1

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

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.

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

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

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

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

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

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

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

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

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,

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

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

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

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

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

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

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

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?

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

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

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

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

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,

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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?

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

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

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

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

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

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

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.

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

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

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

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

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,

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

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,

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

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

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

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

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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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

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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.

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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,

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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

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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

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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

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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

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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,

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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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