different

 

      purposes and on one of your slides you suggested

 

      that finding a discriminating method might be

 

      useful, and I would agree under certain

 

      circumstances.

 

                On the other hand, if you look at that

 

      enteric-coated product really the purpose of the

 

      enteric coating is to protect the tablet for the

                                                                90

 

      first hour, or whatever time it might exist at the

 

      very acidic condition of the stomach.  Whether or

 

      not coating breaks open at one hour, two hours or

 

      three hours might have no relevance to the in vivo

 

      performance of the product.

 

                So, I think it is important, as we talk

 

      about the future of dissolution testing, to

 

      recognize what it is intended for.   If it is

 

      intended to predict in vivo performance, that is

 

      one thing and a predictive or correlative method

 

      then I think would be the ideal.  If it is to look

 

      for product quality and to reduce the inherent

 

      variability in products, well, then a more

 

      discriminating method that might have no relevance

 

      to in vivo performance might be our goal.  I think

 

      we just need to keep that in perspective as we

 

      think about the future of dissolution testing.

 

                DR. HUSSAIN:  If I may since we have time,

 

      I think this is one of the first steps in our

 

      tactical plan.  Since we have time, if we could

 

      engage the advisory committee to make sure is this

 

      an acceptable step further discussion is needed. 

                                                                91

 

      So.

 

                DR. COONEY:  Tom?

 

                DR. LAYLOFF:  Yes, I was going to say

 

      because of my concern with the problem with

 

      degassing--I never degas my stomach before I take

 

      my medication--

 

                [Laughter]

 

                DR. FACKLER:  You probably don't swallow

 

      900 ml of water either.

 

                [Laughter]

 

                DR. MORRIS:  Just a couple of comments.

 

      First, when we validate equipment we have to

 

      understand what tests we are doing and what we are

 

      trying to validate, and the standard tablet just

 

      doesn't--intuitively, it doesn't get there for me

 

      because we are looking at validating a piece of

 

      equipment and all of a sudden the variables that we

 

      are throwing into the pot include what is the

 

      dissolution medium and how we handle that; what is

 

      the size of tablet and how we handle that when we

 

      are trying to validate a piece of equipment.  So,

 

      probably the first step is saying what validates

                                                                92

 

      the equipment, and anything else we do is a waste

 

      of time.

 

                Then, the next step, to get right to what

 

      Paul said, is what is my dissolution test telling

 

      me because I am a manufacturer and I want to keep

 

      my process under control, or am I predicting what

 

      is happening in people?  We have seen for 35 years,

 

      as far as I know, that dissolution doesn't predict

 

      the human results in terms of bioavailability or

 

      bioequivalency.  You can't do it that way.  You

 

      have to get that data and then try to correlate.

 

      So, if we are using dissolution for quality

 

      control, for process, fine, then there is a set of

 

      variables and we do it that way.  But if we are

 

      trying to say that I can do a dissolution study

 

      and, therefore, I will know that my formulation is

 

      going to work in a person I think we are really

 

      biting way more off than we can chew.

 

                DR. HUSSAIN:  I think I agree with you,

 

      but in may aspects you do establish correlation.

 

      Actually, Lawrence, in his talk, will actually make

 

      that same proposal as you did.  So.

 

                DR. COONEY:  Tom?

 

                DR. LAYLOFF:  The early work done on

 

      digoxin was designed to go for in vivo/in vitro

                                                                93

 

      correlation for about 35 manufacturers, and that is

 

      how that standard was set.  Prednisone subsequently

 

      was done the same way.  In reviewing that, it would

 

      determine that if the FDA continued down that path

 

      it would eventually take all the resources of the

 

      FDA to do it because of the cost of performing

 

      those in vivo/in vitro correlations.  Then the

 

      dissolution standard was just arbitrarily applied

 

      across the board.

 

                DR. COONEY:  Marvin?

 

                DR. MEYER:  Ajaz, I think you ask if you

 

      are on the right track and I think you definitely

 

      are.  You know, when you first said we are going to

 

      revisit dissolution I said, oh, my God--

 

                [Laughter]

 

                --so, I think you are on the right track.

 

      I mean, for me, when I used to do some dissolution

 

      just in a university laboratory, I loved the wide

 

      range for the calibrators because then my equipment

                                                                94

 

      always passed and I didn't have to worry about it.

 

      But now, sitting around this table, I have a

 

      different hat on and it is shocking, 51-81 percent.

 

      How can you have a calibrator--if somebody comes in

 

      with analytical data like that you would say go

 

      away; this is a very poorly controlled analytical

 

      procedure.  So, I think that revisiting the issue

 

      is very important.

 

                DR. HUSSAIN:  Marv, in may ways, you know,

 

      I was blind to this.  I actually was not fully

 

      aware of the scenario, and Cindy will attest to

 

      this.  When I started writing this paper I put

 

      Lawrence through hell.  I said how could this

 

      happen?  Because our standard criteria for

 

      specification is plus/minus 10 percent and the

 

      instrument is this way so there was a disconnect

 

      that I was not aware of and I have to apologize for

 

      that.

 

                DR. COONEY:  Are there any other comments

 

      or questions at this point?

 

                [No response]

 

                What I would like to suggest is that we

                                                                95

 

      take a break for 15 minutes and reconvene at 10:25,

 

      and we are in good shape for continued discussion

 

      and I have no doubt there will continue to be more.

 

                [Brief recess]

 

                DR. COONEY:  I would like to now welcome

 

      Dr. Mehta to speak to us about an overview of the

 

      current guidance on the documents and decision

 

      process in biopharmaceutics.

 

              Overview of Guidance Documents and Decision

 

                   Process:  Biopharmaceutics Section

 

                DR. MEHTA:  Good morning.  As you can see

 

      on my slide here, I am asked to give an overview of

 

      guidances documents and decision processes from a

 

      biopharmaceutics perspective.

 

                Before I start, I want to acknowledge a

 

      couple of people in my division, Dr. Ramana Uppoor,

 

      she is sitting in the back in the audience, and Dr.

 

      Patrick Marroum, team leaders in neuro. and

 

      cardiorenal in my division and some of the experts

 

      in biopharmaceutics in my division.

 

                This is the outline of my presentation.  I

 

      am going to give you an overview of

                                                                96

 

      biopharmaceutical aspects of dissolution-related

 

      guidances.  That is a formidable task.  My first

 

      draft that I sent to Ajaz had 100 slides and Ajaz

 

      replied by saying an excellent overview but cut it

 

      down.  So, I am now down to 60.

 

                [Laughter]

 

                But I still intend to finish in time.

 

      Then with a quick overview I will take you through

 

      some examples from our NDA reviews of

 

      immediate-release and modified-release products,

 

      and share with you my perspective on opportunities

 

      for improvement.

 

                These are the guidances I am going to

 

      quickly take you through.  Chronologically they are

 

      different but in terms of science, the way the

 

      ideas are represented I have shifted them around.

 

      I am going to first start with the BCS guidance.

 

      In parentheses are the references.  I will follow

 

      that by the immediate-release dissolution guidance

 

      that came out in 1997.  The BCS guidance was

 

      finalized in 2000.  The IR dissolution guidance

 

      invokes BCS principles and that is why I have

                                                                97

 

      arranged it that way.  That will be followed by a

 

      quick overview of the IVIVC guidance and that is

 

      for modified-release products, in vitro/in vivo

 

      correlation.  Then a couple of slides on general

 

      bioavailability and bioequivalence guidance, which

 

      was finalized in 2003.

 

                I will quickly switch to something known

 

      as scale-up and post-approval changes for

 

      immediate-release products and modified-release

 

      products, and the topics covered there.

 

                So, let me start with the BCS guidance

 

      summary.  Maybe it is known to everybody, but just

 

      for the sake of completeness let me point out the

 

      highlights of the BCS guidance.  This guidance

 

      takes into account three major factors that govern

 

      the rate and extent of drug absorption from the

 

      immediate-release solid oral dosage form.

 

                These are the solubility and intestinal

 

      permeability of the drug substance, and dissolution

 

      of the drug product.  So, based on the solubility

 

      and permeability characteristics of the drug

 

      substance the drugs are classified into four

                                                                98

 

      categories: high solubility, high permeability; low

 

      solubility, high permeability; high solubility, low

 

      permeability; and then the fourth category, low

 

      solubility, low permeability.

 

                The third bullet is the central idea, the

 

      central concept, a very sound scientific concept of

 

      BCS which is, you know, if a drug product is BCS

 

      class 1, and for different formulations of this

 

      class 1 product if they are rapid and similarly

 

      dissolving you can give a biowaiver for the test

 

      formulation without requiring an in vivo

 

      bioequivalency assessment, provided you show

 

      similar dissolution profiles over the physiological

 

      pH range.

 

                The last important point about this

 

      guidance is that in this guidance we have defined

 

      what determines rapid dissolution, and we say if

 

      your drug product dissolves 85 percent in 30

 

      minutes over the pH range absorption should not be

 

      dissolution limited.  So, that is all for BCS.

 

                Moving on quickly to the immediate-release

 

      dissolution guidance summary, and again I will do

                                                                99

 

      my little bit of acknowledgement here, Dr. Shah and

 

      some members on the panel here have contributed to

 

      this guidance and, from my personal perspective,

 

      this is scientifically a very well written document

 

      although it was almost ten years ago.

 

                These are the topics covered in this

 

      guidance.  The guidance lays out approaches for

 

      setting dissolution specifications for a new

 

      chemical entity.  As I said, it takes into

 

      consideration BCS nature of the drug product and,

 

      depending upon that, you can have minimal

 

      dissolution requirements in setting specifications

 

      or more stringent.

 

                Another very important point from my

 

      perspective is that this guidance has outlined

 

      something known as mapping or response surface

 

      methodology.  Again, this is supposed to be for

 

      immediate-release products.  The guidance says that

 

      undefined clinical manufacturing

 

      variables--manufacture your products at the

 

      extremes of CMVs and in vivo performance and, if

 

      you have that information, you will have a very

                                                               100

 

      sound rationale for coming in with appropriate

 

      dissolution specifications.

 

                Finally, in this guidance there is a

 

      discussion of how do you compare dissolution

 

      profiles of two products.  One of the approaches

 

      that I recommend is known as the f2 or the

 

      similarity factor which essentially looks at the

 

      differences in dissolution at each time point, with

 

      a range of 0-100.  An f2 of 50 or greater than 50

 

      indicates similarity of the dissolution profiles.

 

      As we have said in that guidance, dissolution

 

      specifications are established in consultation with

 

      Biopharmaceutics and the CMC review staff. The

 

      general bioavailability/bioequivalence guidance

 

      summary, again limited only to dissolution

 

      considerations, we have a section in there that

 

      talks about what should be submitted in an NDA or

 

      an ANDA in terms of a dissolution method.  There

 

      should be a dissolution method development report

 

      for an NDA, new drug application.  It should

 

      contain a pH solubility profile of the drug

 

      substance; dissolution profiles generated at

                                                               101

 

      different agitation speeds; and dissolution

 

      profiles generated on all strength in at least

 

      three dissolution media.  Essentially you want to

 

      see the in vitro performance of your product over a

 

      variety of conditions, including different media

 

      and different agitation; and select the agitation

 

      speed and medium that provides adequate

 

      discriminating ability, taking into account all the

 

      available in vitro and in vivo data.

 

                For ANDAs, abbreviated new drug

 

      applications, the guidance states that one should

 

      start with an appropriate USP method if it is

 

      there, in the USP.  For some reason, if it is not

 

      there for this product, then if the FDA method is

 

      publicly available, utilize that.  If that is not

 

      available, also publicly available, then submit the

 

      dissolution method development report, as described

 

      above for a new drug application.

 

                Again, for modified-release products for

 

      ANDAs the dissolution profiles use the appropriate

 

      USP method, if available, otherwise use the FDA

 

      method for the reference listed drug if available. 

                                                               102

 

      In addition, and I think this is probably because

 

      you could have for a generic similar or different

 

      release mechanisms, so additional dissolution data

 

      in three different media.

 

                Now switching to the IVIVC guidance which

 

      is, you know, in vivo/in vitro correlation for

 

      modified-release products, again from my

 

      perspective, this is a very useful guidance also.

 

      The main purpose of this guidance was to provide an

 

      outline for waiver of bioequivalency studies for

 

      modified-release products if one was able to

 

      establish an in vivo/in vitro correlation, a

 

      quantitative correlation.

 

                The guidance defines correlation in

 

      different categories, A, B, C and D.  Level A

 

      correlation is most quantitative, and I have listed

 

      in my presentation just the level A discussion.

 

      Level A correlation is supposed to be a

 

      point-to-point relationship between the in vitro

 

      dissolution and the in vivo input rate of the drug

 

      from the dosage form.  Usually this is a two-stage

 

      process, meaning that you take your dissolution

                                                               103

 

      data, convert that into dissolution rate, and you

 

      take your in vivo data and convert that into

 

      absorption rate and correlate the two.  Generally,

 

      this relationship is linear but non-linear

 

      relationship is also acceptable provided it is

 

      adequately characterized.

 

                So, this is an example of how level A

 

      IVIVC would look.  On the Y axis you have percent

 

      of drug absorbed and on the X axis is the percent

 

      of drug dissolved; your linear relationship over

 

      the range and this establishes your correlation.

 

      For the purpose of obtaining biowaivers, you need

 

      validation of this level A correlation.  From the

 

      point of view of setting dissolution

 

      specifications, that level of validation is not

 

      necessary, and I will get into that subsequently in

 

      my examples.

 

                In the IVIVC guidance for modified-release

 

      products we have some general concepts laid out for

 

      what the dissolution specification should mean.

 

      Ideally, as we say in the guidance, all lots within

 

      the lower and upper limit of the specifications

                                                               104

 

      should be bioequivalent.  At the minimum, those

 

      lots should be bioequivalent to the clinical trials

 

      lots or an appropriate reference standard chosen by

 

      the agency.  In other words, you have your

 

      reference performance and the upper limit should be

 

      similar to the reference and the lower limit should

 

      be similar to the reference.  Ideally, the extremes

 

      should be bioequivalent.

 

                Some further considerations are that

 

      variability alone should no longer be a primary

 

      consideration in setting specifications for

 

      modified-release products.  Specifications wider

 

      than 20 percent are acceptable only when evidence

 

      is submitted that lots with mean dissolution

 

      profiles that are allowed by the upper and lower

 

      limits are bioequivalent.  In other words, you can

 

      have specifications wider than 20 percent if you

 

      have a correlation, a quantitative correlation.

 

                If you don't have an IVIVC and you want to

 

      set dissolution specifications for modified-release

 

      products, these are some of the characteristics of

 

      what the data should be.  The profile should have

                                                               105

 

      at least three time points.  The last time point

 

      should be the time where 80 percent of the claimed

 

      labeled amount is dissolved.  Specifications are

 

      set to pass at stage 2, meaning that there are 12

 

      dosage units.

 

                As I mentioned a while ago, for setting

 

      dissolution specifications with the IVIVC, external

 

      validation is not required and, as I already

 

      mentioned, wider specifications based on what the

 

      correlation predicts can be done.

 

                This is graphically presenting that.  On

 

      the left panel you see that in the middle is the

 

      performance of your product, the variability around

 

      the mean dissolution profiles.  The blue line is

 

      the upper limit of the specification.  The red line

 

      or orange line is the lower limit of the

 

      specification.  You take that data using your in

 

      vitro/in vivo correlation model.  You predict the

 

      plasma concentration based on the two limits.

 

                On the right panel, the diamonds are the

 

      actual blood levels, the predicted blood levels at

 

      upper and lower limit, and the predicted level for

                                                               106

 

      Cmax and AUC should not be greater than 20 percent.

 

      Back in '97, what we could come up with was setting

 

      the consideration based on the mean difference.

 

      So, the upper and lower limit would not differ on

 

      the mean AUC and Cmax by 20 percent.  We could not

 

      build into this consideration the variability

 

      aspects and, as we have already heard in an earlier

 

      presentation today, that is an opportunity for

 

      improvement for future consideration.

 

                Switching gears, I am going to quickly

 

      tell you about what the SUPAC guidances mean as far

 

      as immediate-release and modified-release products.

 

      There are also a few guidances that came out

 

      subsequent to the issuance of the SUPAC in 1997,

 

      which is called equipment addendum, FDAMA and the

 

      changes approved to an NDA or ANDA guidance in

 

      2000.  Again, I am going to try to capture this

 

      very quickly.

 

                Conceptually speaking, these guidances

 

      identify what are the changes or what are the

 

      variables that are covered in terms of

 

      manufacturing considerations.  The level of changes

                                                               107

 

      for these variables, what are they?  They are

 

      defined; and then how do you deal with that?

 

                So, the variables covered in this

 

      guidance, manufacturing related, are composition

 

      and components.  For excipients it is

 

      non-release-controlling as well as

 

      release-controlling.  The non-release-controlling

 

      aspect is what is the part of the SUPAC-IR

 

      guidance.  That is taken as it is into the SUPAC-MR

 

      guidance and then what is added is the

 

      considerations for release-controlling excipients.

 

      Other variables covered are site, batch size,

 

      meaning scale-up and scale-down, manufacturing

 

      equipment and manufacturing process.

 

                I am going to take you through only one

 

      set of variables here and show you how the levels

 

      are defined and what are the related tests

 

      recommended and what are the related filing

 

      requirements.

 

                Essentially, the idea is this, the

 

      guidance has defined the level of change into three

 

      categories, level 1 is the minor change; level 2 is

                                                               108

 

      the moderate change; and level 3 is the major

 

      change.  So, moderate could have an in vivo impact

 

      on level 3 or major changes likely to have an in

 

      vivo effect.

 

                Related to those changes, the tests go

 

      along with them in terms of document evidence.  The

 

      lowest level, level 1, would usually require only

 

      application of compendia tests and stability data.

 

      Level 2 change would require extensive in vitro

 

      dissolution and release data.  That typically means

 

      that for immediate-release products you require

 

      profile comparison in five different media.  Then,

 

      for modified-release you need profile comparison in

 

      three different media.  Level 3 is the most

 

      significant change and that will be allowed only if

 

      you have an in vivo bioequivalency study or you had

 

      established in vitro/in vivo correlation.

 

                The filing requirements, again going from

 

      minimal to most which is annual report, changes

 

      being effected supplement, or prior approval

 

      supplement.  In the subsequent discussion I will

 

      just focus on the first two bullets, which is level

                                                               109

 

      of change and the tests.  I am not going to touch

 

      filing documentation at all.

 

                Here is an example of how the guidances

 

      break down changes into different levels.  For

 

      SUPAC-IR excipient levels excipients are listed for

 

      level 1 change, level 2 and level 3.  If you look

 

      at glidant, for example, for talc, plus/minus one

 

      percent change is allowed.  If you look at the top

 

      of the right-hand column, it is percent change

 

      weight of the change of the excipient over the

 

      weight of the total unit.  For talc it is

 

      plus/minus one percent.  Other glidants would be

 

      plus/minus 0.1 percent.  So, that is the lower

 

      limit of change, plus/minus 0.1 for talc.  If you

 

      look at filler, for example, it is also plus/minus

 

      five percent change.  So, this defines level 1

 

      change, minimal change.

 

                If you go to level 2 the ranges double.

 

      So, you go from plus/minus 0.2 to plus/minus 10

 

      percent.  Anything beyond 10 percent is considered

 

      a level 3 change.  Again, this is for

 

      non-release-controlling excipients.

 

                If you go down to release-controlling

 

      excipients for modified-release products, the

 

      criteria are more stringent.  Now, the change is

                                                               110

 

      measured as a percentage of the total

 

      release-controlling excipients and not the total

 

      dosage form unit so your denominator is a smaller

 

      number.  The percentage allowed is smaller for

 

      release-controlling excipients.

 

                For level 1 change, that means that the

 

      total additive effect of all release-controlling

 

      excipients should not be more than plus/minus 5

 

      percent.  Level 2 should not be plus/minus 10

 

      percent.  Changes beyond plus/minus 10 percent are

 

      considered level 3.

 

                So, this is a summary of what we have

 

      recommended in the SUPAC-IR and MR guidances.

 

      These guidances define the tests; filing document

 

      recommendations; level of changes in composition

 

      and components, release-controlling and non-release

 

      controlling excipients; site changes; batch size

 

      changes; equipment and process changes.

 

                The following changes either need a bio.

                                                               111

 

      study or an established IVIVC:  Level 3

 

      release-controlling and level 3 non-release

 

      controlling change; level 2 release-controlling

 

      change for NTR drugs; and level 3 site change and

 

      level 3 process change.  All of those changes,

 

      meaning level 2 changes, would require comparable

 

      dissolution documentation, meaning, as I said,

 

      profile comparison in several media.

 

                As I mentioned in the title slide for

 

      these guidances, the equipment addendum came out a

 

      little later and there we identified equipment by

 

      class and subclass for all major unit operations,

 

      and a change to a different class is generally

 

      considered a change in design and principle.  So,

 

      if you have equipment changes within the same

 

      design and operating principle it is considered a

 

      minor change.  If you go to a different design and

 

      principle it is a major change.  Finally, the

 

      changes guidance allows for multiple different

 

      level changes.  As we all know, these changes do

 

      not occur only one at a time; it is a composite of

 

      changes for any change.  So, if you have, say,

                                                               112

 

      several level 1 changes and one level 2 change for

 

      your new product you would be held to the most

 

      restrictive individual change of level 2, and

 

      whatever requirements go with that level of change.

 

                So, that was a quick overview of the

 

      guidances.  These documents are available on the

 

      web, and if you have any questions please look them

 

      up.  Let me switch gears here and take you through

 

      some examples of the way the specifications are

 

      set.

 

                But before that, let me share with you

 

      generally what we see in an application in terms of

 

      information available for setting specifications.

 

      The data that are available for a typical

 

      immediate-release product in an NDA are as follows:

 

      Dissolution results under a variety of agitation

 

      and media conditions.  Then typically what we see

 

      are several methods.  One method is selected by the

 

      sponsor which generally provides you with a rapid

 

      dissolution profile.  Using that method, we have

 

      data of 6-12 units and that is the limit of data we

 

      have for any given lot.  So, that is the range of

                                                               113

 

      variability that you would typically see for a

 

      particular lot.  Using that method, you have

 

      dissolution data from the bio. batch, the batch on

 

      which bioavailability has been characterized, plus

 

      few to several production lots under this

 

      condition.  Again, as I said, these batches are

 

      usually in very large quantities, hundreds of

 

      thousands to million units.  We see the data on

 

      6-12 units.

 

                Then we do have a lot of bioavailability

 

      data on this product.  Actually, bioavailability,

 

      relative bioavailability, bioequivalency trials and

 

      dissolution data of lots used in efficacy trials

 

      and stability data.  So, we look at all this

 

      information and try and come up with a meaningful

 

      specification.

 

                What do we do when we consider setting

 

      specifications?  These are the factors that are

 

      taken into consideration when setting specs. for an

 

      immediate-release product.  The in vivo behavior of

 

      a drug product, particularly how rapidly the drug

 

      is absorbed and an indicator for that is Tlag time

                                                               114

 

      or what is the Tmax of your product.  Since the

 

      issuance of the BCS guidance we look at the

 

      permeability data very closely.  In vivo

 

      permeability would be based on mass balance studies

 

      as well as absolute bioavailability studies and

 

      that, in my mind, is the gold standard by which you

 

      define whether a drug is highly permeable.  If it

 

      is quantitatively absorbed, then you say this high

 

      permeability, along with your high solubility data,

 

      puts the product into BCS class 1.  Then that

 

      carries its own benefits.  I have an example of

 

      that to show you a little later.

 

                That is what one pays attention to, in

 

      vivo behavior of the drug product from a

 

      bioavailability point of view.  We look at

 

      dissolution behavior across all conditions in vitro

 

      and then we try to come up with an adequately

 

      discriminating method, taking all this data into

 

      consideration based on any quantitative or

 

      qualitative in vitro inference.

 

                What is very helpful for evaluation of an

 

      NDA is if you have data like this where a solid

                                                               115

 

      dosage form in vivo is compared to something that

 

      is even more rapidly dissolving, meaning your solid

 

      dosage form's performance in vivo with respect to,

 

      like, a solution.  If we have this data, this tells

 

      us a lot about what is the in vivo dissolution of

 

      your solid dosage form and that can help us

 

      evaluate the in vitro considerations for setting

 

      specifications for that product.  So, this can

 

      guide how discriminating the in vitro method needs

 

      to be.

 

                As I said, we look at all the available

 

      dissolution data and pay particular attention to

 

      the lots that have in vivo data, and then discuss

 

      with our chemist colleagues about what is available

 

      in the stability domain, the data there and the

 

      specifications we are considering.  If we see a

 

      significant change or time with stability

 

      performance, that will have to be resolved by a

 

      bioequivalency study.

 

                Possible outcomes in terms of setting

 

      specifications, one is everybody is happy.

 

      Sufficient data are submitted and specs are

                                                               116

 

      finalized.  It is possible that insufficient data

 

      are submitted.  Based on the product's indication,

 

      the product needs to be approved with reset interim

 

      specs.  We agree with the sponsor what additional

 

      data needs to be generated.  We agree upon a

 

      time-line.  We evaluate the specs and we finalize

 

      the specs.  In the rare instance where there is

 

      insufficient data submitted--I have not seen this

 

      happen in my lifetime where we have withheld

 

      approval for a drug product because of insufficient

 

      dissolution data.  At the least, we will set specs

 

      on the clinical trial product.  So, if insufficient

 

      data are submitted and specs can't be finalized

 

      even including interim specs, then we have to

 

      resolve that prior to approval.

 

                Now let me take you through some specific

 

      examples, starting with simple to a little bit more

 

      complex.  This is an immediate-release drug product

 

      A.  The drug is highly soluble over the pH range of

 

      1.2-6.8, or 6.9 in this case.  Based on the

 

      bioavailability and the in vitro permeability, we

 

      established that the drug is highly permeable.  So,

                                                               117

 

      we have high solubility, high permeability criteria

 

      met.  The drug product is rapidly dissolving over

 

      the pH range of 1.2-6.8.  So, we have seen this.

 

      We are sure of these characteristics and we say

 

      okay, this is BCS class 1.

 

                We have dissolution results of the

 

      bioavailability lot and the clinical lot so all

 

      that data is utilized in setting the

 

      specifications.  There was stability data also

 

      available that was taken into consideration.  It

 

      turned out to be a straightforward case.  The

 

      sponsor's proposal was that they use a USP 1

 

      apparatus at 100 rpm in 900 ml 0.1 normal

 

      hydrochloric acid; specs of 80 percent in 30

 

      minutes.  We agreed with the sponsor.

 

                Just as a note, Ajaz and I didn't exchange

 

      notes beforehand but in this case the sponsor chose

 

      apparatus 1 to avoid coning effect.  Ajaz had an

 

      example from the Canadian database where that was

 

      the reason why you saw a big investigator

 

      difference compared to the reference, but the in

 

      vivo data turned out to be fine.

 

                Another example for an immediate-release

 

      drug product, product B, the drug is a free base

 

      with 2 pKs of 5.4 and 7.2.  It is highly soluble at

                                                               118

 

      pH 1 but it is practically insoluble at pH 7, and

 

      the solubility drops sharply between pH 4-5.  I

 

      have a graph that shows that clearly.  The drug is

 

      absorbed slowly, at Tmax ranging from 3-5 hours.

 

      The half-life is long, 45 hours.  It is not highly

 

      permeable.  The fraction absorbed is around 0.75.

 

                So, what do we do with this?  This is the

 

      dissolution behavior across the pH ranges.  As you

 

      see, below pH 5, which is the third curve from the

 

      top, dissolution starts dropping rapidly as the pH

 

      increases.  The sponsor chose the dissolution

 

      method at pH 5, and showed that the clinical and

 

      to-be-marketed formulations had similar profiles.

 

                This is what that comparison is at pH 5.

 

      We had bioequivalency data on these two

 

      formulations and that turned out to be clearly

 

      bioinequivalent in vivo for the test, meaning that

 

      to-be-marketed product showed a clear difference in

 

      Cmax.  The Cmax was 17 percent lower.  We

                                                               119

 

      interacted with the sponsor and they optimized

 

      their method to come up with an adequate

 

      discrimination condition to evaluate this

 

      formulation further.

 

                This is what they came up with, 5 percent

 

      volume Tween 80 and the same two formulations that

 

      were clearly bioinequivalent in vivo, they were

 

      able to identify their in vitro performance and

 

      show that, indeed, they were different.  This was

 

      verified further by taking the two formulations

 

      that were bioinequivalent in vivo and the method

 

      showed that they were similar in vitro.

 

                This was the availability of dissolution

 

      data across several batches.  All I want to point

 

      out to you is that, as I said, dissolution data for

 

      different batches, from 6 units, mean and range is

 

      available and if we look at the right-hand column,

 

      the lowest range is 86 percent.

 

                Taking all that data into consideration,

 

      the sponsor proposed the specification with

 

      apparatus 2 at 50 rpm and 1000 ml to Tween 80 in

 

      water; Q of 75 percent in 45 minutes.  We

                                                               120

 

      recommended no changes in the condition but a Q of

 

      80 percent in 45 minutes.  Here is an example of

 

      availability of in vivo data optimizing the

 

      specifications.

 

                The final example I have is for a drug

 

      product, a modified-release drug product with in

 

      vivo/in vivo correlation.  For this drug product a

 

      level A correlation was established.  Correlation

 

      was obtained from in vivo data from 6 different

 

      studies, and the media consisted of pH 1.5 for the

 

      first 1.5 hours and then pH 6.8 for the remainder

 

      of the 24 hours.  This is a once a day product.

 

                These are the results.  I think this was

 

      excellent work on the sponsor's part.  We worked

 

      with them and we were very happy to figure out the

 

      specs with them.  Look at the hatched region.  That

 

      is the observed range of dissolution data.  That is

 

      the extent of variability across the entire

 

      manufacturing experience for this sponsor.  So, the

 

      hatched area is the dissolution variability,

 

      dissolution range the product showed in vitro.  The

 

      specs we agreed upon are the two dotted lines above

                                                               121

 

      that hatched region.  So, those were the

 

      specifications proposed and we agreed with them.

 

                The best part is that if you look at the

 

      third level of curves, which are the topmost dotted

 

      lines, the topmost and the bottom, those are the

 

      predicted in vitro dissolution behaviors of two

 

      formulations that would be comparable in vivo.  So,

 

      the specifications were set within the limits of

 

      what products would be bioequivalent, so a good

 

      IVIVC that could lead to meaningful specifications.

 

                Now let me conclude with some personal

 

      comments on opportunities for improvement.  Before

 

      I get into my own suggestions, I want to cite this

 

      article that Ajaz already mentioned from Dr. Janet

 

      Woodcock, a clinician who has written beautifully

 

      on pharmaceutical quality.  I am just going to cite

 

      two quotations out of this article.  I mean, I can

 

      stand here and tell you a great deal about all the

 

      complexities involved in clinical trials but I

 

      think Dr. Woodcock has summarized this very well in

 

      this first bullet, which is, as she says, for the

 

      purposes of clinical use, the established drug

                                                               122

 

      quality attributes are generally adequate because

 

      they achieve much tighter control of the level of

 

      variability than could be detected in patients

 

      without extensive study.

 

                These are part of all the variabilities,

 

      specially manufacturing variability.  It can be

 

      done but it is a difficult task and it would be

 

      very extensive, and that is not the paradigm

 

      currently used.

 

                But maybe even more important, as she

 

      points out here in the very second line of the

 

      previous quotation, in contrast, for regulatory and

 

      manufacturing processes, the lack of detailed

 

      understanding of the real-world importance of

 

      quality attributes is a serious problem, leading to

 

      many disputes that might be resolved easily were

 

      relevant information available on the relationships

 

      between various quality parameters and clinical

 

      performance.  I personally couldn't agree more with

 

      that concluding comment.

 

                So, clinical performance, if I were to

 

      dissect that further--everybody talks about

                                                               123

 

      variability and this is my share of what are the

 

      different types of variability in therapy.  You

 

      start with manufacturing variability, then you have

 

      variability associated with the drug exposure and

 

      then you have variability associated with the drug

 

      response.  You have compliance issues.  You know, a

 

      lot of people can actually add more bullets to this

 

      and provide a complete picture of how complex the

 

      system is when a patient is being treated in vivo.

 

                But I have taken a shot at just making a

 

      point on exposure-related variability and

 

      manufacturing aspects associated with that.  The

 

      next table is a snapshot.  We have an internal BCS

 

      database of almost 200 NDAs.  That is in the

 

      process of being audited and we hope to publish

 

      that soon.  So, what I requested Dr. Uppoor to do

 

      is to randomly select a few drugs and prepare a

 

      table that would show variability in AUC and Cmax

 

      and the exposure parameters of different BCS

 

      products.

 

                Again, this is tentative because this is

 

      not fully audited so that is why I have starts in

                                                               124

 

      this table.  This is BCS class 1, 2, 3 and 4 across

 

      the top horizontal line.  You have the permeability

 

      associated with the AUC parameter and the Cmax

 

      parameter for these products.  As you can see,

 

      staring with class 1, we have variability in the

 

      range of 17 to about 24 percent.  Class 3 shows

 

      maximum in vivo variability.

 

                So, if I want to take this tentative class

 

      information further, the point I want to make--the

 

      numbers might be off when we have the actual

 

      publication coming out, but this is the point I

 

      want to make, that if I assume that the clinical

 

      trial formulation for this product was

 

      optimized--if it is not optimized, I think it is in

 

      the interest of the sponsor to optimize that so

 

      that even a little bit of manufacturing variability

 

      does not reflect in the in vivo performance at

 

      least from a drug exposure point of view.  But

 

      assuming that this formulation is optimized, even

 

      for BCS class 1 products you do see a decent amount

 

      of variability in vivo.  Again, this is reflecting

 

      how the drug is handled by an individual and the

                                                               125

 

      variability of handling that across individuals.

 

      This information can be utilized by a sponsor to

 

      come up with rational specs.

 

                These are some of my thoughts in terms of

 

      opportunities for improvement.  The first point is

 

      nothing earth-shattering but I still think it is a

 

      point that has to be made, to select an appropriate

 

      dissolution method based on physicochemical in

 

      vitro and in vivo characteristics of the drug and

 

      the drug product.

 

                It would be useful to have an estimate of

 

      in vitro variability for low solubility and low

 

      permeability.  Estimate of variability of lots used

 

      in pivotal efficacy trials would facilitate setting

 

      of rational specifications.  For modified-release

 

      products estimate the in vitro release

 

      variability--the example I showed where if you had

 

      a handle on the variability across your entire

 

      manufacturing process, then you can bring that into

 

      setting a meaningful specification.  As I already

 

      mentioned, right now the IVIVC current guideline is

 

      based on the limit mean estimates only and if you

                                                               126

 

      can build in the variability aspect and in vivo

 

      performance based on estimate of mean as well as

 

      variability, I think that would lead to more

 

      rational specs, maybe even wider specs compared to

 

      what we are doing now.

 

                The things that I see in the near future

 

      are new technologies like PAT.  Hopefully, it can

 

      provide in vitro and in vivo relationships based on

 

      the performance of an individual dosage form unit.

 

      I mean, this would be a non-destructive method.

 

      You would be able to assess the dissolution

 

      performance of a unit without breaking it up and

 

      then you would administer that to an individual and

 

      you would get that individual's exposure parameters

 

      so you would have correlation relationship on an

 

      individual dosage unit form in an individual

 

      patient taking it.  I think that would be a very

 

      powerful set of data to set meaningful

 

      specifications.

 

                We are getting more and more complex

 

      products like drug eluting stents and liposomes.

 

      For these complex dosage forms I think it would be

                                                               127

 

      essential to study drug elution, drug release using

 

      mechanistic models and new techniques in imaging

 

      and fluid dynamics.  Hopefully, future

 

      specifications will be based on in vitro mean and

 

      variability estimates.

 

                Moving from a science point to a process

 

      point--I didn't know our good friend Dr. Chuck

 

      Hoiber [ph.] would be here but this is in those

 

      days when Chuck and I were on the same floor and we

 

      started implementing this which is that from the

 

      process point of view there are also a lot of

 

      opportunities to optimize setting of specifications

 

      and that, from my perspective, is come and meet

 

      with us early.  A meeting would be useful if you

 

      have good quantity and quality of data.  As we have

 

      done on several occasions, we have had separate end

 

      of Phase II meetings with CMC Biopharmaceutics and

 

      colleagues on our side and the industry, going over

 

      the development plan and that has led to a quicker

 

      review and arriving at meaningful specifications at

 

      the time of NDA approval.

 

                Finally, I do personally believe that good

                                                               128

 

      homework will always bring dividends.  If you have

 

      good data, please share them with us and we will

 

      work with you to come out with rational

 

      specifications.  Thank you.

 

                     Questions by Committee Members

 

                DR. COONEY:  Thank you very much.  Some

 

      questions from the committee?  Ken?

 

                DR. MORRIS:  Two things.  I was a little

 

      surprised to see the high variability with BCS 3.

 

      In principle, you would expect BCS 3 to be a good

 

      candidate for waiver because, as long as your

 

      driving force doesn't change, you would expect that

 

      the absorption is rate limiting and falls into the

 

      same basic concept as 1.

 

                DR. MEHTA:  That is a very good

 

      observation.  We are looking at the data carefully

 

      ourselves, but I think it is maybe one product that

 

      is--

 

                DR. MORRIS:  Driving the variability?

 

                DR. MEHTA:  Yes.

 

                DR. MORRIS:  Or is it that the absorption

 

      itself is just variable?

 

                DR. MEHTA:  Again, we can think about it

 

      but it is a question if you have a class 3 high

 

      solubility, low permeability drug and if low

                                                               129

 

      permeability is not leading to the same conditions

 

      in vivo that is going to take away some of your

 

      high solubility benefit.

 

                DR. MORRIS:  Not the same conditions on

 

      which side?  Are you talking about in the gut?

 

                DR. MEHTA:  Yes.

 

                DR. HUSSAIN:  Sorry, if I may, I think one

 

      of the challenges is that this was always a

 

      question when we were deliberating the BCS

 

      guideline, high solubility.  But the in vivo

 

      dissolution actually is more sensitive for low

 

      permeability drugs and we actually have published

 

      on this with Lawrence--

 

                DR. MORRIS:  Right.

 

                DR. HUSSAIN:  So, people often say this is

 

      high solubility so dissolution is not rate limiting

 

      but in vivo dissolution behavior is quite complex.

 

      Plus, you add site-specific absorption of these

 

      compounds that adds to all the sources of

                                                               130

 

      variability.

 

                DR. MORRIS:  Right.  I guess that is my

 

      point in a sense.  Shouldn't the compounds be

 

      segregated into site-specific and passive absorbed

 

      compounds to really do a valid experiment?

 

                DR. HUSSAIN:  I fully agree with you.  We

 

      came up with the classification system and those

 

      four classes are beautiful but there is nothing

 

      that black and white.  Greater than 90 percent

 

      permeability, highly permeable, but there is a

 

      gradation of that and, you know, we have to take

 

      that into account.  You know, there are, like,

 

      windows of absorption.  So, we need to subclassify

 

      those four classes and then come up, you know, with

 

      better--

 

                DR. MORRIS:  Yes, but it would be nice if

 

      you could identify some more waiver-worthy classes.

 

                DR. HUSSAIN:  Yes.

 

                DR. MORRIS:  Just another quick comment is

 

      that I am sure it won't surprise you but, you know,

 

      with the general BA/BE guidance people, because of

 

      what is in the guidance, are actually doing pH

                                                               131

 

      solubility profiles of non-ionizable compounds.

 

                [Laughter]

 

                DR. MEHTA:  That is taking us too

 

      seriously!

 

                DR. COONEY:  Paul?

 

                DR. FACKLER:  I have a comment and a

 

      question.  The comment had to do with the slide

 

      where you suggested there might be about 20 percent

 

      variability for even BCS class 1 compounds.  I

 

      would suggest that that is vastly understated, that

 

      the variability is much higher than that because I

 

      am guessing that your data comes from

 

      bioequivalence studies where all of the subjects

 

      take exactly the same amount of water, the same

 

      amount of food.  None of them are BMI greater than

 

      a particular number.  If they are old studies they

 

      were all men.  I would just say that in the general

 

      population with the way pharmaceuticals are really

 

      taken--some people run three miles, come home and

 

      then swallow their tablets; some people roll out of

 

      bed and swallow them without water--the variability

 

      even for class 1 is significantly higher than 20

                                                               132

 

      percent.  But it is just my opinion.

 

                DR. MEHTA:  That would just add to the

 

      thought I had which is, you know, use that

 

      information to evaluate your in vitro

 

      specifications.  That will help you.

 

                DR. FACKLER:  The question I had had to do

 

      with that same chart where you looked at 17 drugs

 

      that were randomly pulled out of the pool of 200.

 

      It was interesting to see that the class 3 is N

 

      equals 7.  I am just wondering if the distribution

 

      of these 17 in any way represents the distribution

 

      of the 200 drugs.

 

                DR. MEHTA:  I don't think so.  The whole

 

      idea was to see if we can get a handle on what is

 

      the exposure variability for these products.  A few

 

      years ago I presented this database at one of the

 

      APS workshops what was surprising is that we saw a

 

      lot of NDAs falling into class 4 category.  If it

 

      is a class 4, then you would see very few drugs,

 

      low solubility, low permeability.  You know, they

 

      would fall out of drug development.  But, as I

 

      mentioned a little while ago, the way classifying

                                                               133

 

      we have created these four classes, 90 percent of

 

      data goes in class 1 over this 85 percent

 

      absorbed--you know, it is still low permeability.

 

      So, I don't think when we come out with this

 

      information, all audited, that there is going to be

 

      a majority of them falling in class 3.  I don't

 

      think so.

 

                DR. COONEY:  When you presented the table

 

      of the 17 samples, your intent is to expand that?

 

      This is just a piece of work in progress?

 

                DR. MEHTA:  Yes, very much so.

 

                DR. COONEY:  So, the idea is to really

 

      address the question that was just asked, that is,

 

      to have an analysis that is representative of that

 

      whole set?

 

                DR. MEHTA:  Yes.  I mean, right now we are

 

      going through each drug and making sure, to our

 

      level best effort, that the data available

 

      classifies that drug product in the appropriate

 

      class.  We have the information put together and

 

      now it is like careful auditing going on.

 

                DR. COONEY:  Good.  Marvin?

 

                DR. MEYER:  I did come up with a couple of

 

      questions.  It always bothered me that the BCS

 

      system had this quadrant drawn and then the lines

                                                               134

 

      kind of floated depending on how you wanted to

 

      define high and low--

 

                DR. MEHTA:  No, it is rigid right now.

 

                DR. MEYER:  I know it is rigid but the

 

      rigidness was arbitrary.

 

                [Laughter]

 

                It is arbitrarily rigid.

 

                DR. HUSSAIN:  I will defend it tomorrow;

 

      don't worry!

 

                DR. MEYER:  Okay.

 

                DR. MEHTA:  We started out with a

 

      conservative position and now with the availability

 

      of more data we want to expand that rationally with

 

      proper evidence.

 

                DR. MEYER:  It also bothered me that this

 

      permeability goes all the way from a very rigorous

 

      intubation of humans to a K2 cell to looking at

 

      Tmax.  So, how it is defined or determined can be

 

      another source of variability in where it falls in

                                                               135

 

      this rigorously arbitrary quadrant.  So, I think

 

      that may be a reason in part why the class 3 seemed

 

      to be more variable than 2.  One drug in that would

 

      have expanded the range.

 

                DR. MEHTA:  That is just the way those

 

      drugs got pulled out.  That is why I have that

 

      range.  That may not be reflective of what it is.

 

      I don't want to take up too much time, but we look

 

      at permeability assessment now very carefully and,

 

      in my mind, hopefully, if we have data on the NDA

 

      side, which is mass balance data and

 

      bioavailability data, that is the maximum way in

 

      terms of assessing, you know, whether the drug is

 

      90 percent absorbed or not.  Sometimes we have an

 

      issue with that.  Then we utilize the in vitro

 

      methods for that decision.

 

                DR. MEYER:  One last question.  Do you

 

      feel that the f2 test has been rigorously

 

      evaluated?

 

                DR. MEHTA:  A good question, Marv.

 

                [Laughter]

 

                There are people in the audience that--

 

                DR. MEYER:  Do you feel--do you feel it

 

      has been rigorously evaluated so it will detect

 

      differences when they should be detected and will

                                                               136

 

      allow passage when it should be allowed?

 

                DR. MEHTA:  Well, I mean we do state in

 

      our guidances under what conditions this approach

 

      should be employed.  You know, if your variability

 

      is very high in dissolution on each formulation

 

      this is not the right way of comparing those

 

      profiles so then you need to get into more complex

 

      assessment, and all that.  If it is done properly,

 

      yes, I do myself.

 

                DR. COONEY:  Pat?

 

                DR. DELUCA:  In the BA/BE guidance summary

 

      for modified-release products you are saying that

 

      they should profile using at least three other

 

      dissolution media and water.  Why do you need three

 

      others if you have a correlation?

 

                DR. MEHTA:  No, it doesn't say that there

 

      is a correlation.  This is just a question--well,

 

      usually correlation is release formulation

 

      specific.

 

                DR. HUSSAIN:  It is just for that product.

 

      So.

 

                DR. MEHTA:  It is right now.

 

                DR. COONEY:  Nozer?

 

                DR. SINGPURWALLA:  When you don't

 

      understand something you start asking technical

                                                               137

 

      questions.

 

                [Laughter]

 

                You showed a picture of linear correlation

 

      long ago, one of your early slides--

 

                DR. MEHTA:  Yes, level A correlation.

 

                DR. SINGPURWALLA:  Level A correlation.  I

 

      have two comments.  The first is that you are

 

      looking for relationships between the percent of

 

      drug dissolved and the percent of drug absorbed so

 

      correlation only measures linear relationships.

 

      You may have dependence which may be not linear but

 

      still of value to you, but correlation does not

 

      measure that.  So, I just want to say that as a

 

      comment.

 

                The second more serious comment is that

 

      that particular correlation misses the time index. 

                                                               138

 

      What you really need is a third axis also showing

 

      the time at which all these happen.  For you to do

 

      that, you want to look at these two as what we

 

      would call stochastic processes or time series, and

 

      you want to cross-correlate the two time series.

 

      So, if you want to improvise on that particular

 

      theme, you may want to look not at correlation but

 

      what I would consider cross-correlation where you

 

      also introduce the time axis.  That is the only

 

      comment I want to make.

 

                DR. MEHTA:  Thank you.  That is helpful.

 

                DR. SINGPURWALLA:  Do you want to

 

      challenge me now?

 

                DR. MEHTA:  No, I didn't say that.

 

                DR. COONEY:  Are there any other questions

 

      at this point?

 

                [No response]

 

                Thank you.  The next presentation will be

 

      by Dr. Shah establishing dissolution

 

      specifications.

 

                Establishing Dissolution Specifications:

 

                            Current Practice

 

                DR. SHAH:  Good morning.  Mehul gave a

 

      nice overview on the BCS guidance and other

 

      guidances which are used in setting dissolution

                                                               139

 

      specification from a biopharmaceutics perspective.

 

      My job today is to cover the CMC aspects of setting

 

      the dissolution specifications.  In this

 

      presentation I am going to start with an overview

 

      of the current practice, and in that overview I am

 

      going to cover the CMC assessment and bring in some

 

      of the ICH Q6A principles, how we evaluate the ICH

 

      Q6A principles in our CMC assessment, and then I

 

      would like to talk about a case study example for

 

      extended-release oral suspension and in that

 

      example I am going to cover the drug development

 

      strategy by the applicant, the dissolution results

 

      obtained based on that development strategy, then

 

      what we identified as critical issues, followed by

 

      our recommendations and based on those

 

      recommendations, what were the improvements

 

      implemented by the applicant and what was the

 

      outcome out of those implementations.  I would like

 

      to end my talk with some concluding remarks based

                                                               140

 

      on this example as well as general remarks in that

 

      aspect.

 

                As Mehul suggested in his presentation, I

 

      want to reemphasize that establishing dissolution

 

      specification is a shared responsibility between

 

      the Office of New Drug Chemistry and the Office of

 

      Clinical Pharmacology and Biopharmaceutics.

 

                In the next three slides I have presented

 

      the considerations that should be given during that

 

      development, as well as the focus of CMC assessment

 

      during the NDA review, and what forms the basis of

 

      setting the dissolution specifications from CMC

 

      perspective.

 

                As I have pointed out here, it is a known

 

      fact that physicochemical properties of the

 

      formulation components, such as drug substance and

 

      other excipients, such as the solubility, pKa,

 

      particle size distribution, polymorphic forms and

 

      there may be some others, have a significant effect

 

      on the dissolution.  The physicochemical properties

 

      impact the processibility of the formulation

 

      components, as well they may affect also the

                                                               141

 

      safety, efficacy and stability of the drug product.

 

      In addition to that, the manufacturing processes,

 

      especially those having the potential to influence

 

      the release profile of the drug substance also

 

      should be studied during the development.  And, the

 

      control strategy of the critical process parameters

 

      and in-process testing also should be developed

 

      during the development, and those are the focuses

 

      of the CMC assessment.

 

                During the drug development one should

 

      expect that there should be a relationship of

 

      in-process testing to the critical quality

 

      attributes, such as dissolution of the drug

 

      product.  Some of the in-process testing that may

 

      be carried out might be particle size distribution;

 

      release rate; and the compression force, tablet

 

      hardness and friability in the case of solid oral

 

      dosage form.

 

                In addition, during the CMC assessment we

 

      focus also on the development and validation

 

      aspects of the proposed in vitro dissolution

 

      method.  Cindy already covered some of these

                                                               142

 

      aspects in terms of how the methodologies are being

 

      developed and what are the validation criteria that

 

      need to be covered, especially pertaining to

 

      specificity, linearity, accuracy, precision,

 

      ruggedness, etc.  In addition, we also focus on the

 

      release time point intervals and what should be the

 

      adequate tim point intervals.

 

                Once we have this information we need to

 

      see or need to provide during development, as well

 

      as the NDA submission data, what is the

 

      relationship between the in vitro dissolution data

 

      from development, clinical, bio. and primary

 

      stability batches, and also identify a discerning

 

      trend on storage.  We also evaluate the proposed

 

      shelf-life of the drug product on the basis of the

 

      stability data analysis of dissolution, as well as

 

      other drug product attributes.

 

                In the end, it is in coordination with

 

      Office of Clinical Pharmacology and Pharmaceutics

 

      that appropriate dissolution specifications are

 

      recommended and these specifications are reflective

 

      of the dissolution data from various batches

                                                               143

 

      including clinical, bio., stability and other

 

      batches.

 

                In terms of the ICH Q6A document, ICH Q6A

 

      discusses the potential relevance of particle size,

 

      polymorphic content and polymorphic changes, and

 

      how it affects the dissolution.

 

                Here I have these three decision trees

 

      just for reference.  I just wanted to point out

 

      that CMC assessment very well integrates these

 

      principles in our assessment for the quality

 

      assessment of the drug product.  This is about the

 

      particle size distribution and the decision tree

 

      guides you on how to set acceptance criteria.

 

                This is in terms of polymorphic content.

 

      That also guides you on how to set acceptance

 

      criteria.  The next one is how to set the

 

      polymorphic change acceptance criteria in the drug

 

      product.

 

                Now I would like to focus on the case

 

      study example for extended-release oral suspension

 

      for the remainder of my talk.

 

                Let me give you just some background. 

                                                               144

 

      This was submitted as a 505(b)(2) application.  As

 

      a result, there was no clinical trial required

 

      because the safety and efficacy of the proposed

 

      active ingredients for the proposed indication was

 

      established through immediate-release products

 

      available under the tentative OTC monograph for the

 

      same indication.  The proposed dose was a single

 

      dose given every 12 hours to patients 6 years of

 

      age or older.  That was equivalent to the nominal

 

      OTC monograph which was given every 6 hours twice.

 

                In terms of the formula, the drug product

 

      contained two different active ingredients, and I

 

      will call them drug substance 1 and drug substance

 

      2.  For proprietary reasons, most of the data I am

 

      going to discuss here are well concealed and they

 

      are masked but the data are real.  Drug substance 1

 

      is anchored to a drug carrier support and coated

 

      separately with semipermeable polymer to prevent

 

      dose dumping and to impart the extended-release

 

      profile.  Drug substance 2 binds the drug carrier

 

      support in situ during the manufacturing process,

 

      but it is not coated.  Both active ingredients,

                                                               145

 

      along with other excipients, are suspended in

 

      aqueous solution.

 

                The concerns we had here arise from the

 

      safety implications due to the potential dose

 

      dumping, and efficacy implications due to

 

      insufficient rate and the extent of release of the

 

      actives.  These concerns were brought to the

 

      applicant's attention during the end of Phase II

 

      meeting as well as pre-NDA meetings, and they were

 

      very mindful of those two concerns.

 

                This was the strategy adopted by the

 

      applicant in the beginning.  They wanted to

 

      demonstrate bioavailability of the drug product

 

      formulas, and that was coated with 6 percent

 

      coating of drug substance 1, to a reference drug

 

      which as an immediate-release solution, and it was

 

      containing the same two active ingredients.  They

 

      had no other choice but to start with the

 

      immediate-release solution because there was no

 

      existing extended-release product containing these

 

      two ingredients.

 

                Their plan was to formulate three

                                                               146

 

      experimental drug formulations, each differing only

 

      by the coating level of semipermeable polymer on

 

      drug substance 1.  They were low coating, for

 

      example, 2 percent; medium coating, example, 5.5

 

      percent; and high with 9 percent coating on drug

 

      substance 1.  They labeled them as fast-release

 

      solution, intermediate-release formulation and

 

      slow-release formulation.  The approach was to

 

      establish IVIVC for each active among these three

 

      experimental formulations, and establish

 

      dissolution specifications for both actives based

 

      on generated dissolution profiles from the slow-

 

      and fast-release drug product formulations.

 

                In the NDA the data submitted include five

 

      formulations of the drug product containing drug

 

      substance 1 coated with varying levels of

 

      semipermeable polymer, 2 percent, 5.5 percent 9

 

      percent, as well as 6 percent and 10 percent.  They

 

      performed the following PK studies, multi dose

 

      bioavailability studies with immediate-release

 

      solution and single dose food effect study

 

      containing 6 percent polymer coating, and single

                                                               147

 

      dose IVIVC study containing three formulations, 2

 

      percent, 5.5 percent and 9 percent polymer coating.

 

      In support, there were PK results from four batches

 

      and stability results from four PK and five

 

      stability batches.

 

                Based on these PK studies, these were the

 

      applicant's claims, that level A IVIVC was

 

      established for both actives of the ER suspension.

 

      The mean individual level A IVIVC models for drug

 

      substance 2 met the FDA validation criteria and, in

 

      their opinion, it can be used for setting

 

      dissolution specifications and biowaivers.

 

                The mean and individual level A IVIVC

 

      models for drug substance 1, which is coated,

 

      failed the FDA validation criteria in that the

 

      predicted values had a larger error than

 

      recommended.  However, if the dissolution criteria

 

      remain within dissolution profiles tested in IVIVC,

 

      they proposed that the drug substance 1 results can

 

      serve as a mapping study for the formulations.

 

                Now let's see what was the agency's

 

      finding in terms of the PK results.  On the

                                                               148

 

      bioavailability and food effect studies, which was

 

      the 6 percent coating of drug substance 1, the

 

      agency found that systemic exposures of both

 

      actives were favorable between the extended-release

 

      suspension and multi dose of reference

 

      immediate-release solution, and there was no food

 

      effect on both actives.

 

                However, in terms of the IVIVC study,

 

      where the drug substance was coated with the 2

 

      percent formulation, 5.5 percent formulation and 9

 

      percent formulation, with respect to drug substance

 

      1, the agency found that it failed to establish the

 

      in vivo/in vitro correlation, and observed more

 

      than 20 percent of difference in Cmax for

 

      formulation of fast and slow dissolution profiles.

 

                With respect to drug substance 2 that was

 

      not coated, level A IVIVC was established, however

 

      it failed to validate the IVIVC.  The formulations

 

      used in the IVIVC study were found to be

 

      bioinequivalent, that is to say the Cmax of the

 

      formulations used in the IVIVC study were different

 

      by more than 20 percent.  The proposed dissolution

                                                               149

 

      specification and the approach to set a dissolution

 

      specification based on IVIVC by mapping was found

 

      unacceptable.

 

                Now let me share the stability results

 

      analysis.  This is what we review in our CMC

 

      assessment.  What we found was contradictory

 

      release profiles observed between drug product

 

      formulations containing 6 percent and 9 percent

 

      coated drug substance.  Drug substance 2 showed

 

      more decrease in dissolution than drug substance 1,

 

      and we observed substantial decrease in dissolution

 

      at 1-hour, 3-hour and 6-hour time points for both

 

      actives from the corresponding initial values among

 

      all batches, including bio. and primary stability

 

      batches, at all storage conditions.  The decrease

 

      in dissolution was most notable at 3-hour and

 

      6-hour time points.  The decrease in dissolution is

 

      minimum at the 12-hour time point and the decrease

 

      in dissolution for both actives levels off by 9

 

      months on storage.

 

                This is displayed on this slide.  This is

 

      the dissolution results of drug substance 1.  For

                                                               150

 

      clarity purpose, I have labeled the coating for the

 

      dissolution curves.  The yellow bar shows the 6

 

      percent coating that was used in the

 

      bioavailability study.  The purple is the 2

 

      percent.  The middle one is blue, which is 5.5

 

      percent coating of drug substance 1.  The red one

 

      is the 9 percent coating of drug substance 1.

 

                Now, what I explained in the previous

 

      slide is what you can see is a decrease in

 

      dissolution profiled for all the solutions.  You

 

      would expect the 9 percent would be showing a slow

 

      dissolution compared to the 6 percent but it is

 

      quite the other way.

 

                If you look at drug substance 2, the

 

      decrease is more compared to drug substance 1,

 

      which is shown basically from the least point and

 

      at the 18 months time point.  That is more than

 

      about 20 percent decrease in dissolution over time.

 

                So, based on this analysis these were the

 

      critical issues discussed with the applicant, and

 

      they concerned the raw material controls,

 

      manufacturing processing and in-process controls

                                                               151

 

      and controls related to particle size distribution

 

      and dissolution method.

 

                I just want to point out over here that

 

      these discrepancies in the results showed that the

 

      coating process was not in control and we discussed

 

      that issue with the applicant.  They decided to

 

      reformulate the drug product and decided to abandon

 

      the idea of the IVIVC approach to set dissolution

 

      acceptance criteria; conduct PK studies on

 

      commercial scale bio. batch containing drug

 

      substance 1 at the specified target coating level,

 

      rather than a range, and compare it to the

 

      reference IR solution; manufacture additional 3

 

      pilot scale primary stability batches of the drug

 

      product containing drug substance 1 at the same

 

      specified target coating level; and propose

 

      dissolution acceptance criteria based on in vitro

 

      dissolution profiles obtained for both actives from

 

      the bio. batch.

 

                These were the process improvements

 

      implemented.  They coated the drug substance with a

 

      specified target coating level of semipermeable

                                                               152

 

      polymer; revised the coating and subsequent

 

      manufacturing processes; instituted appropriate

 

      process controls to stabilize binding of both

 

      actives to the drug carrier support in the

 

      suspension; and manufactured one commercial scale

 

      bio. batch and three pilot scale stability batches.

 

                They instituted appropriate particle size

 

      measurement method, for example laser diffraction,

 

      for drug carrier support and coated drug-bound

 

      carrier particles.  They revised particle size

 

      distribution acceptance criteria for the drug

 

      carrier support, coated drug substance bound

 

      carrier support particles and suspension

 

      stabilizing excipients.

 

                Based on these results, they conducted

 

      three PK studies utilizing the drug product

 

      formulation with coating of drug substance 1.  They

 

      conducted BA/BE assessment; PK at steady state; and

 

      food effect studies.  The results showed that the

 

      PK profiles of drug substance 1 and drug substance

 

      2 from test extended-release suspension were found

 

      comparable to the reference IR solution following

                                                               153

 

      single and multiple dose administration, and food

 

      had no effect on bioavailability of both actives.

 

                Now let me share with you the stability

 

      results analysis.  After the implementation of the

 

      improvements in manufacturing process for coating

 

      and instituting adequate process controls in terms

 

      of particle size, we observed stable and consistent

 

      release profiles at 1-hour, 3-hour, 6-hour and

 

      12-hour time points for both drug substance 1 and

 

      drug substance 2 on storage within each of the bio.

 

      and three primary stability batches.  There was no

 

      discernible trend in release profiles of drug

 

      substance 1 and drug substance 2 and on bio. and

 

      primary stability batches at all storage

 

      conditions.  And, there were comparable release

 

      profiles for both drug substance 1 and drug

 

      substance 2 among bio. and three primary stability

 

      batches.

 

                This is displayed in this graph for drug

 

      substance 1.  You can see, as opposed to the

 

      dissolution rates that we saw before and after

 

      implementation of manufacturing processes.  This is

                                                               154

 

      with respect to drug substance 1, which was coated.

 

      This is the bio. batch and these are the three

 

      primary stability batches.  Most of the

 

      dissolution, as you can see, ranges between 5-7

 

      percent.

 

                This is with respect to drug substance 1

 

      dissolution profile.  This is the bio. batch and

 

      you can see these are the three primary stability

 

      batches and you do not see any discernible trend

 

      and most of the dissolution ranges between 5

 

      percent if you compare it to drug substance 2 prior

 

      to the implement.

 

                Then I would like to conclude my

 

      presentation with the following remarks.  We were

 

      able to identify probable causes of discrepant and

 

      inconsistent dissolution results for drug substance

 

      1 and drug substance 2, and recommend corrective

 

      measures to address the issues.  The outcome was

 

      consistent manufacturing process; acceptable BA/BE

 

      results; stable and consistent release profiles

 

      without any discernible trend on storage for both

 

      drug substance and drug substance 2.  Dissolution

                                                               155

 

      criteria which were set were better reflective of

 

      the data.  There was a substantial improvement in

 

      the quality of the drug product and there was a

 

      significant improvement in assurance of the safety

 

      and efficacy concerns.

 

                However, the case study example

 

      highlighted two significant points.  There was a

 

      lack of or poor understanding of the raw material

 

      properties and manufacturing processes that were

 

      critical to be controlled for consistent quality

 

      and thereby desired performance, for example,

 

      extended-release dissolution of the drug product.

 

      It also identified inadequate efforts invested by

 

      the applicant during the drug development to

 

      understand the causal links of dissolution

 

      failures.

 

                The case study example stresses a dire

 

      need for improvement to the existing drug

 

      development efforts to understand the relationship

 

      between the raw material properties of formulation

 

      components and critical quality attributes of the

 

      drug product; the effect of raw material properties

                                                               156

 

      of formulation components on their processibility

 

      for selected manufacturing processes, and the

 

      effect of manufacturing processes and associated

 

      critical process parameters on the critical quality

 

      attributes of the drug product.

 

                I would like to end my talk with the last

 

      remark that there is no substitute to a systematic

 

      and scientific approach to drug development for a

 

      safe, efficacious and quality drug product.  Thank

 

      you.

 

                     Questions by Committee Members

 

                DR. COONEY:  Thank you.  There is an

 

      opportunity for questions.  Nozer?

 

                DR. SINGPURWALLA:  Just a point of

 

      information, you repeatedly used distribution,

 

      particle size distribution.  What particle size

 

      distributions do you use in your activities?

 

                DR. SHAH:  I am not following the

 

      question.

 

                DR. SINGPURWALLA:  Particle sizes are

 

      random.

 

                DR. SHAH:  Correct.

 

                DR. SINGPURWALLA:  They are not the same.

 

      So, they have a probability of distribution.

 

                DR. SHAH:  Yes.

                                                               157

 

                DR. SINGPURWALLA:  Now, there is a lot of

 

      literature, perhaps not in your business, on what

 

      should be the distribution of particle sizes.  This

 

      morning we heard the viable distribution attacked

 

      by my colleague here, but the log normal

 

      distribution is often used as a distribution of

 

      particle sizes.  My question is what distributions

 

      are used in the pharmaceutical industry for

 

      particle sizes, or is this a completely different

 

      scenario?

 

                DR. SHAH:  I am not sure how to answer

 

      that question, but I will tell you what we practice

 

      in CMC review.  We ask for the applicant to

 

      identify the particle size range in D10, D15 and

 

      D90.  That means 90 percent of the particles--

 

                DR. SINGPURWALLA:  Right.

 

                DR. SHAH:  And we ask for the span,

 

      basically the ratio of D10 to D90 divided by D15

 

      and that gives you where the distribution lies. 

                                                               158

 

      Basically, that kind of gives control of

 

      consistency of the particle size distribution.

 

                DR. SINGPURWALLA:  Actually, you answered

 

      my question.  What seems to be not there in your

 

      industry is you are just looking at the percentiles

 

      and if the distributions are skewed one way or the

 

      other it makes a big difference what they are when

 

      you simply work with the percentiles.  So, I am

 

      just encouraging you to look into that.

 

                DR. SHAH:  I agree.  Thank you.

 

                DR. COONEY:  Ken?

 

                DR. MORRIS:  I think one of the things

 

      that occurs is that people don't control the

 

      distributions.  They tend to be log normal sort of

 

      in a general sense but people don't intentionally

 

      control this.  They usually control to a mean,

 

      which is a real big problem--

 

                DR. SINGPURWALLA:  If you control the mean

 

      you start to control the distribution.

 

                DR. MORRIS:  Yes, you try to control the

 

      mean but there is no real--and I am not sure what

 

      historically the reason is for that but that is

                                                               159

 

      sort of the case.

 

                DR. SINGPURWALLA:  You need to know what

 

      it is.

 

                DR. MORRIS:  But you need to know what it

 

      is.

 

                DR. SINGPURWALLA:  You can't control it.

 

                DR. MORRIS:  That is right.  My question

 

      is do you think that there problem was control

 

      simply of film thickness or was it perhaps

 

      incorporation of one of the compounds into the film

 

      unintentionally during the coating process?

 

                DR. SHAH:  No, that was definitely the

 

      coating process, and this was like black art in

 

      that they were mixing and matching and they never

 

      had a handle on the coating process itself.

 

                DR. HUSSAIN:  One point that I think I

 

      wanted to illustrate with this presentation was

 

      that really to control, to achieve a state of

 

      control, and so forth, you have to get down to

 

      upstream activities, starting with raw materials,

 

      and so forth.

 

                The point I also wanted to sort of

                                                               160

 

      emphasize was that just focusing on a test, even

 

      when you have a correlation, which is just a

 

      correlation and may not be causal, I think is that

 

      gap that we are also trying to fill with focusing

 

      on the CMC part of the manufacturing controls.

 

      Without that the system really--the method is

 

      weakened.  So, the quality by design aspect is to

 

      emphasize that part of it.  So.

 

                DR. COONEY:  I think another dimension

 

      with this particular case is that there is a

 

      significant amount of complexity because you are

 

      dealing with multiple products, complexity both in

 

      the process as well as in the product itself.  This

 

      is I think a particularly good example where

 

      quality by design can have a greater impact with

 

      these more complex processes and products, and the

 

      processes and the products need to be thought

 

      through together, which is your point.  It is very

 

      clear.

 

                I think we are actually going to begin

 

      lunch ten minutes early.  However, beginning lunch

 

      ten minutes early does not mean that you get an

                                                               161

 

      extra ten minutes for lunch.  We will reconvene at

 

      12:50--guess what, you can get an extra ten minutes

 

      for lunch.  We will reconvene at one o'clock.

 

                [Whereupon, at 11:50 a.m., the proceedings

 

      were recessed for lunch, to resume at 1:00 p.m.]

                                                               162

 

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

 

                DR. COONEY:   If I could have people's

 

      attention, welcome back from lunch.  I hope that

 

      everyone appreciated the extra 9.5 minutes that you

 

      had for lunch.  It is one o'clock.  It is the

 

      opening period for open public hearing.  We have

 

      one presentation for this afternoon by Will Brown

 

      from USP, and he will speak with us on USP and

 

      dissolution testing.  Thank you.  Welcome

 

                          Open Public Hearing

 

                DR. BROWN:  Thank you so much, and I would

 

      like to thank the various FDA staff members for

 

      giving a staff member at USP the opportunity to

 

      speak before this committee.  I am a member of the

 

      staff of the Department of Standards Development at

 

      USP, and I serve as one of the liaisons to the

 

      Biopharmaceutics Expert Committee.

 

                This is breaking news.  USP reorganizes

 

      itself once every five years, and part of that

 

      reorganization is the election of the chair of the

 

      Council of Experts.  We have a reelected chair,

 

      Thomas Foster, for the Biopharmaceutics Expert

                                                               163

 

      Committee.  You can see on this slide the

 

      membership, and you will see names you recognize

 

      hopefully.

 

                USP and dissolution--well, we are terming

 

      dissolution one of the performance tests.

 

      Performance tests currently mean dissolution or

 

      disintegration test, and by test I mean part of the

 

      specification.  The ICH definition, and it is very

 

      easy to use terms loosely, says that a

 

      specification is a list of tests, associated

 

      procedures and acceptance criteria.  So, that is

 

      kind of the idea of the USP dissolution.  It is

 

      part of the specification.  You will find the

 

      public specification in the USP monograph.

 

                The general dissolution test is found in

 

      the general chapter, 7-11 on dissolution, and that

 

      gives a general description of the techniques that

 

      are available, with the understanding that those

 

      techniques can be modified.  We saw this morning

 

      what the modifications might represent.  They might

 

      represent the appropriate medium or agitation or

 

      apparatus as determined by the applicant and the

                                                               164

 

      FDA.

 

                Now, the study design that is embedded in

 

      the dissolution test and the analysis is in three

 

      stages.  We have a fixed number of samples tested

 

      at each stage and there are acceptance criteria

 

      again that are determined by the applicant and the

 

      agency, and then communicated to USP by what I am

 

      terming the sponsor, who is the same party as the

 

      applicant.

 

                The general approach is to test by

 

      attribute.  In other words, a product is either

 

      good or bad.  It either conforms or it doesn't and

 

      that is a fairly decent approximation and

 

      convenient for application by an independent

 

      analyst but it doesn't necessarily address

 

      underlying distributions of performance.

 

                In the USP test by attributes there is a

 

      control on the spread of the data.  By example, at

 

      the S3 level where you tested 24 units there is a

 

      limit that says that no individual unit value can

 

      be below Q-25 percent.  So, there is an

 

      acknowledgement that there may be an underlying

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      distribution at least on stability.

 

                For the Biopharmaceutics Expert Committee,

 

      in this cycle the expert committee is working on

 

      revising general chapters to include performance

 

      tests by dosage form, by route of administration.

 

      The current approach to applied dissolution is

 

      typically two oral products and some transdermals.

 

      The routes of administration that USP has

 

      identified were discussed in a stimuli article in

 

      Pharmacopeia Forum, in September, 2003 and

 

      basically identified five basic routes of

 

      administration, topical dermal, gastrointestinal,

 

      mucosal, by injection and by inhalation.  It is

 

      just a way to cut the universe.

 

                The intention is to work with the FDA and

 

      industry as appropriate but to facilitate this work

 

      the Biopharmaceutics Expert Committee has asked for

 

      the formation of advisory panels, which have been

 

      formed.  They were formed in the last cycle and

 

      they are currently meeting.

 

                My general feeling is that meetings may be

 

      productive but oftentimes they are not.  I have two

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      examples of meetings that are productive.  In 1993,

 

      I am told that the predecessor to this committee

 

      met and out of that ultimately, in '97, came the

 

      immediate-release and extended-release guidances

 

      that were talked about this morning.  Another set

 

      of meetings that happened in that same time frame

 

      are the meetings of the Pharmacopeia discussion

 

      group.  The Pharmacopeia discussion group includes

 

      the Japanese pharmacopeia, the  European

 

      pharmacopeia, the USP and the World Health

 

      Organization.  In the process of harmonization,

 

      there actually has been a common statement with

 

      respect to system suitability.  It doesn't talk

 

      about calibrators, however there is a provision to

 

      have national text and in the national text portion

 

      of system suitability the USP continues to describe

 

      calibrators as part of the system suitability

 

      determination.  The general chapters are currently

 

      at stage six and that information can be found in

 

      the current PF and the corresponding Japanese and

 

      European documents.

 

                I was told that I only had ten minutes so

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      this presentation is briefer than I usually intend,

 

      but I would like to draw the committee's attention

 

      to possibly a useful document.  This document

 

      article by Walter Hauck and a group at USP talks

 

      about oral dosage form performance tests, new

 

      dissolution approaches.  It is in the recent

 

      Pharmaceutical Research, I think February 22.2.  It

 

      talks about an approach that has explicit

 

      hypothesis testing.  Parametric tolerance interval

 

      is involved.  It gives an improved way, or at least

 

      the authors believe that it is an improved way to

 

      set dissolution acceptance criteria, and allows

 

      more flexibility in the design of a protocol.  So,

 

      I will just point you at that resource.  It may

 

      have some value.

 

                It allows the industry representatives

 

      more control on study design; allows the

 

      opportunity for tiered testing.  It doesn't

 

      specifically talk about tiered testing but allows

 

      that there may be an opportunity for some kind of

 

      successive testing on failing to meet the criteria

 

      at the first level.  It allows some flexibility in

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      the number of units that are tested within each

 

      tier, and it allows the possibility that the test

 

      protocol, the test design could be changed from

 

      manufacturer to manufacturer.

 

                The idea is to set a probability of

 

      passing units from a batch where the clinical

 

      properties are known.  So, you characterize the

 

      batch for in vitro dissolution; determine, in some

 

      kind of a discussion with the agency--again, I am

 

      speaking from industry perspective even though I

 

      don't represent any industry perspective--sets the

 

      fraction of the units in this idealized reference

 

      population or this actual reference population that

 

      must conform to the standard.

 

                This approach, and I won't be able to

 

      describe this more fully, the authors believe will

 

      allow the consumer and producer risks to be clearly

 

      assessed, managed and communicated.  Ideally, if we

 

      continue with the model of dissolution for

 

      performance assessment, this could be communicated

 

      publicly in the compendium.  The basic underlying

 

      approach conforms to the approach for uniformity of

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      metered dose inhalers that I believe this committee

 

      will be talking about tomorrow.

 

                Finally on to calibrators, the system

 

      suitability determination is written into the

 

      general chapter and, as I interpret it, is part of

 

      the performance of any dissolution test.  So, if a

 

      dissolution test is performed for compendial

 

      purposes, currently USP requires that the apparatus

 

      is demonstrated to be suitable, and the

 

      demonstration of suitability includes successful

 

      performance of the calibrators.

 

                In actual point of fact, the use of the

 

      calibrators has a GMP function.  Test apparatuses

 

      need to be demonstrated to be suitable twice a

 

      year.  So, that is the actual application of what I

 

      believe to be more comprehensive suitability

 

      determination.  I don't currently work in the lab

 

      but when I was in the lab if there were critical

 

      dissolution experiments to be performed, they were

 

      performed on an apparatus that was calibrated

 

      before and after so that the integrity of the data

 

      was not suspect on the grounds of an unsuitable

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      apparatus.  The idea of calibration is not to focus

 

      on the performance of the apparatus but to rule out

 

      unsuccessful or unacceptable apparatus, so rule out

 

      apparatus on the extremes.

 

                The extremes--there is a range of

 

      acceptable results that is determine from a

 

      collaborative study, and we try to cast the net as

 

      widely as possible so that we can capture the

 

      sources of variability in properly operating labs.

 

      Inter-laboratory variability is a major component

 

      of the ranges.  I would submit that any one

 

      dissolution apparatus or assembly, because the USP

 

      looks at the apparatus as a single vessel, single

 

      spindle combination but, in fact, we have

 

      assemblies, groups of apparatus.  So, that is part

 

      of the wideness of the range.  We can talk about

 

      that if you wish.

 

                Calibrators, what we do with calibrators,

 

      USP is aware of problems.  Salicylic acid has

 

      elegance problems.  And, we go into unit packaging

 

      in the latest batch.  Prednisone tablets, the

 

      prednisone tablets that we distribute are a

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