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
2
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.
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C O N T E N T S
PAGE
Call to Order
Charles Cooney, Ph.D.,
Chair 5
Conflict of Interest Statement
Hilda Scharen, M.S., Executive
Secretary 5
Introduction to Meeting--OPS Update
Helen Winkle 7
Opening Remarks
Charles Cooney, Ph.D. 16
Establishing Drug Release or Dissolution
Specifications:
Topic Introduction
Ajaz Hussain, Ph.D. 18
Dissolution Measurement System:
Current State
and Opportunities for Improvement
Lucinda Buhse, Ph.D. 45
Questions by Committee Members 76
Overview of Guidance Documents
and Decision Process:
Biopharmaceutics Section
Mehul Mehta, Ph.D. 95
Questions by Committee Members 128
Establishing Dissolution
Specifications:
Current Practice
Vibhakar Shah, Ph.D. 138
Questions by Committee Members 156
Open Public Hearing:
Will Brown, USP 162
Questions by Committee Members 171
4
C O N T E N T S
(Continued)
PAGE
Establishing Drug Release or Dissolution
Specifications: (Continued)
Factors Impacting Drug Dissolution and
Absorption: Current State of Science
Lawrence Yu, Ph.D. 179
Questions by Committee Members 198
Summary of Tactical Plan
Ajaz Hussain, Ph.D. 208
Committee Discussion and
Recommendations 229
Clinical Pharmacology Subcommittee Report
(via teleconference)
Jurgen Venitz, M.D., Ph.D. 284
Questions by Committee Members 301
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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
6
Subcommittee and, two, discuss and
provide comments
on the general topic of establishing drug
release
or dissolution specifications.
This meeting is being held by
the Center
for Drug Evaluation and Research. Unlike issues
before a committee in which a particular
product is
discussed, issues of broad applicability,
such as
the topic of today's meeting, involve
many
industrial sponsors and academic
institutions. The
committee members have been screened for
their
financial interests as they may apply to
the
general topic at hand. Because general topics
impact so many institutions, it is not
practical to
recite all potential conflicts of
interest as they
apply to each member. FDA acknowledges that there
may be potential conflicts of interest
but, because
of the general nature of the discussions
before the
committee, these potential conflicts are
mitigated.
With respect to FDA's invited
industry
representatives, we would like to
disclose that Dr.
Paul Fackler and Dr. Gerald Migliaccio
are
participating in this meeting as
non-voting
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industry representatives, acting on
behalf of
regulated industry. Dr. Fackler's and Dr.
Migliaccio's role on this committee is to
represent
industry interests in general and not any
one
particular company. Dr. Fackler is employed by
Teva Pharmaceuticals and Dr. Migliaccio
is employed
by Pfizer.
In the event that the
discussions involve
any other products or firms, not already
on the
agenda, for which FDA participants have a
financial
interest, the participant's involvement
and
exclusion will be noted for the
record. With
respect to all other participants, we ask
in in the
interest of fairness that they address
any current
or previous financial involvement with
any firm
whose product they may wish to comment
upon. Thank
you.
DR. COONEY: Thank you.
Now Helen Winkle
will provide an update.
Introduction to Meeting--OPS
Update
MS. WINKLE: Good morning, everyone. I
would like to welcome all the members of
the
8
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
9
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
10
the changing world of pharmaceutical
development
and manufacturing while we continue to be
able to
serve the consumer. It is the right time too to
ensure that our regulatory involvement
does not
hinder the innovation and continuous
improvement in
manufacturing and ensuring the quality of
pharmaceutical products.
So, FDA has begun a journey
towards this
paradigm shift. I want to say it is a long
journey.
It started several years ago but we have
a long way to go, and we have numerous
challenges
along that way. However, with these challenges
come opportunities and I think this is the
important thing for us and the advisory
committee
to remember, that we need to take
advantage of
these opportunities. It is important not only to
take advantage of the opportunities to
help us
improve on how we regulate product
quality, but
also to ensure that we provide for
modernization
both at FDA and within industry for the
21st
century.
The guiding principles of the
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Pharmaceutical cGMP for the 21st Century,
which
include risk-based orientation,
science-based
policies and standards, integrated
quality systems
orientation, international cooperation
and strong
public health protection, serve to help
us in
developing the pathway to restructure the
oversight
of the pharmaceutical quality. As each of you
knows, there are a number of forks in
that path and
you, as members of this advisory
committee, are
really here to help us determine the right path in
the road to go from a scientific
perspective, and
to help and advise us on how to fill the
gaps which
exist in the FDA. These include gaps in
organization, gaps in science and gaps in
policy.
The committee has already
participated in
discussions on a number of scientific
issues which
have helped in formulating a strategy for
addressing many of the questions that
have emerged
as a result of this paradigm shift. We have
already discussed a number of issues
which have
significance as we develop our future
regulatory
paradigm, including such issues as
polymorphism,
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bio-inequivalence of generic products,
and we have
worked together to support such
initiatives as the
Process Analytical Technology
Initiative. The
committee has also been extremely helpful
in moving
toward this new paradigm with other
discussions
that we have had on various topics. However,
again, the journey has only just begun.
The agenda for the next two
days was
developed to provide an opportunity to
discuss two
other scientific topics which are
important to us
to better understand and manage in order
to move us
steadily along the path of change. The first topic
is on establishing drug release or
dissolution
specifications. Obviously, how we set
specifications is important to the
future. As we
move to the desired state of
pharmaceutical quality
we want to ensure that specifications are
based on
mechanistic understanding of how product
and
process factors impact product
performance. We are
currently in the process of developing a
tactical
plan for setting dissolution
specifications. As
you will hear from the presentations
today, we have
13
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
14
the tactical plan for setting dissolution
specification and will lay the foundation
for our
thinking in setting specifications for
CMC and
addressing the specific issues that were
identified
at the workshop.
We would appreciate the
committee's
comments and suggestions as to what data
is needed
to support our plans. This would include looking
at statistical methodology, etc., and how
we might
improve on our thinking in our tactical
plan and
specifications setting in general.
At this meeting we will also
discuss, as
our second big topic, quality by design
and
pharmaceutical equivalence. As you will remember,
at
the last meeting we set the stage in our
discussions on bioinequivalence and
bioequivalence
testing of locally acting GI drugs. At this
meeting our goal is to modernize our
general
thinking about pharmaceutical equivalence
and to
explore how quality by design can be
leveraged to
ensure more rational approaches to
decision-making
so that we can move from a reactive
environment to
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a
proactive regulatory scheme of assessing
equivalence.
We will discuss a number of
relevant
topics, including biopharm.
classification system;
using product development information to
address
highly variable drugs; and we will
revisit the
concept of decision trees for ensuring a
rational
approach to determining bioequivalence
for topical
drug products. We look forward to the committee's
feedback on these extremely important
topics, and
that discussion is for tomorrow.
There are a number of other
topics we will
cover at this meeting, including an
update from the
working group on parametric tolerance
interval test
for dose content uniformity. Bob O'Neill will give
that update. And an update from the Clinical
Pharmacology Subcommittee. We will also discuss
with the committee our perceived need to
establish
a working group for the review and
assessment of
OPS' research programs. Our goal in looking at our
research programs is to ensure a common
approach to
all laboratory work and to ensure that
our research
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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
17
cGMP Initiative and the Critical Path
Initiative
and these, indeed, lay a foundation that
we all
need to work within. In fact, it is an exciting
opportunity to work within those
initiatives to
look at how we can better address some of
the
challenges going forward.
Certainly, as we look forward there are
more challenges than there have been in
the past.
We are facing a world of increasing
molecular
complexity; a world of increasing demands
by
consumers; a world in which we have
increasing
complexity not just in the molecules but
in the
delivery formats of these products and
the role of
this committee is very important in
helping to
provide advice to the FDA and to the
division to
deal with these problems. I must say, I applaud
the forward-looking and the proactive
stance that
is being taken on these issues.
We have some challenging goals
today and
tomorrow, not the least of which, of
course, is to
stay on time. But the reason that the challenge of
staying on time is a challenge is because
of the
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very high content of material that we
need to deal
with.
So, I will do my best to try and keep us
within the proper boundaries.
Again, I look forward to
working with
everyone.
This will be a very interesting two days
and I see it as an important step in what
will be a
continuing series of discussions and
activities and
recommendations that we will need to work
on with
the FDA.
With that, the first presentation and
discussion this morning will be by Ajaz
Hussain,
and we will begin by digging in to
establishing
drug release and dissolution
specifications. Ajaz,
please?
Establishing Drug Release or
Dissolution
Specifications Topic
Introduction
DR. HUSSAIN: Thank you, Dr. Cooney. I
think topic one is entitled quality by
design
approach for quality control and
assurance of
dissolution rate. In the background packet, as
well as in the presentations, I have
tried to keep
the terminology dissolution rate all along
to
illustrate the one challenge which we
will not be
19
discussing today, and that is the metrics
for
dissolution rate itself. We express dissolution
rate as a Q factor which tends to be
confounded
with the variability of the assay
itself. So, that
is not the topic for discussion today but
I just
wanted to alert you on why the word
"rate" keeps
coming back and back again. So.
Topic one: Our goal is to seek your
recommendations and endorsement of the
proposed
regulatory tactical plan. With this tactical plan
we hope to start moving towards putting
together a
set of regulatory tools and policies that
will help
us define elements and details of the
elements
necessary to realize the goals of quality
by
design.
The question that we are posing
to you is
are the tactical steps outlined
consistent with the
goals that we have shared with you? What initial
steps and/or changes would you recommend
to improve
this plan? What additional scientific evidence do
you feel would be necessary to support
the
development and implementation of this
plan?
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General considerations for identifying
and
developing statistical procedures and, in
particular, I want to emphasize for this
discussion
today that we have left out a discussion
on
statistical procedures because our
experience has
been that if we start with that as a
topic it leads
to protracted debate, and you will hear
one report
on that debate from Bob O'Neill tomorrow,
the
debate on parametric tolerance interval
that has
been going on for years and hasn't come
to any
resolution. We feel that if you approach it from
scientific foundations first, statistics
is simply
a tool to implement the scientific
decision
framework. So, that is the reason we have kept
that out of discussion for today. Clearly, we are
seeking your specific recommendations and
other
recommendations that you may have including
how we
should prioritize our work to develop
this tactical
plan to a full proposal, which we hope to
bring to
you at a subsequent meeting.
What are the proposed
steps? The proposed
steps are to develop an alternate
regulatory
21
approach to demonstrate the suitability
of
dissolution measurements system;
introduce and
utilize the concept of reproducibility
and
repeatability study using the actual
pharmaceutical
product for which we set
specification. Here, the
proposal is to consider using the pivotal
clinical
lot or the bio. lot as a basis for
identifying how
sensitive, or lack of it, it is to a
dissolution
test method and estimate the variability
in the
method and, therefore, of the product.
So, the first two steps are
sort of
together.
But the next three steps are also sort
of in one clump. We want to move towards a
system-based decision tree for
establishing
dissolution rate specification. Within that
framework I think we would like to
utilize
opportunities to utilize the PAT approach
for
controlling dissolution rate and
development of
real-time quality assurance
strategies. Also, a
decision tree for design-based concepts
articulated
in the draft ICH Q8 guideline, which is
in your
background packet.
So, those are the decision
trees which we
would like to develop. At the same time, when we
come back with the full proposal to you,
we would
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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
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Saturday I leave for Brussels for our ICH
meeting,
is that we do intend to seek the
discussion here,
and utilize the discussion here, to seek
harmonization of the approach we are
proposing
under the ICH, especially the ICH Q8 Part
2, and we
will start developing that guideline in
Brussels
next week.
ICH Q8 draft guideline
essentially brought
a basis for getting and considering
pharmaceutical
development information in a structured way
for
pharmaceutical decision-making in the CMC
arena at
FDA.
The guideline was constructed with this
figure, on your right, in mind. You have to focus
your design efforts on the intended use
of the
product, the patient population and so
forth, that
leads to a product design and that
product design
dictates the design specification, which
are
customer requirements, and these
requirements, some
of them if they are critical, become
regulatory
specifications. Then the product design and design
specification dictates or leads to design
of a
manufacturing process to reliably and
predictably
24
deliver those specifications back to
deliver the
intended use.
In a systematic way, if you
approach
pharmaceutical development in a
structured way, you
get some benefit, we believe. You achieve a higher
degree of process understanding and give
regulators
high confidence of low risk of releasing
a poor
quality product; high efficiency through
continuous
learning and improvement. And, I think it helps us
to
address some of the gaps we have in the current
system.
I have tried to illustrate the current
process within FDA and the manufacturing
and R&D
process within industry. Research and development
will develop the products, transfer them
to
manufacturing and then we have, by law, a
separate
quality unit to maintain quality
assurance. You
have all the specification results and
you have
products which don't have all the
specification
results.
In approaching and assessing
the quality
we bring a team approach, a
multi-disciplinary team
approach which includes pharmacology,
toxicology,
25
CMC review, clin. pharm., bio. pharm.
review and
the clinical assessment. And the decision
collectively is a risk-benefit decision
that leads
to an approval of a product. The approved product
is then transferred--it is called technology
transfer--and the process is validated.
The validation process includes
qualification criteria and so forth, but
there is
an element of that which is process
qualification.
Process qualification is essentially, in
my
opinion, the interaction between
materials and
equipment and environment that you really
have to
study.
In the current state that essentially is
judged on your ability to repeat it three
times.
Since the pharmaceutical development
information is
not available for CMC reviewers, the
quality of
that and the understanding containing
that is not
well understood in the regulatory
sense. So, we
are losing an opportunity to make more
rational
decisions.
Now, we have a divide, an
organizational
divide within the agency between, say,
review and
26
GMP inspection. The cGMP process is helping
bridge.
The PAT is an example of how we have
bridged it. Our experience or learning from the
initiative clearly identified a need for
a quality
system orientation. I would be wrong if I said
that I really did not understand what
this really
meant or really didn't care about what
quality
system issues were because I was looking
from
several years ago. But I think I have gained a
much deeper understanding of the
importance of the
quality system orientation.
So, here is a representation of
that from
a paper that we published on innovation
and
continuous improvement in pharmaceutical
manufacturing. Say what you do, do what you say,
prove it and improve it are the elements
that make
up a quality system. Consider the way what you do
is your application to FDA. So, that is a CMC
review assessment process. Now, do what you say
can be considered as are you able to manufacture
to
the commitments that you have placed in
your
application? Now, there is a gap since our
27
reviewers don't have an idea that they
really do
what they say. That is a GMP function so there is
uncertainty there. And prove it.
How do you prove
it?
I think metrics for proving it could be
process capability and the recalls, and
this and
that.
If you are unable to prove it you need to
have a collective action and a preventive
action.
Our experience has suggested
that in most
cases root cause is unknown or a poor
analyst is
blamed.
So, we actually don't get to a root cause
generally. Does the current system support or
facilitate getting to the root
cause? I think that
is the question. In many ways I think say what you
do and do what you say, if you take that
ratio is
process understanding and your ability to
prove.
So, in many ways I think you have to
think about
that.
Now, a modern quality system
has a
dimension of improvement, continuous
improvement
and innovation. The dotted line simply says that
is an option that should be available for
industry
to do.
It is dotted because that is not a
28
requirement per se, but the rest are all
requirements. So, I think we are trying to address
some of these gaps along the way.
Now, the definition of
continuous
improvement is interesting and it really
sets the
stage for this discussion. I have taken the
definition from QS-9000 to illustrate the
challenge
we face for continuous improvement. For those
product characteristics and process
parameters that
can be validated using variable data,
that is
continuous data, continuous improvement
means
optimizing the characteristics and
parameters at a
target value and reducing variation
around the
target value. So, in a sense, you need a target
value and you need to have an estimate of
variation
to start thinking of continuous improvement. In
our specification setting often we don't
even have
a target value. So.
And forget variation. So.
But the second bullet is more
important.
For those product characteristics and
process
parameters that can be only evaluated
using
attribute data, pass/fail, continuous
improvement
29
is not possible until characteristics are
conforming. If attribute data results do not equal
zero defect it is by definition a
non-conforming
product.
Improvements made in these situations are
by definition corrective actions, not
continuous
improvement. And, we have clearly distinguished
between corrective action, which is a
risky
scenario, and continuous improvement,
which can be
managed differently.
Continuous improvement in
processes that
have demonstrated stability,
acceptability,
capability and performance--continuous
improvement
really is only possible for those
products that
have demonstrated stability. Process validation
today does not give us the assurance that
the
process is stable. So, that is another element.
Acceptable capability, we don't have an
estimate of
the capability value.
Now, the reason for finding
this out is
that I think we don't use compendial
methods as
release specifications. Actually, the compendium
approach to specifications is right. That is the
30
way they should be. There is nothing wrong with
this specification criteria for the
market
standard.
It is perfectly all right. But it
is,
as Janet Woodcock says in her paper,
different from
release specification and that is the
distinguishing feature that I think is
the problem
here.
If you use market standard as release
specification, then you have all the
elements that
hold back continuous improvement. So, you really
need to distinguish between standards and
specifications. Unfortunately, in the current
paradigm specifications equals
standard. So, what
we are moving towards is a control
strategy that
will allow you to have your market
standard but
then have a control philosophy that
allows you a
risk-based decision process.
A recent proposal from USP I think
is a
step in the right direction. It is essentially a
similar proposal to the parametric
tolerance
interval test to take dissolution
specification
criteria towards more of a tolerance
interval
approach.
But as you will hear tomorrow from the
31
parametric tolerance interval discussion,
you
cannot approach it as hypothesis testing
for every
product batch, and that is one of the discussions
that we will have. And, there are many challenges
before we even can get to that, and that
is a part
of this discussion. We believe one has to start
with a pharmaceutical science discussion
before
developing appropriate statistical tools.
One other challenge for
continuous
improvement is the mind set--and this is
a major
challenge not only within the U.S. but
globally--that corrective actions is the
only way
to force improvement of quality on
industry. This
is direct current paste from the paper
that we
issued.
Some would argue that corrective actions
provide the necessary constancy of
purpose for
improvement, necessary since
manufacturing is a
stepchild of industry because the
difference
between cost of manufacturing and price
of drugs is
large.
Keeping the system of corrective action
provides the leverage for ensuring
improvement, to
ensure the cGMP.
That is a fundamental challenge.
How do
we achieve that? If you improve your manufacturing
process by reducing variability your
regulatory
32
acceptance criteria will be narrow. So, that takes
things into a way for continuous
improvement. So,
that is another challenge that we will
start
addressing.
The argument has some validity
but it is
based on an assumption that current
practices,
including measurement systems and product
specification, provide efficient means
for
identifying, understanding and then
reducing
variability. For quality assurance in the 21st
century we need a sound basis to verify
such
assumptions in the current system.
To emphasize this point
further, we
discussed the case of dissolution and
that is what
we present to you today. Let me illustrate an
example, a real case example. This is an example
of an approved and validated
manufacturing process
at a major pharmaceutical company. I will read the
middle portion of this. This is the warning
33
letter:
There is no assurance that the production
in process control procedures
established--this is
controlled-release product--to produce a
product
that has the quality it is purported to
have or
represented to possess. How did we approve it?
How was it validated? So, this is after the fact.
The duration of each coating cycle is
determined by
the pan operator but is based on visual
determination that the coating solutions
are evenly
distributed before proceeding to the next
step. It
is noted that literally 50 percent of the
batches
are thrown out every year because of
dissolution
failures, and then you have partial
release
occurring too. Doesn't this undermine the entire
credibility of our system? And, this was
catastrophic for the company.
Now, inability to resolve our
specification observations I think
undermines the
credibility of our decision system. It raises
questions of adequacy of the current
decision
system.
It increases the risk of releasing an
unacceptable quality product to the
consumer, and
34
contributes to low efficiency.
Now, corrective action,
preventive
action--there are some challenges. There are
difficult questions faced by
manufacturing groups
and regulators since we have a calibrated
system
that we use for dissolution and a
calibrated system
is a tablet similar to any other tablet
that we
use, and the quality is an issue
there. If you
choose to use a calibrated tablet for
gauge R&R
study, reproducibility and repeatability
study,
what you see there is that the calibrator
variability and its manufacturing process
is
confounded within that system. I am not going to
go through the equations but it is simple
algebra.
In addition, we have another challenge.
The challenge is that the assumption of
independent
variable cannot be really verified
because the
hydrodynamics of the vessels are such--I
see our
colleagues from Health Canada here who have
been
criticizing this for a long time. Thank you for
coming, sir. So, how representative is the
suitability for that product is an issue.
But the need for improvement is
not
limited.
We need to be confident of our analysis,
of surveillance samples, consumer
complaints, other
35
investigations. One of the frustrating jobs that I
have is where we get consumer complaints;
we do
investigations; we do dissolution--no
answers. I
mean, you really don't get to the root
cause.
I think the basic philosophy
that Walter
Shewhart sort of proclaimed years ago is
very
important. Pure and applied science have gradually
pushed further and further the
requirements of
accuracy and precision. However, applied science,
particularly in the mass production of
interchangeable parts, is even more
exacting than
pure science in certain matters of
accuracy and
precision. That is the basis of this discussion.
Is the current approach to
calibration
adequate?
Dr. Cindy Buhse will share with you her
challenges--as one of the premier labs,
probably
the world standard for dissolution at FDA
and
elsewhere, and Tom Layloff had started
some of
these processes and he is here
too--dissolution
36
testing of the USP wants to require
diligent
attention to details, mechanical and
chemical.
Dosage forms can respond definitely to
small
variations; large differences in
dissolution
results are possible unless all
parameters are
carefully controlled. Differences in
reproducibility can often be traced to
improper
mechanical calibration or degassing. Much of that
is mechanical. When you only have suitability
criteria just based on a tablet, it hides
some of
this variability.
We had a rude awakening to this
ourselves.
This is really when I started realizing
the
confounding nature of the problem that we
have.
Just to illustrate how frustrating this
experience
was, our marines were contracting malaria
when they
were in Liberia and we were asked to see
whether
this was a quality problem. We faced significant
challenges in analysis because I had
insisted that
two labs would do this because this was a
grave
situation. Unexpected inter-laboratory differences
highlighted limitations of current
calibration.
37
Here is just a quote from our DPA
lab: We are at a
loss to explain the difference between
DPA and the
Philadelphia district office initial
results. Then
we started tracing it back. It had to be
mechanical differences and degassing.
Well, I think that is not the
only issue.
I think the bigger issue that we are
confronted
with is that we need to better understand
the
sources of variability in product
performance and
quality so as to establish the most
appropriate
design specifications for the product
that support
continuous improvement and address the
increasing
complexity of product designs.
This is another concern. We are moving
towards drug eluting, towards nano materials,
towards other complex devices and, yet,
we don't
have good measurement systems for these
products.
We want measurement systems for products
intended
for non-oral administration and non-oral
drug
delivery systems; develop and implement
globally
harmonized proactive regulatory decision
system,
including Q6A and Q8.
I just want to sort of lay the
foundation
for other aspects that Mehul and Vibhakar
will
share with you. Pharmaceutical development and
38
dissolution specification without
pharmaceutical
development information creates more
challenges.
Decisions focus only on dissolution test
data.
Tests are often used for both in-process
control
and final product testing. Decision
characteristics focused only on the mean
value will
deal with variability indirectly. Variability
managed indirectly using "disconnecting
test
conditions" and acceptance criteria
leads to
deterministic interpretation of
specifications and
ignores background variability and, as
Dr. Woodcock
has said, we need to move towards a
probabilistic
decision system. Specifications are standards and
standards don't give any room for
uncertainty or
risk-based decisions. If you don't meet the
standards, you are off the market. It is as simple
as that.
So. And you have event trees as
opposed
to decision trees. It is difficult to resolve
specification observations which could be
related
39
to how we set specifications, and
post-approval
changes and optimization in continuous
improvement
is difficult.
This is simply an illustration
of the gap
that we base all of our decisions on
test-to-test
comparison, in vivo to in vitro, and
there is an
opportunity to use the design information
to make
rational decisions. Just to illustrate this, again
this is from Health Canada which has been
very
proactive and pushing this agenda and I
am sorry we
just didn't react more quickly--here is
an
illustration of the false-positive and
false-negatives that you get. The reference
product dissolves 95 percent in 15
minutes, and the
reference AUC, Cmax. But if you look at product F,
it dissolves very slowly in vitro but,
yet, in vivo
it meets the criteria--it is almost
identical to
that.
So, there is a formulation
attribute that
does this. For example, if you have a large amount
of organic or insoluble excipient it is a
hydrodynamic effect. That doesn't happen in vivo.
40
The in vivo media, the surface tension,
the
hydrodynamics are completely
different. So, you
tend to see this but you also get
false-positives
and false-negatives. If I look at product C, it
has only 62 percent dissolution compared
to product
F and has half the Cmax.
There are other differences in
how we
approach specification setting. The difference
between the U.S. and Japan--we included a
paper of
the Japanese perspective on this in your
background
packet.
Because of the new restrictions I took the
names off. I had to go back and erase those. This
is a published paper so I was surprised
that I
needed to take the names off.
The point here is this, all are
basic
drugs and this is a rule of thumb that
has been
known for 30 years, if you have a drug
with PK
between 4-6 the best media to illustrate
in vivo
performance is that of the PK value. That is where
the dissolution is slower. So, the Japanese have
been in that direction. All our specifications use
0.1
normal, here. Is that important? Well, the
41
Japanese think so because they are very
concerned
with hypoacidity in the subjects. If I really look
at it, with antacids and H2 blockers most
of us are
hypoacidic too. So, is this a gap that we need to
fill is the question that I think we will
address
as we go along. So, you can see the dramatic
difference in dissolution as pH 1.2 to pH
7.2 and
the resulting blood levels.
So, in a sense, the opportunity
we are
trying to realize is ICH Q6A actually had
it quite
nicely captured in this quote: The quality of a
drug substance and drug product is
determined by
the design development, in-process
controls, GMP
controls, process validation and by
specifications
applied throughout development and
manufacture.
So, you have the goal; you have the
decision
characteristics; and you have the life
cycle. The
design development was the missing
element in our
decision characteristics. Now we have an
opportunity to use it more effectively.
This is how ICH Q8 captured
that
opportunity, to bring the development and
design
42
information not only to ask the right
question but
also to realize the opportunities of
flexibility
that might bring. So, design and development
should impact positively on how we set
specifications in process controls and
have more
confidence in process validation and GMP
controls.
With that as a background and
the reason
for this topic for discussion, in many
ways the
tactical plan is an attempt now to go
back ten
years and to see how we can do better
with our new
information that could come through the
PAT process
and the ICH Q8 process. In many ways we are
reexamining the SUPAC guideline, the
dissolution
guideline for '97, the biopharmaceutics
classification assumed in ICH Q6A. The vector for
the desired state is that we are adding
another
layer of variability assessment,
identification
assessment and utilization of variability
in our
decision-making. So, the basic fundamental is that
the quality of decisions can only be
better so the
current system is the minimum level of
quality that
we
achieve.
So, for the discussion today
Cindy Buhse
will share with you her proposal on
measurement
system, how mechanical calibration will
be better
43
and
that is what we want to use. Mehul Mehta
will
share with you the general overview of
our decision
process in our guidances. Lawrence Yu is one of
the leading experts I think in sort of
modeling
dissolution and in vivo absorption. So, I have
asked him to share a perspective on the
current
state of science. Then I will come back and
outline the steps of the proposal. I have a number
of slides in your packet but I will not
be using
those slides. I will be using only the first 16
slides to give you ample opportunity for
discussion. Those are backup slides. If there are
questions I will come back to them.
In your background packet I
specifically
identified one person by name for his
contributions, and that is Dr. Vinotcha
[ph.]. I
think the work he has done in
particular--the
reason I am pointing him out today is
because he
has decided to retire and I want to recognize
his
44
contribution to dissolution. He has brought it to
this level and I think taking it beyond
that, and I
thank him for that and he is here
today. A number
of people are there from DPA who are
experts in
this and I will recognize them at some
other point.
With that, I will stop and
invite Cindy to
share her thoughts with you. Any questions before
I leave?
DR. COONEY: Thank you, Ajaz. We will
certainly have time for extensive
discussion later
but I think, particularly since we are
right on
schedule, if anyone has any questions for
Ajaz
right now, particularly for clarification
of any of
the points he has made, this would be a
very
appropriate time to take a moment for
this. Ken?
DR. MORRIS: Yes, just one quick point on
an early slide where you were talking
about the
development process, it actually goes
from the
intended use through to development. I would just
say for clarification, because this is
something
that I get quite a lot, what we really
want to get
across I think is the idea that when you
have the
45
intended use and the characteristics you
really
select your process first.
DR. HUSSAIN: Yes.
DR. MORRIS: And then come back to the
formulation. So, it doesn't necessarily change the
order but it adds a level because that is
a
constant source of confusion,
particularly when you
are talking about building in dissolution
characteristics.
Dissolution Measurement System:
Current State and Opportunities for
Improvement
DR. BUHSE: Thank you, Ajaz. It is going
to be my job to tell everybody a little
bit about
dissolution. Some of you, I know, are very
familiar with it but some of you may
never have
experienced it or seen it done and it is
kind of a
very different way of testing so I am
going to show
you a little bit about the different
apparatus you
can choose to do dissolution testing;
talk a little
bit about how we currently determine
instrument
suitability in terms of calibration, both
mechanical and chemical; and also
validation of
46
dissolution of test methods and what we
typically
see in our lab when we take a look at
method
validation packages. Then I am going to show you
some sources of variability within
dissolution,
show you examples of how some
formulations are
sensitive to some parameters and some
formulations
are sensitive to others and we really
need to
understand for your particular
formulation where
your sources of variability are coming
from. Then
I will just briefly talk about some
opportunities
for improvement, many of which Ajaz
already alluded
to in his talk.
If you go to USP, there are
seven
different dissolution apparatus
listed. They are
all up here. You can see that the ones I am going
to talk about today mostly are apparatus
1 and 2
because those are the two that are used
the most by
most pharmaceutical companies. We do see some of
the other apparatus occasionally. Apparatus 3,
reciprocating cylinder, can also be set
up for
apparatus 7 so those are actually the
same piece of
equipment. The flow-through cell is used more in
47
Europe than it is in the United
States. We don't
see much with that here. Then, apparatus 5 and 6
are used for transdermal delivery systems
and they
are actually a modification of apparatus
1 and 2.
What I am going to talk about most today
is apparatus 1 and 2, which is actually
the same
piece of equipment and what you are doing
is you
are changing the shaft on the different
vessels to
change it from apparatus 1 to apparatus
2.
Actually shown in the picture there is
apparatus 2
and you can see there are paddles above
each one of
the about 900 ml vessels there. The way
dissolution works is that you are
actually testing
6 tablets at once. I think Ajaz showed that in the
specifications there usually is a
specification
which says 6 tablets have to have a
certain
dissolution value and if one of those 6
fails you
go to 12 tablets and then you go to
24. So, you
start with just 6 and if everything goes
right,
then you will be done after the 6
tablets.
So, you essentially have 6
different
pieces of apparatus here because each one
of those
48
vessels acts independently. You would fill each
one with whatever media it is that you
want to test
in, whether it is 0.1 normal HCL or water
or
simulated intestinal fluid. There are all sorts of
ranges of media that people use. So, you put
500-900 ml in these vessels and then for
apparatus
2 you just lower the paddle down and
start it going
at whatever rpm you decide. Certainly, that is
another variable you can manipulate. Then you drop
your tablet or capsule in and then you
take a
sample out of the media at whatever time
point your
specification is. If your specification may be 80
percent dissolved after an hour, then
after an hour
you
would withdraw a small portion of the media and
then you would determine how much the
drug has
dissolved. Usually the determinative step there is
HPLC.
So, you do that for all 6 of these vessels
and then, hopefully, everything dissolves
in the
right amount of time and you will be
done.
the basket--similar. You just change the
shaft and you put a basket on and you
actually put
the drug in the basket and then you lower
the
49
basket and start it spinning and you go
through the
same procedure.
Just so you can see what it
looks like,
this shows you what apparatus 3 looks
like, which
you can also turn into apparatus 7 by
changing the
holders.
You actually would put the tablet or
capsule inside each one of those up at
the top.
What it does, it comes up and down inside
each one
of these little vessels down at the
bottom. What
you can do with this apparatus is you can
change
the media so in every row you can put a
different
medium if you want. So, if you want to start your
capsule dissolving at 0.1 normal HCL and
move it to
simulated intestinal fluid, in the first
row you
could put acid. In the next row you could put
intestinal fluid. In the next row you could put
whatever you want. Then you can move this
apparatus up, you know make it go up and
down for
an hour in one and then move to the next
and go up
and down.
So, that is how you could do it with
apparatus 3.
This is apparatus 4, and I
think I
50
mentioned we don't see a lot of this
one. This is
a flow-through cell. You can see over there, on
the far side, that is what the actual
cell looks
like.
So, if you had a capsule or tablet that
didn't completely disintegrate you could
put it in
this cell and actually flow through,
somewhat like
actually happens in humans--flow through
a media
and change it as you go. You can either recycle it
around or you can actually have a one
pass through
media as well and then analyze the media
as it is
coming out to see how much drug is
dissolved. For
this one there is also a bunch of
different cells,
different geometries that you could put
in this. I
kind of show examples of that there.
Most of what I am going to talk
about
today is apparatus 1 and 2, and that is
because
that is the majority of what we see in
methods that
are given to us for method
validation. When they
use apparatus 1 or 2 they use the USP
criteria for
setting up the equipment and for
calibrating the
equipment, and I will go over what those
parameters
are.
Then, as I think Ajaz said, most tablets and
51
capsules have a one point acceptance
criteria. For
immediate-release products we see
anywhere from 2
to 4 time points, maybe 1 hour, 4 hours,
8 hours,
24 hours depending on the product.
The first thing you are going
to do if you
have one of these apparatus, you are
going to run a
test method. You need to ensure that you have
instrument suitability. The first point I have up
there is which one of these 7 instruments
you are
going to use. What we find is that most people use
1 and 2.
Most people believe that that is what the
FDA wants to see. I have been to many different
dissolution conferences and, you know,
consultants
and companies will get up there and say
if at all
possible use apparatus 1 or 2 because
that is what
the FDA wants. I have heard many people say that
so a lot of people try to use 1 and 2.
Then, once you have chosen your
instrument, you need to make sure it is
set up
properly for mechanical calibration. You can see
by the picture that if your shaft is not
quite
centered, or if your vessel is not quite
seated
52
right, your rpm aren't calibrated, etc.,
you can
imagine that you can get different
hydrodynamics
from vessel to vessel or from time to
time. You
need to really carefully make sure that
everything
is set up properly. Then, once you have everything
set up properly, you can then run a
calibrator
tablet provided by the USP to see if you
get within
the range that the calibrator tablet says
you
should get. Then that gives you some measure of
confidence that perhaps you have set this
thing up
properly with mechanical
calibration. I think Ajaz
has mentioned that the calibrator tablets
actually
are U.S. phenomena and they are not used
either in
the European or Japanese pharmacopeias.
Once you have instruments all
set up, then
you can certainly do method
development/method
validation, and I will talk a little bit
about what
we
see and what is actually given to us, as the
agency, when it comes to validating the
dissolution
method.
Here is an example of some of
the
mechanical calibration parameters out of
the USP.
53
Some of them have specific values. For instance,
the shaft has to be 2 mm from the
centerline, which
means you actually have a 4 mm spread
because you
can have one direction and then it spins
around to
the other. You can see there are other parameters
which don't really have any hard numbers
associated
with them, such as the wobble--no
significant
wobble and that is kind of nebulous
there, or no
significant vibration. So, those are the some of
the USP criteria for setting up the
basket and
paddle methods.
The actual calibrator
tablets--actually,
our lab in St. Louis had a lot to do with
calibrator tablets coming into
being. It is
certainly the current 10 mg one that is
used today.
But they came around in the 1970s and
there are two
different calibrator tablets. One is
disintegrating and one is
non-disintegrating. So,
one
pretty much falls apart when it goes into the
dissolution apparatus; the other stays
together as
a tablet throughout the calibration
procedure.
In 1997 a 50 mg prednisone
tablet, the
54
disintegrating one, was replaced with a
10 mg
tablet which was manufactured at the
University of
Maryland, here, and was based on the
formulation of
a product that our lab had found was
sensitive to a
lot of the parameters of calibration,
including
degassing and mechanical calibration, so
we thought
it would be a good calibrator tablet.
Actually, last year the working
group at
the USP was actually looking for a
replacement for
the 10 mg tablet. It does have quite a bit of
variability associated with it and some
stability
issues so they would like to see if they
can find
something else.
So, if you are actually calibrating
your
apparatus what you would do, if you use
your
equipment for both basket and paddle
which is what
we do in our lab--a lot of pharmaceutical
companies
will have one that will always stay
paddle and
another will always stay basket but we go
back and
forth.
If you are using the same instrument for
both paddle and basket, what you would do
is you
would do 4 different calibration
runs. You would
55
do both calibrators with the paddle
installed and
then you would turn around and do both
calibrators
with the basket installed to make sure
that your
instrument is set up properly.
How often do you do these? In our lab we
do it every 6 months. We do the calibration using
the prednisone 10 mg tablet. Here is the actual
data on the current lots of calibrator
tablets.
The O lot, which has been in effect now
for almost
two years I think--you can see there are
different
dissolution criteria depending on whether
you are
running it in the basket or the paddle
method. You
see there is a fairly wide range. You can see that
for the basket as long as you are
anywhere between
53-77 percent for each vessel you are
going to pass
calibration. So, you have your 6 vessels and this
one, over here, can be 53 and this one,
over here,
could be 77 but you are still going to
pass
calibration. Actually, late last year they changed
the ranges of the prednisone tablet
because there
were stability issues and a lot of
failures in the
market, and you can see that the range is
even
56
wider now, 51-81 percent.
I have also included up there
the values
we get in our lab for at least the
prednisone
tablet.
For the basket method we get 72.6.
You
can
see we run very much on the high end of that
range.
In fact, we do quite often fall out on the
high end.
You can see we tend to run on the low
end of the range on the paddle method for
these
calibrator tablets.
The salicylic acid tablet has a much
narrower range. It is also much less sensitive to
many of the parameters that you set for
dissolution
testing so it is not sensitive to
degassing; it is
not sensitive to mechanical calibration
setup.
The problem often with running
these
calibrator tablets is if you do get an
out of
specification value, then what do you
do? You
check your mechanical calibration. It can be
difficult to decide whether the issue is
the actual
calibrator tablet itself or the issue is
some way
that you set up the instrumentation.
The other problem with the
calibrator
57
tablet is that you can see it has a
fairly wide
range.
It can often interfere with a continuous
improvement process. If your vessels can be
anywhere from 51-81 percent and you are
still
passing, what does that say when you are
running
your own product and you want to try to
narrow down
the variability of your product? You don't have
much room here I guess to try to keep
everything
consistent.
I am going to talk just a little
bit about
development and validation. We don't see a lot of
development data but we do see the
validation data
in our lab. Obviously, when you are developing a
dissolution method you have to decide
about all
these different parameters, a lot of
which I have
alluded to, and you want to develop a
method that
is going to be discriminatory. You want to be able
to tell between good product and bad
product. You
want the method to be repeatable. You would like
the method to give you the same results
no matter
which lab you are running it in. I think Ajaz said
we had some trouble with the malaria drug
in trying
58
to get two different labs get the same
results.
You have to decide which instrument to
use. Like I
said, most people try to pick 1 and 2 if
at all
possible; then what media to run it
in. A lot of
the test methods we get either are in 0.1
normal or
HCL; a lot of them are just plain
water. Then you
have to decide whether degassing is going
to be
important or not for your product; and
decide
whether or not you need sinkers. Some products
don't automatically go to the bottom of
the vessel
if you are using the paddle method. You can buy
commercial sinkers, which are these
little devices
that you put the tablet in that will
actually make
it fall to the bottom, or you can just
wrap a wire
around, which is what is in the USP, to
make it go
down to the bottom.
Once you have decided all these
parameters, you still need a
determinative step,
and that is what the main focus of
validation is
for most companies. So, when we get validation
packages in from companies on their
dissolution
test methods, their validation really
focuses on
59
the determinative step. They do a lot of work on
varying the parameters on the HPLC method
but less
data do we see on varying the parameters
on the
actual dissolution method. So, we see more on the
determinative step and less on the actual
parameters that are associated with the
dissolution
apparatus.
You can see that there are a
lot of places
here where variability can be introduced,
and
certainly when developing a product if
you want to
have a test method that is going to allow
you to
continuously improve your product you
really need
to understand what all the sources of
variability
are going to be.
This is one of Ajaz's slides. I think he
showed a similar one earlier which is
basically a
slide just to show you that the total
variability
you are going to see in any test method
is going to
be the variability that is inherent to
your product
and your manufacturing process and the
variability
that is inherent to your test
method. For
dissolution the variability inherent to
the test
60
method can be quite large, especially if
you don't
understand how all the different
parameters can
affect your product.
I am going to just show some
examples of
some of the variability. You can see I have a lot
of information up on this slide, and
every single
one of these bullets can be a source of
variability
when running a dissolution test
method. You have
to make sure your operators are well
trained. You
have to make sure you have set things up
properly.
You have to make sure that you understand
how all
the different media and equipment
parameters,
sinkers etc., can affect the variability
of your
specific product. So, there are a lot of places in
here where, you know, if you add a tenth
or so, or
a percent or two of variability by the
end you have
quite a wide range of potential
dissolution
parameters you could get even with the
same lot of
material.
When it comes to mechanical
calibration, I
think I showed some of the USP parameters
earlier
and what I want to show you here is
actually that
61
in our lab, DPA, we use more stringent
mechanical
calibration than what is listed in the
USP. A lot
of the criteria we use come directly out
of the
PhARMA recommendation. I think that paper is in
your packet. It came out in the '90s, where they
did a collaborative study to take a look
at
mechanical calibration a little more
closely to see
if tighter mechanical calibration might
reduce
variability when running the calibrator
tablet.
Because we run so many products
in our lab
and we don't necessarily have the time to
stop and
see if this product is really sensitive
to
centering or not, etc., we just try to be
very
careful about how we set up our
equipment. Some
tools are now available to very easily
set these
parameters much tighter than what is
currently in
the USP.
So, you can see that for quite a few of
these we are tighter, and for others we
have added
criteria that are not actually in the USP
as
specific numbers. For instance for shaft wobble
and vibration, we actually measure those
and set
criteria for those.
Degassing is one of the things
I think
that really got us into trouble--I don't
want to
use that word, but with the malaria drug
the
62
different labs were degassing in
different ways and
this drug happened to be very sensitive
to
degassing. So, typically in the past the way you
decided whether your media was well
degassed or not
is that you ran the calibrator
tablet. The 10 mg
prednisone is very sensitive to dissolved
gasses in
the media so if you weren't sure if you
were
degassed or not you could just run that
calibrator
tablet to see if you were in range and
then decide
if you were degassed properly.
Well, it turns out that there
is some
equipment on the market that you can use
to
actually measure dissolved gasses so this
is
something we have done recently in our
lab. We
have taken this meter, which is actually
used in
other industries and not in the
pharmaceutical
industry, and used it to try to determine
how much
dissolved gases are left after using
different
degassing techniques.
There are many different ways
in which
people degas their media. The reason you need to
degas your media is because there are
some products
that if you take a vessel and you drop in a tablet
or capsule, what will happen is you have
gases in
the media. The bubbles will form around this
63
tablet or capsule and oftentimes will
prevent it
from dissoluting. So, you actually need to get the
gases out of there before you start.
Here is a little graph of the
different
ways people degas and the results we got
with the
total gas meter, measuring both total gas
and
oxygen.
You can see that for the first bar over
there that is obviously atmospheric
pressure and
atmospheric oxygen in the media. These are all
done in just plain water. The next bar is the way
we degas at DPA, which is point of vacuum
at less
than 150 ml of mercury with agitation,
and you can
see we get rid of about a little more
than half of
the total dissolved gases and quite a bit
of the
oxygen.
The USP method is also very
good. There
64
you are heating up to about 41 degrees
and
aspirating to remove the dissolved
gases. They
also get half the total gone and about
half the
oxygen.
Some people actually helium
sparge and you
can see helium sparging and although you
do reduce
the oxygen significantly you do not
reduce the
total dissolved gases.
So, does this matter or not matter?
You
know, this all depends on the product you
are
testing.
So, I just want to show you some examples
here.
These are 3 different products, called
product 1, 2 and 3 so I don't give any
product
names.
You can see that for product 1 and product
2 there is a huge difference between
non-degassing
and degassing. For both of those graphs I have
shown two different ways of
degassing. One is the
USP and DPA method, both of which give
similar
results.
The other is helium sparging. You
can
see in both cases that the helium
sparging does
give slightly higher results than either
the USP or
the DPA method. Certainly, for product 2 helium
65
sparging gives much more variable results
than the
DPA degassing. You can see that on the helium
sparging line which is kind of the
green-yellow
one.
You can see that product 3
doesn't really
care whether you degas or not. One of those lines
is non-degassed and one is the DPA method
which had
the lowest percent of dissolved
gases. You can see
that you get essentially very similar
dissolution
whether you degas or not.
Larger than just degassing is
the actual
composition of the media. I think as Ajaz
mentioned, Japan is looking at what type
of media
you actually want to be using. We see a lot of
acid here and some buffers. Here is a product and
the dissolution method is pH 7.2. So, 7.2, as you
can see on your left I guess, is the
media that is
used in this product. It also turns out that with
these 6 different tablets there is some
variability
between the 6 but they all passed the
dissolution
specification for this particular
product.
This is a product where we
wanted to take
66
a look at some lower pHs just because
there are
some patients who happen to use this drug
who may
have lower intestinal pH than 7.2 and so
we went
down to 6.8 and, lo and behold, every
single tablet
looked different to us and no two tablets
were the
same.
We repeated this over and over again, trying
to figure out what is going on. You can actually
do a lot with dissolution by just
watching your
product.
There is nothing like the human eye
sometimes.
If you watch this product in
the vessel
what you will see is that it sits there
and does
not dissolve and you get no dissolution
until you
see the coating split open. Once the coating
splits open, then it dissolves fairly
quickly. So,
taking a look at that we were trying to
figure out
what could be the sources of variability
of this
product.
Is it the way we are handling it when we
put it into the dissolution vessel? Are we
damaging the coating in some way? Are these tablet
differences real or is this the
manufacturing
process itself? Do we have instrument variation?
67
These 6 tablets are in 6 different
vessels so is
there some difference in these vessels
where maybe
we have improper calibration or
something?
Well, after much investigation,
what we
found is that this is actually a product
problem.
If you cut open these tablets and take a
look at
the coating, not all of them have uniform
coating.
You can see there, on the left, one of
the tablets
that has a very uniform coating
thickness. Then
every once in a while you ran across a
tablet that
had a void between the drug and the
coating. The
drug is actually on the left side here;
it is kind
of the yellow sparkly stuff and the red
is the
coating.
So, some of the tablets had very uniform
coating; some of the tablets had
defects. These
defects were dissolving much faster or
were
breaking open, splitting open much faster
than the
ones that didn't have defects. This is a situation
where perhaps dissolution could help this
manufacturer make a more consistent
product if they
were doing their dissolution at a
slightly
different pH or doing a dissolution test
method at
68
several different pHs to try to make sure
they were
making a consistent product.
I was just going to mention
sinkers
because I talked about them and also
because they
do make a big difference. The graph up there
actually has nothing to do with the
sinkers but it
shows you what happens if you don't get
your tablet
at the center of your vessel. The bottom blue line
is product 1, right down at the bottom of
the
vessel, centered completely. The green-yellow line
is if it is off center by 1 cm. So, if it is just
off center by a centimeter you can see
that it
dissolves much faster. There are different
hydrodynamics in that area than at the
bottom of
the vessel. So, if you have a tablet that is
fairly light and is not going to stay
put, then
often you will put it inside a sinker.
Traditionally, in our lab we
have used the
sinker at the top to the right. That is the one
that we have used in our lab. It is very easy to
use.
It has a spring load and you just pull back
the spring and drop the capsule or tablet
in and it
69
is, you know, very convenient I
guess. The USP
method is to use a wire and wrap the wire
three
times around the tablet or capsule.
Well, we did run across a
product--this is
what I talked about, that you have to
understand
your product and how it reacts to
different
variables--that was sensitive to this
actual
commercial sinker. This is the product we tested
and with the commercial sinker that I
just showed
you it failed dissolution. The specification here
was 80 percent at 30 minutes and you can
see that
all 6 tablets failed. Of course, we thought the
product was perhaps a failure but it actually
turned out that if you visually looked at
what was
going on, the product was being
trapped. It was
swelling up and getting trapped inside
that
commercial sinker and so it could not
essentially
dissolve.
We went back to the USP method with three
wire turns around the tablet, and you can
see that
the product passes wonderfully with no
problems
whatsoever. So, we no longer use commercial
70
sinkers in our lab but a lot of people
use them so
I just wanted to make you aware of the
fact that
something as simple as a sinker can
affect the
individual product that you are looking
at.
So, what I have tried to show you is just
some data that illustrates the fact that
different
products are sensitive to different
parameters when
you are doing dissolution, and there are
obviously
a lot of places where you can introduce
variability
in your test method. What we would like to propose
is an alternate approach to calibration
and
validation which includes complete
understanding of
how dissolution and the measurement
system in your
product specific variables affect
variability, and
try and understand the relationship
between your
product properties and your dissolution
results.
This includes understanding the
dissolution
apparatus that you are using, why you are
choosing
it and why you are choosing the media you
are
choosing, and determine, hopefully, the
best method
to give you opportunities for improvement
and to
ensure that the quality of your product
is good.
You can see that because of the way
dissolution is currently set up there are
a lot of
things you have to control, and perhaps
there are
71
new approaches we can also use to get the
same type
of information that might have inherently
less
variability. Then, obviously, a part of this whole
process needs to be communication and
training. If
people are out there saying that FDA
wants us to
use apparatus 1 and 2, then that is what
people are
going to do. So, the FDA is trained in a more
open-minded look at other things. If people feel
that way at least, then they might be
willing to
look at other approaches.
When it comes to alternative
approaches to
dissolution calibration validation, I
think as I
told you in our lab we do more stringent
mechanical
calibration because some products are
very
sensitive to how the apparatus is set up
and,
certainly, if you set it up properly your
variability will be less than the
variability of
the calibrator tablet. Certainly, when you are
using your specific product itself, you
need to ID
72
and control all the source of variability
that you
are going to see. You need to determine how your
product is sensitive to things like the
apparatus
type, the setup parameters and the media,
both type
of media and whether it is degassed or
not. There
is an interaction between the instrument
you use
and your product, and understanding that
is going
to also help you reduce the variability
in the
dissolution test method. People like to use
calibrator tablets. I think it gives them a
measure of confidence that they set
everything up
and their system is suitable.
So, what we are proposing is
that
certainly the USP calibrator can be used
if
somebody wants to take a look and see
that they
have set up properly. Perhaps it also might be
useful to set up an internal calibrator
maybe based
on a bio. batch or clinical batch to make
sure of
system suitability. The calibrators dissolve in a
certain way or are sensitive to certain
things and
not sensitive to certain things, the USP
ones, and
those parameters may not be the
parameters that
73
your particular product is or is not
sensitive to.
So, creating your own internal calibrator
and
understanding how your product is
sensitive to all
the parameters is going to be perhaps
better than
an outside product that may not have the
same
sensitivities that yours does. Obviously, you need
to confirm the suitability of your
internal
calibrator using some kind of a gauge
R&R study so
you can really understand what the
variability is
in your product.
Ajaz mentioned gauge R&R a
little bit. If
you pick a lot of product or a piece of a
lot to
maybe set up as an internal calibrator
you need to
carefully characterize that and determine
what its
variability is. You want to make sure it is
representative of your manufacturing
process. You
want to make sure that it was
manufactured while
your process was under control. Obviously, when
you are doing a gauge R&R you need to
take a look
at what variability is introduced
instrument to
instrument, vessel to vessel. As you can see, each
instrument is like 6 individual little
instruments.
74
And variability from personnel to
personnel and,
obviously, media and whether it is
degassed or not.
We need to understand the
benefits and
limitations of the different dissolution
apparatus.
I showed you that there are 7 different
ones in the
USP.
We also sometimes get ones that are non-USP
apparatus when people submit test
methods. So,
there are a lot of different things out
there to
choose from and, better than just
choosing one that
someone thinks maybe the FDA wants to
see, maybe
try to understand how the hydrodynamics
work; try
to model your system. Actually, I have been told
by people who do modeling that apparatus
1 and 2
are difficult to model so there may be
some better
systems out there where we can do some
better
predicting of what is going to happen as
we change
physical parameters of our product, and
take a look
at some other things we might be able to
do.
Of course, what would even be
better is
just quit doing dissolution as it is
known today
and maybe find some other ways to assess
product
quality.
People have done some work in our sister
75
lab here, in White Oak, to try to
correlate
dissolution with NIR. There is a lot of
spectroscopy out there that can be used
online as
part of a PAT feedback loop, and perhaps good
correlations and good models could be
developed
between those and quality and in vivo
availability
and we can dispense perhaps with the
current
dissolution test method, which has all of
its
parameters--things that can go wrong and
need to be
set very carefully. Obviously, key to this is
going back to the first principles and
modeling and
understanding your formulation, and how
each
component of your formulation contributes
to the
quality of your product.
So, that is all I had to say
and I just
wanted to acknowledge Terry Moore, who is
actually
here today, who probably knows more about
dissolution than anybody in the
world. He is
sitting over there, if you want to know
more about
dissolution. Then, Zongming Gao is also in our lab
doing dissolution; and Lawrence who also
knows a
lot about dissolution; and Ajaz all
helped with
76
this.
So, thank you.
DR. COONEY: Thank you very much, Cindy.
There certainly is time for
questions. Gerry?
Questions by Committee Members
MR. MIGLIACCIO: Cindy, first I applaud
your last comment about using alternate
methods. I
just want to point out that you made
several
comments about the use of apparatus 1 and
2 and,
speaking I think for most companies, we
don't use 1
and 2 because we think FDA wants us to
use them.
You did a great job of pointing out the
variability
of the different parameters that can
impact
variability. It is very important when you are
testing thousands of batches a year that
you have a
really well trained work force that knows
how to
use this apparatus, and that you have
consistency
in the way you test because if you are
switching
from one apparatus to another it presents
another
level of complexity. So, it is really the
consistency. Because of the variability that is
inherent here, it is the consistency that
drives us
to apparatus 1 and 2 and not a lack of
desire--
DR. BUHSE: To try something else?
MR. MIGLIACCIO: --but, you know, it is
complicated enough so it is really
consistency that
77
drives us there.
DR. COONEY: Marvin?
DR. MEYER: The data you showed from your
lab versus the specs on prednisone, and
you said in
one case you tend to be high and some
cases fail,
when you do fail the calibration what do you
do
about it?
Is it the calibration that is no good?
Is it the USP specs that is no good? Is it the lab
that is no good? Or, do you just keep going until
you have 36 samples?
DR. BUHSE: Well, historically what we
have done is double check your mechanical
calibration and then you really run the
calibrator
tablet.
So, was the original failure the tablet?
Rarely do we find something to adjust
when we check
the mechanical calibration. We do the mechanism
calibration much tighter than the USP
anyway so
essentially you rerun. We actually don't run them
anymore in the lab, the USP calibrator
tablets.
DR. MEYER: That solves that problem!
DR. BUHSE: That solves that problem! We
have an internal calibration tablet that
we use now
that we have characterized ourselves in
our lab
that has lower variability. We stopped using this
one probably at the end of last
year. The data I
78
showed was the data from 2004, 2003.
DR. MEYER: The other question I have or
comment is that on one of the slides you
suggest
using perhaps an internal calibrator, a
bio. batch
or some known that you have produced.
DR. BUHSE: Right.
DR. MEYER: How do you know that that
product, over the lifetime of the product
being
manufactured, hasn't changed? Dissolution doesn't
change, you are satisfied your equipment
is in good
order when, in fact, it isn't because you
couldn't
pick up the change--
DR. BUHSE: Stability is a big issue.
Stability is an issue with the current USP
calibrator. It is known to drift down I believe
with the paddle method over time, or
whatever. Do,
79
you want to talk about that, Ajaz?
DR. HUSSAIN: Yes.
Marvin, I am going to
go over that in detail. The gauge R&R is actually
for three purposes. It is to establish and
benchmark the variability. I think the proposal
actually is that mechanism calibration
actually is
sufficient. The gauge R&R is an opportunity to
establish your target. You benchmark your
variability and then use that variability
for
setting specifications, and so
forth. But then you
have that and then you can keep the
system stable.
I think stability of the system has to be
based on
mechanism calibration. That is what other
countries do anyway. So, I will go over that in a
bit more detail. So, the opportunity is more than
just the internal calibrator. So.
DR. MEYER: One follow-up, I kind of joked
that you made the problem go away because
you are
not using it anymore. What if you are a company
and had in your NDA or ANDA that you
would
calibrate your dissolution using the
prednisone and
USP and you started to fail, your
dissolution
80
couldn't meet the calibration? They don't have the
luxury of just saying, well, we are going
to use
our own now because they are stuck with
using what
they said in the NDA, right? What should a company
do about that?
DR. BUHSE: You want to talk about that,
Ajaz?
DR. HUSSAIN: Well, I think this meeting
is step one to start addressing that in a
sense.
Here is an alternate procedure. So, I think if the
advisory committee will sort of endorse
this and we
move that way, we will put that in policy
and there
are many different ways to implement
that. So.
But from the compendia perspective, I
think you
have to comply with the compendia so that
is a
different challenge that the industry and
companies
have to deal with. So, all we are doing right now
is creating an alternate regulatory
decision
pathway and our enforcement strategy
based on that.
DR. COONEY: Nozer?
DR. SINGPURWALLA: Slide number 13, I
thought you said it was Ajaz's
slide. Therefore,
81
it is wrong!
[Laughter]
DR. BUHSE: Yes, it was Ajaz's slide.
DR. SINGPURWALLA: Well, how do you
distinguish between repeatability and
reproducibility?
DR. BUHSE: Well, I was going to say with
a destructive test it is very difficult.
DR. HUSSAIN:
See, this is gauge R&R for a
destructive test. You really have to have design
experiment and I was going to cover that
in my
talk.
What this does is, it actually ensures that
the lot you choose is stable and in a
state of
control.
That is the only way you can actually
move in this direction. So, that achieves that
target.
The destructive gauge R&R is a very formal
experiment and it is a nested design
which does get
an estimate of whether a practice or an
operator
can repeat it. That is repeatability.
Reproducibility is the variability
associated with
that.
DR. SINGPURWALLA: So, the repeatability
82
refers to a physical thing. The other thing is I
don't know how important it is for you to
manage
variability but if it is important to you
to manage
variability, then my sense is that as the
product
variability increases the measurement
variability
will also increase. Therefore, there will be
correlation and, therefore, the sigma
squared total
that you have will be underestimated the
way you
have put it down. If it is of any importance, you
may want--
DR. HUSSAIN: I think it is. That is the
reason the leverage--the quality by
design having
the pharmaceutical development
information starts
to allow us to dilute some of this. But the
variability that you are observing you
are
observing to the eyes of the measurement
system so
the measurement system and variability in
the
product are together. I will try to come back and
sort of explain some of that.
DR. DELUCA: I apologize for my voice.
You very nicely pointed out the multitude
of
variables that are involved. There is instrument
83
variability as well as product variability so
you
have interaction. You mentioned degassing. But
you are using a set agitation in your
system. When
you start degassing, are you not
sparging? Now,
you can create agitation or sparging
during the
test?
DR. BUHSE: No, it is done beforehand.
You do it before you start and you put
the media in
the different vessels and there is no
degassing
during dissolution itself. Questions come up,
especially for extended-release products,
where
actually the dissolution test method
lasts for 24
hours per product, and the question then
becomes
what happens to the gas level over that
time. We
hope to test that with this meter. The one I
showed you here is actually one that has
a probe
that is, like, 3 inches around so you
have to put
it in a giant vessel. They are making a new probe
that is small and will fit inside the
dissolution
vessel so we can see what happens actually
in the
dissolution vessel over time. Like you say, with
some of these test methods at high rpm,
100 rpm, we
84
are getting a lot of agitation. So, that is a good
question.
DR. DELUCA: And I was worried about the
product and how product variation can
affect--so,
you have an interaction between the
instrument and
the product where particle size might
influence,
you might have a set agitation rate. If the
particle size changes then it is going to
change
the result.
DR. BUHSE: Right, unless you have a
method that can discriminate that if it
is
important to the acting of the drug.
DR. DELUCA: You have talked about
modeling, I mean you mentioned it. Maybe it is
going to be covered later on, but I
wondered if you
include anything here to look at profiles,
release
profiles.
DR. BUHSE: We haven't done a lot of
modeling yet in our lab. I don't know if we are
going to talk about that specifically
later on or
not today.
DR. COONEY: Ken?
DR. MORRIS: Just a couple of things. One
is that given the sort of lag--I guess I
just have
a philosophical problem with calibrator
tablets in
85
that if you are looking at a process and
want to
independently establish that it is in
control or
that it is doing what you think it is
doing--we are
producing these the same way we produce
the tablets
for testing--
DR. BUHSE: That are no better.
DR. MORRIS: What is that?
DR. BUHSE: That are no better.
DR. MORRIS: In fact, there are some data
that I think we will see to day that
there are some
liabilities. I think maybe this is something we
will talk a lot more about, I am sure,
but I think
one of the things that may come out of
this is that
calibrator tablets just don't have a
prominent
role.
What I would say is that if you look at an
immediate-release system--and we will
also get into
BCS exemptions--then the issues become
sort of
treatable in other ways. If you are looking at
sustained-release or modified-release,
such as
86
enteric or extended, then my argument is
that you
ought to be controlling the coating
process and
that sort of activity is really much more
advanced
than it was. I mean, you have your example of the
tablet that has the air pocket but
probably what
was more important was the difference
between the
80 and 50 micron coating thickness. This is
clearly a failure of reproducibility of
coating and
the dissolution may catch it or may
not. I mean,
the statisticians--I don't know, there is
the
Bayesian argument but I have talked to
Sandy
Bolton, for one so, you know, if you have
high
variability dissolution maybe 6 tablets
is enough
to pick it up but, depending on what
constitutes
high variability, you know, it is in the
laps of
the gods whether you get it or not. So, to the
extent that things are surface-based
alternate
methods--I mean, in the first place, you
want to be
controlling the coating processes and
then, to the
extent they are surface-based, have you
considered
things within the group like the
combination of
that and, like, IGC to look at surface
free
87
energies or something that is at least a
little
less subjective? I don't know if you have talked
about it because everything else is a
correlated
technique.
DR. BUHSE: Right.
DR. DELUCA: Whereas, something that
actually measures surface free energy,
even though
there is no practical instrument right
now, is a
direct measure.
DR. BUHSE: We haven't done that with that
particular product. We have tried to do some
spectroscopy correlations.
DR. HUSSAIN: If I may?
DR. COONEY: Yes.
DR. HUSSAIN: I think you make a good
point, and I think the goal that we have,
number
two, desired state, specification based
on
mechanistic understanding--so, if the
mechanism is
controlling the dissolution based on a
coating
thickness, if you are able to measure the
coating
thickness reliably, and so forth, that
should be
sufficient. So, I think that is the direction we
88
wish to move in, and some of the new
technologies
and science sort of helps that.
There is another point I think
which I do
want to make and this is my graduate
school
training; this is biopharmaceutics
101. When we
approach trying to develop a product we
first think
about the patient, and so forth. Prof. Richard
always insisted you don't even think
about an in
vitro test. You first try to get initial
information in humans and then say, all
right, what
sort of testing will we need. So, you establish
your formulation, human connection or
patient
connection first before spending time in
an
artificial way. In my consulting role before I
came to FDA, one company I worked for
carried out
53 experiments, screening and so forth;
they had no
idea whether dissolution was useful or
not. They
spent all this development effort trying
to
optimize a hypothetical, what they
thought was the
dissolution rate and the first experiment
they did
was completely off. So, all the experiments were
actually off target.
So, there is a tendency within
industry to
assume that in vitro dissolution is going
to guide
them to a formulation without even understanding
89
its relevance. I think Marvin knows that company
very well. We actually had a paper on that issue
together.
So, there are challenges I think.
So,
quality by design actually forces us to
think what
is the patient and then think about the
tests so
that is what we are trying to achieve
here.
DR. COONEY: Ajaz, perhaps we can capture
that as a point, that the purpose of
formulation
development is to optimize patient care,
not
dissolution assay. We hear you.
DR. FACKLER: Could I just make a point?
Dissolution can function for a number of
different
purposes and on one of your slides you
suggested
that finding a discriminating method
might be
useful, and I would agree under certain
circumstances.
On the other hand, if you look
at that
enteric-coated product really the purpose
of the
enteric coating is to protect the tablet
for the
90
first hour, or whatever time it might
exist at the
very acidic condition of the
stomach. Whether or
not coating breaks open at one hour, two
hours or
three hours might have no relevance to
the in vivo
performance of the product.
So, I think it is important, as
we talk
about the future of dissolution testing,
to
recognize what it is intended for. If it is
intended to predict in vivo performance,
that is
one thing and a predictive or correlative
method
then I think would be the ideal. If it is to look
for product quality and to reduce the inherent
variability in products, well, then a
more
discriminating method that might have no
relevance
to in vivo performance might be our
goal. I think
we just need to keep that in perspective
as we
think about the future of dissolution
testing.
DR. HUSSAIN: If I may since we have time,
I think this is one of the first steps in
our
tactical plan. Since we have time, if we could
engage the advisory committee to make
sure is this
an
acceptable step further discussion is needed.
91
So.
DR. COONEY: Tom?
DR. LAYLOFF: Yes, I was going to say
because of my concern with the problem
with
degassing--I never degas my stomach
before I take
my medication--
[Laughter]
DR. FACKLER: You probably don't swallow
900 ml of water either.
[Laughter]
DR. MORRIS: Just a couple of comments.
First, when we validate equipment we have
to
understand what tests we are doing and
what we are
trying to validate, and the standard
tablet just
doesn't--intuitively, it doesn't get there
for me
because we are looking at validating a
piece of
equipment and all of a sudden the
variables that we
are throwing into the pot include what is
the
dissolution medium and how we handle
that; what is
the size of tablet and how we handle that
when we
are trying to validate a piece of
equipment. So,
probably the first step is saying what
validates
92
the equipment, and anything else we do is
a waste
of time.
Then, the next step, to get
right to what
Paul said, is what is my dissolution test
telling
me because I am a manufacturer and I want
to keep
my process under control, or am I predicting
what
is happening in people? We have seen for 35 years,
as far as I know, that dissolution
doesn't predict
the human results in terms of
bioavailability or
bioequivalency. You can't do it that way. You
have to get that data and then try to
correlate.
So, if we are using dissolution for
quality
control, for process, fine, then there is
a set of
variables and we do it that way. But if we are
trying to say that I can do a dissolution
study
and, therefore, I will know that my
formulation is
going to work in a person I think we are
really
biting way more off than we can chew.
DR. HUSSAIN: I think I agree with you,
but in may aspects you do establish
correlation.
Actually, Lawrence, in his talk, will
actually make
that same proposal as you did. So.
DR. COONEY: Tom?
DR. LAYLOFF: The early work done on
digoxin was designed to go for in vivo/in
vitro
93
correlation for about 35 manufacturers,
and that is
how that standard was set. Prednisone subsequently
was done the same way. In reviewing that, it would
determine that if the FDA continued down
that path
it would eventually take all the
resources of the
FDA to do it because of the cost of
performing
those in vivo/in vitro correlations. Then the
dissolution standard was just arbitrarily
applied
across the board.
DR. COONEY: Marvin?
DR. MEYER: Ajaz, I think you ask if you
are on the right track and I think you
definitely
are.
You know, when you first said we are going to
revisit dissolution I said, oh, my God--
[Laughter]
--so, I think you are on the
right track.
I mean, for me, when I used to do some
dissolution
just in a university laboratory, I loved
the wide
range for the calibrators because then my
equipment
94
always passed and I didn't have to worry
about it.
But now, sitting around this table, I
have a
different hat on and it is shocking,
51-81 percent.
How can you have a calibrator--if
somebody comes in
with analytical data like that you would
say go
away; this is a very poorly controlled
analytical
procedure. So, I think that revisiting the issue
is very important.
DR. HUSSAIN: Marv, in may ways, you know,
I was blind to this. I actually was not fully
aware of the scenario, and Cindy will
attest to
this.
When I started writing this paper I put
Lawrence through hell. I said how could this
happen?
Because our standard criteria for
specification is plus/minus 10 percent
and the
instrument is this way so there was a
disconnect
that I was not aware of and I have to
apologize for
that.
DR. COONEY: Are there any other comments
or questions at this point?
[No response]
What I would like to suggest is
that we
95
take a break for 15 minutes and reconvene
at 10:25,
and we are in good shape for continued
discussion
and I have no doubt there will continue
to be more.
[Brief recess]
DR. COONEY: I would like to now welcome
Dr. Mehta to speak to us about an
overview of the
current guidance on the documents and
decision
process in biopharmaceutics.
Overview of Guidance Documents
and Decision
Process:
Biopharmaceutics Section
DR. MEHTA: Good morning.
As you can see
on my slide here, I am asked to give an
overview of
guidances documents and decision
processes from a
biopharmaceutics perspective.
Before I start, I want to
acknowledge a
couple of people in my division, Dr.
Ramana Uppoor,
she is sitting in the back in the
audience, and Dr.
Patrick Marroum, team leaders in neuro.
and
cardiorenal in my division and some of
the experts
in biopharmaceutics in my division.
This is the outline of my
presentation. I
am going to give you an overview of
96
biopharmaceutical aspects of
dissolution-related
guidances. That is a formidable task. My first
draft that I sent to Ajaz had 100 slides
and Ajaz
replied by saying an excellent overview
but cut it
down.
So, I am now down to 60.
[Laughter]
But I still intend to finish in
time.
Then with a quick overview I will take
you through
some examples from our NDA reviews of
immediate-release and modified-release
products,
and share with you my perspective on
opportunities
for improvement.
These are the guidances I am
going to
quickly take you through. Chronologically they are
different but in terms of science, the
way the
ideas are represented I have shifted them
around.
I am going to first start with the BCS
guidance.
In parentheses are the references. I will follow
that by the immediate-release dissolution
guidance
that came out in 1997. The BCS guidance was
finalized in 2000. The IR dissolution guidance
invokes BCS principles and that is why I
have
97
arranged it that way. That will be followed by a
quick overview of the IVIVC guidance and
that is
for modified-release products, in
vitro/in vivo
correlation. Then a couple of slides on general
bioavailability and bioequivalence
guidance, which
was finalized in 2003.
I will quickly switch to
something known
as scale-up and post-approval changes for
immediate-release products and
modified-release
products, and the topics covered there.
So, let me start with the BCS
guidance
summary.
Maybe it is known to everybody, but just
for the sake of completeness let me point
out the
highlights of the BCS guidance. This guidance
takes into account three major factors
that govern
the rate and extent of drug absorption from
the
immediate-release solid oral dosage form.
These are the solubility and
intestinal
permeability of the drug substance, and
dissolution
of the drug product. So, based on the solubility
and permeability characteristics of the
drug
substance the drugs are classified into
four
98
categories: high solubility, high
permeability; low
solubility, high permeability; high
solubility, low
permeability; and then the fourth
category, low
solubility, low permeability.
The third bullet is the central
idea, the
central concept, a very sound scientific
concept of
BCS which is, you know, if a drug product
is BCS
class 1, and for different formulations
of this
class 1 product if they are rapid and
similarly
dissolving you can give a biowaiver for
the test
formulation without requiring an in vivo
bioequivalency assessment, provided you
show
similar dissolution profiles over the
physiological
pH range.
The last important point about
this
guidance is that in this guidance we have
defined
what determines rapid dissolution, and we
say if
your drug product dissolves 85 percent in
30
minutes over the pH range absorption
should not be
dissolution limited. So, that is all for BCS.
Moving on quickly to the
immediate-release
dissolution guidance summary, and again I
will do
99
my little bit of acknowledgement here,
Dr. Shah and
some members on the panel here have
contributed to
this guidance and, from my personal
perspective,
this is scientifically a very well
written document
although it was almost ten years ago.
These are the topics covered in
this
guidance.
The guidance lays out approaches for
setting dissolution specifications for a
new
chemical entity. As I said, it takes into
consideration BCS nature of the drug
product and,
depending upon that, you can have minimal
dissolution requirements in setting
specifications
or
more stringent.
Another very important point
from my
perspective is that this guidance has
outlined
something known as mapping or response
surface
methodology. Again, this is supposed to be for
immediate-release products. The guidance says that
undefined clinical manufacturing
variables--manufacture your products at
the
extremes of CMVs and in vivo performance
and, if
you have that information, you will have
a very
100
sound rationale for coming in with
appropriate
dissolution specifications.
Finally, in this guidance there
is a
discussion of how do you compare
dissolution
profiles of two products. One of the approaches
that I recommend is known as the f2 or
the
similarity factor which essentially looks
at the
differences in dissolution at each time
point, with
a range of 0-100. An f2 of 50 or greater than 50
indicates similarity of the dissolution
profiles.
As we have said in that guidance,
dissolution
specifications are established in
consultation with
Biopharmaceutics and the CMC review
staff. The
general bioavailability/bioequivalence
guidance
summary, again limited only to
dissolution
considerations, we have a section in
there that
talks about what should be submitted in
an NDA or
an ANDA in terms of a dissolution
method. There
should be a dissolution method
development report
for an NDA, new drug application. It should
contain a pH solubility profile of the
drug
substance; dissolution profiles generated
at
101
different agitation speeds; and
dissolution
profiles generated on all strength in at
least
three dissolution media. Essentially you want to
see the in vitro performance of your
product over a
variety of conditions, including
different media
and different agitation; and select the
agitation
speed and medium that provides adequate
discriminating ability, taking into
account all the
available in vitro and in vivo data.
For ANDAs, abbreviated new drug
applications, the guidance states that
one should
start with an appropriate USP method if
it is
there, in the USP. For some reason, if it is not
there for this product, then if the FDA
method is
publicly available, utilize that. If that is not
available, also publicly available, then
submit the
dissolution method development report, as
described
above for a new drug application.
Again, for modified-release
products for
ANDAs the dissolution profiles use the
appropriate
USP method, if available, otherwise use
the FDA
method for the reference listed drug if
available.
102
In addition, and I think this is probably
because
you could have for a generic similar or
different
release mechanisms, so additional
dissolution data
in three different media.
Now switching to the IVIVC
guidance which
is, you know, in vivo/in vitro
correlation for
modified-release products, again from my
perspective, this is a very useful
guidance also.
The main purpose of this guidance was to
provide an
outline for waiver of bioequivalency
studies for
modified-release products if one was able
to
establish an in vivo/in vitro
correlation, a
quantitative correlation.
The guidance defines
correlation in
different categories, A, B, C and D. Level A
correlation is most quantitative, and I
have listed
in my presentation just the level A
discussion.
Level A correlation is supposed to be a
point-to-point relationship between the
in vitro
dissolution and the in vivo input rate of
the drug
from the dosage form. Usually this is a two-stage
process, meaning that you take your
dissolution
103
data, convert that into dissolution rate,
and you
take your in vivo data and convert that
into
absorption rate and correlate the
two. Generally,
this relationship is linear but
non-linear
relationship is also acceptable provided
it is
adequately characterized.
So, this is an example of how
level A
IVIVC would look. On the Y axis you have percent
of drug absorbed and on the X axis is the
percent
of drug dissolved; your linear
relationship over
the range and this establishes your
correlation.
For the purpose of obtaining biowaivers,
you need
validation of this level A
correlation. From the
point of view of setting dissolution
specifications, that level of validation
is not
necessary, and I will get into that
subsequently in
my examples.
In the IVIVC guidance for
modified-release
products we have some general concepts
laid out for
what the dissolution specification should
mean.
Ideally, as we say in the guidance, all
lots within
the lower and upper limit of the
specifications
104
should be bioequivalent. At the minimum, those
lots should be bioequivalent to the
clinical trials
lots or an appropriate reference standard
chosen by
the agency. In other words, you have your
reference performance and the upper limit
should be
similar to the reference and the lower
limit should
be similar to the reference. Ideally, the extremes
should be bioequivalent.
Some further considerations are
that
variability alone should no longer be a
primary
consideration in setting specifications
for
modified-release products. Specifications wider
than 20 percent are acceptable only when
evidence
is submitted that lots with mean
dissolution
profiles that are allowed by the upper
and lower
limits are bioequivalent. In other words, you can
have specifications wider than 20 percent
if you
have a correlation, a quantitative
correlation.
If you don't have an IVIVC and
you want to
set dissolution specifications for
modified-release
products, these are some of the
characteristics of
what the data should be. The profile should have
105
at least three time points. The last time point
should be the time where 80 percent of
the claimed
labeled amount is dissolved. Specifications are
set to pass at stage 2, meaning that
there are 12
dosage units.
As I mentioned a while ago, for
setting
dissolution specifications with the
IVIVC, external
validation is not required and, as I
already
mentioned, wider specifications based on
what the
correlation predicts can be done.
This is graphically presenting
that. On
the
left panel you see that in the middle is the
performance of your product, the
variability around
the mean dissolution profiles. The blue line is
the upper limit of the
specification. The red line
or orange line is the lower limit of the
specification. You take that data using your in
vitro/in vivo correlation model. You predict the
plasma concentration based on the two
limits.
On the right panel, the
diamonds are the
actual blood levels, the predicted blood
levels at
upper and lower limit, and the predicted
level for
106
Cmax and AUC should not be greater than
20 percent.
Back in '97, what we could come up with
was setting
the consideration based on the mean
difference.
So, the upper and lower limit would not
differ on
the mean AUC and Cmax by 20 percent. We could not
build into this consideration the
variability
aspects and, as we have already heard in an earlier
presentation today, that is an
opportunity for
improvement for future consideration.
Switching gears, I am going to
quickly
tell you about what the SUPAC guidances
mean as far
as immediate-release and modified-release
products.
There are also a few guidances that came
out
subsequent to the issuance of the SUPAC
in 1997,
which is called equipment addendum, FDAMA
and the
changes approved to an NDA or ANDA
guidance in
2000.
Again, I am going to try to capture this
very quickly.
Conceptually speaking, these
guidances
identify what are the changes or what are
the
variables that are covered in terms of
manufacturing considerations. The level of changes
107
for these variables, what are they? They are
defined; and then how do you deal with
that?
So, the variables covered in this
guidance, manufacturing related, are
composition
and components. For excipients it is
non-release-controlling as well as
release-controlling. The non-release-controlling
aspect is what is the part of the
SUPAC-IR
guidance.
That is taken as it is into the SUPAC-MR
guidance and then what is added is the
considerations for release-controlling
excipients.
Other variables covered are site, batch
size,
meaning scale-up and scale-down, manufacturing
equipment and manufacturing process.
I am going to take you through
only one
set of variables here and show you how
the levels
are defined and what are the related
tests
recommended and what are the related
filing
requirements.
Essentially, the idea is this,
the
guidance has defined the level of change
into three
categories, level 1 is the minor change;
level 2 is
108
the moderate change; and level 3 is the
major
change.
So, moderate could have an in vivo impact
on level 3 or major changes likely to
have an in
vivo effect.
Related to those changes, the tests go
along with them in terms of document
evidence. The
lowest level, level 1, would usually
require only
application of compendia tests and
stability data.
Level 2 change would require extensive in
vitro
dissolution and release data. That typically means
that for immediate-release products you
require
profile comparison in five different
media. Then,
for modified-release you need profile
comparison in
three different media. Level 3 is the most
significant change and that will be
allowed only if
you have an in vivo bioequivalency study
or you had
established in vitro/in vivo correlation.
The filing requirements, again going
from
minimal to most which is annual report,
changes
being effected supplement, or prior
approval
supplement. In the subsequent discussion I will
just focus on the first two bullets,
which is level
109
of change and the tests. I am not going to touch
filing documentation at all.
Here is an example of how the
guidances
break down changes into different
levels. For
SUPAC-IR excipient levels excipients are
listed for
level 1 change, level 2 and level 3. If you look
at glidant, for example, for talc,
plus/minus one
percent change is allowed. If you look at the top
of the right-hand column, it is percent
change
weight of the change of the excipient
over the
weight of the total unit. For talc it is
plus/minus one percent. Other glidants would be
plus/minus 0.1 percent. So, that is the lower
limit of change, plus/minus 0.1 for
talc. If you
look at filler, for example, it is also
plus/minus
five percent change. So, this defines level 1
change, minimal change.
If you go to level 2 the ranges
double.
So, you go from plus/minus 0.2 to
plus/minus 10
percent.
Anything beyond 10 percent is considered
a level 3 change. Again, this is for
non-release-controlling excipients.
If you go down to
release-controlling
excipients for modified-release products,
the
criteria are more stringent. Now, the change is
110
measured as a percentage of the total
release-controlling excipients and not
the total
dosage form unit so your denominator is a
smaller
number.
The percentage allowed is smaller for
release-controlling excipients.
For level 1 change, that means
that the
total additive effect of all release-controlling
excipients should not be more than
plus/minus 5
percent.
Level 2 should not be plus/minus 10
percent.
Changes beyond plus/minus 10 percent are
considered level 3.
So, this is a summary of what
we have
recommended in the SUPAC-IR and MR
guidances.
These guidances define the tests; filing
document
recommendations; level of changes in
composition
and components, release-controlling and
non-release
controlling excipients; site changes;
batch size
changes; equipment and process changes.
The following changes either
need a bio.
111
study or an established IVIVC: Level 3
release-controlling and level 3
non-release
controlling change; level 2
release-controlling
change for NTR drugs; and level 3 site
change and
level 3 process change. All of those changes,
meaning level 2 changes, would require comparable
dissolution documentation, meaning, as I
said,
profile comparison in several media.
As I mentioned in the title
slide for
these guidances, the equipment addendum
came out a
little later and there we identified
equipment by
class and subclass for all major unit
operations,
and a change to a different class is
generally
considered a change in design and
principle. So,
if you have equipment changes within the
same
design and operating principle it is
considered a
minor change. If you go to a different design and
principle it is a major change. Finally, the
changes guidance allows for multiple
different
level changes. As we all know, these changes do
not occur only one at a time; it is a
composite of
changes for any change. So, if you have, say,
112
several level 1 changes and one level 2
change for
your new product you would be held to the
most
restrictive individual change of level 2,
and
whatever requirements go with that level
of change.
So, that was a quick overview
of the
guidances. These documents are available on the
web, and if you have any questions please
look them
up.
Let me switch gears here and take you through
some examples of the way the
specifications are
set.
But before that, let me share
with you
generally what we see in an application in
terms of
information available for setting
specifications.
The data that are available for a typical
immediate-release product in an NDA are
as follows:
Dissolution results under a variety of
agitation
and media conditions. Then typically what we see
are several methods. One method is selected by the
sponsor which generally provides you with
a rapid
dissolution profile. Using that method, we have
data of 6-12 units and that is the limit of
data we
have for any given lot. So, that is the range of
113
variability that you would typically see
for a
particular lot. Using that method, you have
dissolution data from the bio. batch, the
batch on
which bioavailability has been
characterized, plus
few to several production lots under this
condition. Again, as I said, these batches are
usually in very large quantities,
hundreds of
thousands to million units. We see the data on
6-12 units.
Then we do have a lot of
bioavailability
data on this product. Actually, bioavailability,
relative bioavailability, bioequivalency
trials and
dissolution data of lots used in efficacy
trials
and stability data. So, we look at all this
information and try and come up with a
meaningful
specification.
What do we do when we consider
setting
specifications? These are the factors that are
taken into consideration when setting
specs. for an
immediate-release product. The in vivo behavior of
a drug product, particularly how rapidly
the drug
is absorbed and an indicator for that is
Tlag time
114
or what is the Tmax of your product. Since the
issuance of the BCS guidance we look at
the
permeability data very closely. In vivo
permeability would be based on mass
balance studies
as well as absolute bioavailability
studies and
that, in my mind, is the gold standard by
which you
define whether a drug is highly
permeable. If it
is
quantitatively absorbed, then you say this high
permeability, along with your high
solubility data,
puts the product into BCS class 1. Then that
carries its own benefits. I have an example of
that to show you a little later.
That is what one pays attention
to, in
vivo behavior of the drug product from a
bioavailability point of view. We look at
dissolution behavior across all
conditions in vitro
and then we try to come up with an
adequately
discriminating method, taking all this
data into
consideration based on any quantitative
or
qualitative in vitro inference.
What is very helpful for
evaluation of an
NDA is if you have data like this where a
solid
115
dosage form in vivo is compared to
something that
is even more rapidly dissolving, meaning
your solid
dosage form's performance in vivo with
respect to,
like, a solution. If we have this data, this tells
us a lot about what is the in vivo
dissolution of
your solid dosage form and that can help
us
evaluate the in vitro considerations for
setting
specifications for that product. So, this can
guide how discriminating the in vitro
method needs
to be.
As I said, we look at all the
available
dissolution data and pay particular
attention to
the lots that have in vivo data, and then
discuss
with our chemist colleagues about what is
available
in the stability domain, the data there
and the
specifications we are considering. If we see a
significant change or time with stability
performance, that will have to be
resolved by a
bioequivalency study.
Possible outcomes in terms of
setting
specifications, one is everybody is
happy.
Sufficient data are submitted and specs
are
116
finalized. It is possible that insufficient data
are submitted. Based on the product's indication,
the product needs to be approved with
reset interim
specs.
We agree with the sponsor what additional
data needs to be generated. We agree upon a
time-line. We evaluate the specs and we finalize
the specs. In the rare instance where there is
insufficient data submitted--I have not
seen this
happen in my lifetime where we have
withheld
approval for a drug product because of
insufficient
dissolution data. At the least, we will set specs
on the clinical trial product. So, if insufficient
data are submitted and specs can't be
finalized
even including interim specs, then we have
to
resolve that prior to approval.
Now let me take you through
some specific
examples, starting with simple to a
little bit more
complex.
This is an immediate-release drug product
A.
The drug is highly soluble over the pH range of
1.2-6.8, or 6.9 in this case. Based on the
bioavailability and the in vitro
permeability, we
established that the drug is highly
permeable. So,
117
we have high solubility, high
permeability criteria
met.
The drug product is rapidly dissolving over
the pH range of 1.2-6.8. So, we have seen this.
We are sure of these characteristics and
we say
okay, this is BCS class 1.
We have dissolution results of
the
bioavailability lot and the clinical lot
so all
that data is utilized in setting the
specifications. There was stability data also
available that was taken into
consideration. It
turned out to be a straightforward
case. The
sponsor's proposal was that they use a
USP 1
apparatus at 100 rpm in 900 ml 0.1 normal
hydrochloric acid; specs of 80 percent in
30
minutes.
We agreed with the sponsor.
Just as a note, Ajaz and I
didn't exchange
notes beforehand but in this case the
sponsor chose
apparatus 1 to avoid coning effect. Ajaz had an
example from the Canadian database where
that was
the reason why you saw a big investigator
difference compared to the reference, but
the in
vivo data turned out to be fine.
Another example for an
immediate-release
drug product, product B, the drug is a
free base
with 2 pKs of 5.4 and 7.2. It is highly soluble at
118
pH 1 but it is practically insoluble at
pH 7, and
the solubility drops sharply between pH
4-5. I
have a graph that shows that
clearly. The drug is
absorbed slowly, at Tmax ranging from 3-5
hours.
The half-life is long, 45 hours. It is not highly
permeable. The fraction absorbed is around 0.75.
So, what do we do with this? This is the
dissolution behavior across the pH
ranges. As you
see, below pH 5, which is the third curve
from the
top, dissolution starts dropping rapidly
as the pH
increases. The sponsor chose the dissolution
method at pH 5, and showed that the
clinical and
to-be-marketed formulations had similar
profiles.
This is what that comparison is
at pH 5.
We had bioequivalency data on these two
formulations and that turned out to be
clearly
bioinequivalent in vivo for the test,
meaning that
to-be-marketed product showed a clear
difference in
Cmax.
The Cmax was 17 percent lower. We
119
interacted with the sponsor and they
optimized
their method to come up with an adequate
discrimination condition to evaluate this
formulation further.
This is what they came up with,
5 percent
volume Tween 80 and the same two
formulations that
were clearly bioinequivalent in vivo,
they were
able to identify their in vitro
performance and
show that, indeed, they were
different. This was
verified further by taking the two
formulations
that were bioinequivalent in vivo and the
method
showed that they were similar in vitro.
This was the availability of
dissolution
data across several batches. All I want to point
out to you is that, as I said,
dissolution data for
different batches, from 6 units, mean and
range is
available and if we look at the
right-hand column,
the lowest range is 86 percent.
Taking all that data into
consideration,
the
sponsor proposed the specification with
apparatus 2 at 50 rpm and 1000 ml to
Tween 80 in
water; Q of 75 percent in 45
minutes. We
120
recommended no changes in the condition
but a Q of
80 percent in 45 minutes. Here is an example of
availability of in vivo data optimizing
the
specifications.
The final example I have is for
a drug
product, a modified-release drug product
with in
vivo/in vivo correlation. For this drug product a
level A correlation was established. Correlation
was obtained from in vivo data from 6
different
studies, and the media consisted of pH
1.5 for the
first 1.5 hours and then pH 6.8 for the
remainder
of the 24 hours. This is a once a day product.
These are the results. I think this was
excellent work on the sponsor's
part. We worked
with them and we were very happy to figure
out the
specs with them. Look at the hatched region. That
is the observed range of dissolution
data. That is
the extent of variability across the
entire
manufacturing experience for this
sponsor. So, the
hatched area is the dissolution
variability,
dissolution range the product showed in
vitro. The
specs we agreed upon are the two dotted
lines above
121
that hatched region. So, those were the
specifications proposed and we agreed
with them.
The best part is that if you
look at the
third level of curves, which are the
topmost dotted
lines, the topmost and the bottom, those
are the
predicted in vitro dissolution behaviors
of two
formulations that would be comparable in
vivo. So,
the specifications were set within the
limits of
what products would be bioequivalent, so
a good
IVIVC that could lead to meaningful specifications.
Now let me conclude with some
personal
comments on opportunities for
improvement. Before
I get into my own suggestions, I want to
cite this
article that Ajaz already mentioned from
Dr. Janet
Woodcock, a clinician who has written
beautifully
on pharmaceutical quality. I am just going to cite
two quotations out of this article. I mean, I can
stand here and tell you a great deal
about all the
complexities involved in clinical trials
but I
think Dr. Woodcock has summarized this
very well in
this first bullet, which is, as she says,
for the
purposes of clinical use, the established
drug
122
quality attributes are generally adequate
because
they achieve much tighter control of the
level of
variability than could be detected in
patients
without extensive study.
These are part of all the
variabilities,
specially manufacturing variability. It can be
done but it is a difficult task and it
would be
very extensive, and that is not the
paradigm
currently used.
But maybe even more important,
as she
points out here in the very second line
of the
previous quotation, in contrast, for
regulatory and
manufacturing processes, the lack of
detailed
understanding of the real-world
importance of
quality attributes is a serious problem,
leading to
many disputes that might be resolved
easily were
relevant information available on the
relationships
between various quality parameters and
clinical
performance. I personally couldn't agree more with
that concluding comment.
So, clinical performance, if I
were to
dissect that further--everybody talks
about
123
variability and this is my share of what
are the
different types of variability in
therapy. You
start with manufacturing variability,
then you have
variability associated with the drug
exposure and
then you have variability associated with
the drug
response.
You have compliance issues. You
know, a
lot of people can actually add more
bullets to this
and provide a complete picture of how
complex the
system is when a patient is being treated
in vivo.
But I have taken a shot at just
making a
point on exposure-related variability and
manufacturing aspects associated with
that. The
next table is a snapshot. We have an internal BCS
database of almost 200 NDAs. That is in the
process of being audited and we hope to
publish
that soon. So, what I requested Dr. Uppoor to do
is to randomly select a few drugs and
prepare a
table that would show variability in AUC
and Cmax
and the exposure parameters of different
BCS
products.
Again, this is tentative because
this is
not fully audited so that is why I have
starts in
124
this table. This is BCS class 1, 2, 3 and 4 across
the top horizontal line. You have the permeability
associated with the AUC parameter and the
Cmax
parameter for these products. As you can see,
staring with class 1, we have variability
in the
range of 17 to about 24 percent. Class 3 shows
maximum in vivo variability.
So, if I want to take this
tentative class
information further, the point I want to
make--the
numbers might be off when we have the
actual
publication coming out, but this is the
point I
want to make, that if I assume that the
clinical
trial formulation for this product was
optimized--if it is not optimized, I
think it is in
the interest of the sponsor to optimize
that so
that even a little bit of manufacturing
variability
does not reflect in the in vivo
performance at
least from a drug exposure point of
view. But
assuming that this formulation is
optimized, even
for BCS class 1 products you do see a
decent amount
of
variability in vivo. Again, this is
reflecting
how the drug is handled by an individual
and the
125
variability of handling that across
individuals.
This information can be utilized by a
sponsor to
come up with rational specs.
These are some of my thoughts
in terms of
opportunities for improvement. The first point is
nothing earth-shattering but I still
think it is a
point that has to be made, to select an
appropriate
dissolution method based on
physicochemical in
vitro and in vivo characteristics of the
drug and
the drug product.
It would be useful to have an
estimate of
in vitro variability for low solubility
and low
permeability. Estimate of variability of lots used
in pivotal efficacy trials would
facilitate setting
of rational specifications. For modified-release
products estimate the in vitro release
variability--the example I showed where
if you had
a handle on the variability across your
entire
manufacturing process, then you can bring
that into
setting a meaningful specification. As I already
mentioned, right now the IVIVC current
guideline is
based on the limit mean estimates only
and if you
126
can build in the variability aspect and
in vivo
performance based on estimate of mean as
well as
variability, I think that would lead to
more
rational specs, maybe even wider specs
compared to
what we are doing now.
The things that I see in the
near future
are new technologies like PAT. Hopefully, it can
provide in vitro and in vivo
relationships based on
the performance of an individual dosage
form unit.
I mean, this would be a non-destructive
method.
You would be able to assess the
dissolution
performance of a unit without breaking it
up and
then you would administer that to an
individual and
you would get that individual's exposure
parameters
so you would have correlation
relationship on an
individual dosage unit form in an
individual
patient taking it. I think that would be a very
powerful set of data to set meaningful
specifications.
We are getting more and more
complex
products like drug eluting stents and
liposomes.
For these complex dosage forms I think it
would be
127
essential to study drug elution, drug
release using
mechanistic models and new techniques in
imaging
and fluid dynamics. Hopefully, future
specifications will be based on in vitro
mean and
variability estimates.
Moving from a science point to
a process
point--I didn't know our good friend Dr.
Chuck
Hoiber [ph.] would be here but this is in
those
days when Chuck and I were on the same
floor and we
started implementing this which is that
from the
process point of view there are also a
lot of
opportunities to optimize setting of
specifications
and that, from my perspective, is come
and meet
with us early. A meeting would be useful if you
have good quantity and quality of
data. As we have
done on several occasions, we have had
separate end
of Phase II meetings with CMC
Biopharmaceutics and
colleagues on our side and the industry,
going over
the development plan and that has led to
a quicker
review and arriving at meaningful
specifications at
the time of NDA approval.
Finally, I do personally
believe that good
128
homework will always bring
dividends. If you have
good data, please share them with us and
we will
work with you to come out with rational
specifications. Thank you.
Questions by Committee
Members
DR. COONEY: Thank you very much. Some
questions from the committee? Ken?
DR. MORRIS: Two things.
I was a little
surprised to see the high variability
with BCS 3.
In principle, you would expect BCS 3 to
be a good
candidate for waiver because, as long as
your
driving force doesn't change, you would
expect that
the absorption is rate limiting and falls
into the
same basic concept as 1.
DR. MEHTA: That is a very good
observation. We are looking at the data carefully
ourselves, but I think it is maybe one
product that
is--
DR. MORRIS: Driving the variability?
DR. MEHTA: Yes.
DR. MORRIS: Or is it that the absorption
itself is just variable?
DR. MEHTA: Again, we can think about it
but it is a question if you have a class
3 high
solubility, low permeability drug and if
low
129
permeability is not leading to the same
conditions
in vivo that is going to take away some
of your
high solubility benefit.
DR. MORRIS: Not the same conditions on
which side? Are you talking about in the gut?
DR. MEHTA: Yes.
DR. HUSSAIN: Sorry, if I may, I think one
of the challenges is that this was always
a
question when we were deliberating the
BCS
guideline, high solubility. But the in vivo
dissolution actually is more sensitive
for low
permeability drugs and we actually have
published
on this with Lawrence--
DR. MORRIS: Right.
DR. HUSSAIN: So, people often say this is
high solubility so dissolution is not
rate limiting
but in vivo dissolution behavior is quite
complex.
Plus, you add site-specific absorption of
these
compounds that adds to all the sources of
130
variability.
DR. MORRIS: Right.
I guess that is my
point in a sense. Shouldn't the compounds be
segregated into site-specific and passive
absorbed
compounds to really do a valid
experiment?
DR. HUSSAIN: I fully agree with you. We
came up with the classification system
and those
four classes are beautiful but there is
nothing
that black and white. Greater than 90 percent
permeability, highly permeable, but there
is a
gradation of that and, you know, we have
to take
that into account. You know, there are, like,
windows of absorption. So, we need to subclassify
those four classes and then come up, you
know, with
better--
DR. MORRIS: Yes, but it would be nice if
you could identify some more
waiver-worthy classes.
DR. HUSSAIN: Yes.
DR. MORRIS: Just another quick comment is
that I am sure it won't surprise you but,
you know,
with the general BA/BE guidance people,
because of
what is in the guidance, are actually
doing pH
131
solubility profiles of non-ionizable
compounds.
[Laughter]
DR. MEHTA: That is taking us too
seriously!
DR. COONEY: Paul?
DR. FACKLER: I have a comment and a
question.
The comment had to do with the slide
where you suggested there might be about
20 percent
variability for even BCS class 1
compounds. I
would suggest that that is vastly
understated, that
the variability is much higher than that
because I
am guessing that your data comes from
bioequivalence studies where all of the
subjects
take exactly the same amount of water,
the same
amount of food. None of them are BMI greater than
a particular number. If they are old studies they
were all men. I would just say that in the general
population with the way pharmaceuticals
are really
taken--some people run three miles, come
home and
then swallow their tablets; some people
roll out of
bed and swallow them without water--the
variability
even for class 1 is significantly higher
than 20
132
percent.
But it is just my opinion.
DR. MEHTA: That would just add to the
thought I had which is, you know, use
that
information to evaluate your in vitro
specifications. That will help you.
DR. FACKLER: The question I had had to do
with that same chart where you looked at
17 drugs
that were randomly pulled out of the pool
of 200.
It was interesting to see that the class
3 is N
equals 7.
I am just wondering if the distribution
of these 17 in any way represents the
distribution
of the 200 drugs.
DR. MEHTA: I don't think so. The whole
idea was to see if we can get a handle on
what is
the exposure variability for these
products. A few
years ago I presented this database at
one of the
APS workshops what was surprising is that
we saw a
lot of NDAs falling into class 4
category. If it
is a class 4, then you would see very few
drugs,
low solubility, low permeability. You know, they
would fall out of drug development. But, as I
mentioned a little while ago, the way
classifying
133
we have created these four classes, 90
percent of
data goes in class 1 over this 85 percent
absorbed--you know, it is still low
permeability.
So, I don't think when we come out with
this
information, all audited, that there is
going to be
a majority of them falling in class
3. I don't
think so.
DR. COONEY: When you presented the table
of the 17 samples, your intent is to
expand that?
This is just a piece of work in progress?
DR. MEHTA:
Yes, very much so.
DR. COONEY: So, the idea is to really
address the question that was just asked,
that is,
to have an analysis that is
representative of that
whole set?
DR. MEHTA: Yes. I
mean, right now we are
going through each drug and making sure,
to our
level best effort, that the data
available
classifies that drug product in the
appropriate
class.
We have the information put together and
now it is like careful auditing going on.
DR. COONEY: Good.
Marvin?
DR. MEYER: I did come up with a couple of
questions. It always bothered me that the BCS
system had this quadrant drawn and then
the lines
134
kind of floated depending on how you
wanted to
define high and low--
DR. MEHTA: No, it is rigid right now.
DR. MEYER: I know it is rigid but the
rigidness was arbitrary.
[Laughter]
It is arbitrarily rigid.
DR. HUSSAIN: I will defend it tomorrow;
don't worry!
DR. MEYER: Okay.
DR. MEHTA: We started out with a
conservative position and now with the
availability
of more data we want to expand that
rationally with
proper evidence.
DR. MEYER: It also bothered me that this
permeability goes all the way from a very
rigorous
intubation of humans to a K2 cell to
looking at
Tmax.
So, how it is defined or determined can be
another source of variability in where it
falls in
135
this rigorously arbitrary quadrant. So, I think
that may be a reason in part why the
class 3 seemed
to be more variable than 2. One drug in that would
have expanded the range.
DR. MEHTA: That is just the way those
drugs got pulled out. That is why I have that
range.
That may not be reflective of what it is.
I don't want to take up too much time,
but we look
at permeability assessment now very
carefully and,
in my mind, hopefully, if we have data on
the NDA
side, which is mass balance data and
bioavailability data, that is the maximum
way in
terms of assessing, you know, whether the
drug is
90 percent absorbed or not. Sometimes we have an
issue with that. Then we utilize the in vitro
methods for that decision.
DR. MEYER: One last question. Do you
feel that the f2 test has been rigorously
evaluated?
DR. MEHTA: A good question, Marv.
[Laughter]
There are people in the
audience that--
DR. MEYER: Do you feel--do you feel it
has been rigorously evaluated so it will
detect
differences when they should be detected
and will
136
allow passage when it should be allowed?
DR. MEHTA: Well, I mean we do state in
our guidances under what conditions this
approach
should be employed. You know, if your variability
is very high in dissolution on each
formulation
this is not the right way of comparing
those
profiles so then you need to get into
more complex
assessment, and all that. If it is done properly,
yes, I do myself.
DR. COONEY: Pat?
DR. DELUCA: In the BA/BE guidance summary
for modified-release products you are
saying that
they should profile using at least three
other
dissolution media and water. Why do you need three
others if you have a correlation?
DR. MEHTA: No, it doesn't say that there
is a correlation. This is just a question--well,
usually correlation is release
formulation
specific.
DR. HUSSAIN: It is just for that
product.
So.
DR. MEHTA: It is right now.
DR. COONEY: Nozer?
DR. SINGPURWALLA: When you don't
understand something you start asking
technical
137
questions.
[Laughter]
You showed a picture of linear
correlation
long ago, one of your early slides--
DR. MEHTA: Yes, level A correlation.
DR. SINGPURWALLA: Level A correlation. I
have two comments. The first is that you are
looking for relationships between the
percent of
drug dissolved and the percent of drug
absorbed so
correlation only measures linear
relationships.
You may have dependence which may be not
linear but
still of value to you, but correlation
does not
measure that. So, I just want to say that as a
comment.
The second more serious comment
is that
that particular correlation misses the
time index.
138
What you really need is a third axis also
showing
the time at which all these happen. For you to do
that, you want to look at these two as
what we
would call stochastic processes or time
series, and
you want to cross-correlate the two time
series.
So, if you want to improvise on that
particular
theme, you may want to look not at
correlation but
what I would consider cross-correlation
where you
also introduce the time axis. That is the only
comment I want to make.
DR. MEHTA: Thank you.
That is helpful.
DR. SINGPURWALLA: Do you want to
challenge me now?
DR. MEHTA: No, I didn't say that.
DR. COONEY: Are there any other questions
at this point?
[No response]
Thank you. The next presentation will be
by Dr. Shah establishing dissolution
specifications.
Establishing Dissolution
Specifications:
Current Practice
DR. SHAH: Good morning.
Mehul gave a
nice overview on the BCS guidance and
other
guidances which are used in setting
dissolution
139
specification from a biopharmaceutics
perspective.
My job today is to cover the CMC aspects
of setting
the dissolution specifications. In this
presentation I am going to start with an
overview
of the current practice, and in that
overview I am
going to cover the CMC assessment and
bring in some
of the ICH Q6A principles, how we
evaluate the ICH
Q6A principles in our CMC assessment, and
then I
would like to talk about a case study
example for
extended-release oral suspension and in
that
example I am going to cover the drug
development
strategy by the applicant, the
dissolution results
obtained based on that development
strategy, then
what we identified as critical issues,
followed by
our recommendations and based on those
recommendations, what were the
improvements
implemented by the applicant and what was
the
outcome out of those
implementations. I would like
to end my talk with some concluding
remarks based
140
on this example as well as general
remarks in that
aspect.
As Mehul suggested in his
presentation, I
want to reemphasize that establishing
dissolution
specification is a shared responsibility
between
the Office of New Drug Chemistry and the
Office of
Clinical Pharmacology and
Biopharmaceutics.
In the next three slides I have
presented
the considerations that should be given
during that
development, as well as the focus of CMC
assessment
during the NDA review, and what forms the
basis of
setting the dissolution specifications
from CMC
perspective.
As I have pointed out here, it
is a known
fact that physicochemical properties of
the
formulation components, such as drug
substance and
other excipients, such as the solubility,
pKa,
particle size distribution, polymorphic
forms and
there may be some others, have a
significant effect
on the dissolution. The physicochemical properties
impact the processibility of the
formulation
components, as well they may affect also
the
141
safety, efficacy and stability of the
drug product.
In addition to that, the manufacturing
processes,
especially those having the potential to
influence
the release profile of the drug substance
also
should be studied during the development. And, the
control strategy of the critical process
parameters
and in-process testing also should be
developed
during the development, and those are the
focuses
of the CMC assessment.
During the drug development one
should
expect that there should be a
relationship of
in-process testing to the critical
quality
attributes, such as dissolution of the
drug
product.
Some of the in-process testing that may
be carried out might be particle size
distribution;
release rate; and the compression force,
tablet
hardness and friability in the case of
solid oral
dosage form.
In addition, during the CMC
assessment we
focus also on the development and
validation
aspects of the proposed in vitro
dissolution
method.
Cindy already covered some of these
142
aspects in terms of how the methodologies
are being
developed and what are the validation
criteria that
need to be covered, especially pertaining
to
specificity, linearity, accuracy,
precision,
ruggedness, etc. In addition, we also focus on the
release time point intervals and what should
be the
adequate tim point intervals.
Once we have this information
we need to
see or need to provide during
development, as well
as the NDA submission data, what is the
relationship between the in vitro dissolution
data
from development, clinical, bio. and
primary
stability batches, and also identify a
discerning
trend on storage. We also evaluate the proposed
shelf-life of the drug product on the
basis of the
stability data analysis of dissolution,
as well as
other drug product attributes.
In the end, it is in
coordination with
Office of Clinical Pharmacology and
Pharmaceutics
that appropriate dissolution
specifications are
recommended and these specifications are
reflective
of the dissolution data from various
batches
143
including clinical, bio., stability and
other
batches.
In terms of the ICH Q6A document, ICH Q6A
discusses the potential relevance of
particle size,
polymorphic content and polymorphic
changes, and
how it affects the dissolution.
Here I have these three
decision trees
just for reference. I just wanted to point out
that CMC assessment very well integrates
these
principles in our assessment for the
quality
assessment of the drug product. This is about the
particle size distribution and the
decision tree
guides you on how to set acceptance
criteria.
This is in terms of polymorphic
content.
That also guides you on how to set
acceptance
criteria.
The next one is how to set the
polymorphic change acceptance criteria in
the drug
product.
Now I would like to focus on
the case
study example for extended-release oral
suspension
for the remainder of my talk.
Let me give you just some
background.
144
This was submitted as a 505(b)(2)
application. As
a result, there was no clinical trial
required
because the safety and efficacy of the
proposed
active ingredients for the proposed
indication was
established through immediate-release
products
available under the tentative OTC
monograph for the
same indication. The proposed dose was a single
dose given every 12 hours to patients 6
years of
age or older. That was equivalent to the nominal
OTC monograph which was given every 6
hours twice.
In terms of the formula, the
drug product
contained two different active
ingredients, and I
will call them drug substance 1 and drug
substance
2.
For proprietary reasons, most of the data I am
going to discuss here are well concealed
and they
are masked but the data are real. Drug substance 1
is anchored to a drug carrier support and
coated
separately with semipermeable polymer to
prevent
dose dumping and to impart the
extended-release
profile.
Drug substance 2 binds the drug carrier
support in situ during the manufacturing
process,
but it is not coated. Both active ingredients,
145
along with other excipients, are
suspended in
aqueous solution.
The concerns we had here arise
from the
safety implications due to the potential
dose
dumping, and efficacy implications due to
insufficient rate and the extent of
release of the
actives.
These concerns were brought to the
applicant's attention during the end of
Phase II
meeting as well as pre-NDA meetings, and they
were
very mindful of those two concerns.
This was the strategy adopted
by the
applicant in the beginning. They wanted to
demonstrate bioavailability of the drug
product
formulas, and that was coated with 6
percent
coating of drug substance 1, to a
reference drug
which as an immediate-release solution,
and it was
containing the same two active
ingredients. They
had no other choice but to start with the
immediate-release solution because there
was no
existing extended-release product
containing these
two ingredients.
Their plan was to formulate
three
146
experimental drug formulations, each
differing only
by the coating level of semipermeable
polymer on
drug substance 1. They were low coating, for
example, 2 percent; medium coating,
example, 5.5
percent; and high with 9 percent coating
on drug
substance 1. They labeled them as fast-release
solution, intermediate-release
formulation and
slow-release formulation. The approach was to
establish IVIVC for each active among
these three
experimental formulations, and establish
dissolution specifications for both
actives based
on generated dissolution profiles from
the slow-
and fast-release drug product
formulations.
In the NDA the data submitted
include five
formulations of the drug product
containing drug
substance 1 coated with varying levels of
semipermeable polymer, 2 percent, 5.5
percent 9
percent, as well as 6 percent and 10
percent. They
performed the following PK studies, multi
dose
bioavailability studies with
immediate-release
solution and single dose food effect
study
containing 6 percent polymer coating, and
single
147
dose IVIVC study containing three
formulations, 2
percent, 5.5 percent and 9 percent
polymer coating.
In support, there were PK results from
four batches
and stability results from four PK and
five
stability batches.
Based on these PK studies,
these were the
applicant's claims, that level A IVIVC
was
established for both actives of the ER
suspension.
The mean individual level A IVIVC models
for drug
substance 2 met the FDA validation
criteria and, in
their opinion, it can be used for setting
dissolution specifications and
biowaivers.
The mean and individual level A
IVIVC
models for drug substance 1, which is
coated,
failed the FDA validation criteria in
that the
predicted values had a larger error than
recommended. However, if the dissolution criteria
remain within dissolution profiles tested
in IVIVC,
they proposed that the drug substance 1
results can
serve as a mapping study for the
formulations.
Now let's see what was the
agency's
finding in terms of the PK results. On the
148
bioavailability and food effect studies,
which was
the 6 percent coating of drug substance
1, the
agency found that systemic exposures of
both
actives were favorable between the
extended-release
suspension and multi dose of reference
immediate-release solution, and there was
no food
effect on both actives.
However, in terms of the IVIVC
study,
where the drug substance was coated with
the 2
percent formulation, 5.5 percent
formulation and 9
percent formulation, with respect to drug
substance
1, the agency found that it failed to
establish the
in vivo/in vitro correlation, and
observed more
than 20 percent of difference in Cmax for
formulation of fast and slow dissolution
profiles.
With respect to drug substance
2 that was
not coated, level A IVIVC was
established, however
it failed to validate the IVIVC. The formulations
used in the IVIVC study were found to be
bioinequivalent, that is to say the Cmax
of the
formulations used in the IVIVC study were
different
by more than 20 percent. The proposed dissolution
149
specification and the approach to set a
dissolution
specification based on IVIVC by mapping
was found
unacceptable.
Now let me share the stability
results
analysis.
This is what we review in our CMC
assessment. What we found was contradictory
release profiles observed between drug
product
formulations containing 6 percent and 9
percent
coated drug substance. Drug substance 2 showed
more decrease in dissolution than drug
substance 1,
and we observed substantial decrease in
dissolution
at 1-hour, 3-hour and 6-hour time points
for both
actives from the corresponding initial
values among
all batches, including bio. and primary
stability
batches, at all storage conditions. The decrease
in dissolution was most notable at 3-hour
and
6-hour time points. The decrease in dissolution is
minimum at the 12-hour time point and the
decrease
in dissolution for both actives levels
off by 9
months on storage.
This is displayed on this
slide. This is
the dissolution results of drug substance
1. For
150
clarity purpose, I have labeled the
coating for the
dissolution curves. The yellow bar shows the 6
percent coating that was used in the
bioavailability study. The purple is the 2
percent.
The middle one is blue, which is 5.5
percent coating of drug substance 1. The red one
is
the 9 percent coating of drug substance 1.
Now, what I explained in the
previous
slide is what you can see is a decrease
in
dissolution profiled for all the
solutions. You
would expect the 9 percent would be showing
a slow
dissolution compared to the 6 percent but
it is
quite the other way.
If you look at drug substance
2, the
decrease is more compared to drug
substance 1,
which is shown basically from the least
point and
at the 18 months time point. That is more than
about 20 percent decrease in dissolution
over time.
So, based on this analysis
these were the
critical issues discussed with the
applicant, and
they concerned the raw material controls,
manufacturing processing and in-process
controls
151
and controls related to particle size
distribution
and dissolution method.
I just want to point out over here that
these discrepancies in the results showed
that the
coating process was not in control and we
discussed
that issue with the applicant. They decided to
reformulate the drug product and decided
to abandon
the idea of the IVIVC approach to set
dissolution
acceptance criteria; conduct PK studies
on
commercial scale bio. batch containing
drug
substance 1 at the specified target
coating level,
rather than a range, and compare it to
the
reference IR solution; manufacture
additional 3
pilot scale primary stability batches of
the drug
product containing drug substance 1 at
the same
specified target coating level; and
propose
dissolution acceptance criteria based on
in vitro
dissolution profiles obtained for both
actives from
the bio. batch.
These were the process
improvements
implemented. They coated the drug substance with a
specified target coating level of
semipermeable
152
polymer; revised the coating and
subsequent
manufacturing processes; instituted
appropriate
process controls to stabilize binding of
both
actives to the drug carrier support in
the
suspension; and manufactured one
commercial scale
bio. batch and three pilot scale
stability batches.
They instituted appropriate
particle size
measurement method, for example laser
diffraction,
for drug carrier support and coated
drug-bound
carrier particles. They revised particle size
distribution acceptance criteria for the
drug
carrier support, coated drug substance
bound
carrier support particles and suspension
stabilizing excipients.
Based on these results, they
conducted
three PK studies utilizing the drug
product
formulation with coating of drug
substance 1. They
conducted BA/BE assessment; PK at steady
state; and
food effect studies. The results showed that the
PK profiles of drug substance 1 and drug
substance
2 from test extended-release suspension
were found
comparable to the reference IR solution
following
153
single and multiple dose administration,
and food
had no effect on bioavailability of both
actives.
Now let me share with you the
stability
results analysis. After the implementation of the
improvements in manufacturing process for
coating
and instituting adequate process controls
in terms
of particle size, we observed stable and
consistent
release profiles at 1-hour, 3-hour,
6-hour and
12-hour time points for both drug
substance 1 and
drug substance 2 on storage within each
of the bio.
and three primary stability batches. There was no
discernible trend in release profiles of
drug
substance 1 and drug substance 2 and on
bio. and
primary stability batches at all storage
conditions. And, there were comparable release
profiles for both drug substance 1 and
drug
substance 2 among bio. and three primary
stability
batches.
This is displayed in this graph
for drug
substance 1. You can see, as opposed to the
dissolution rates that we saw before and
after
implementation of manufacturing
processes. This is
154
with respect to drug substance 1, which
was coated.
This is the bio. batch and these are the
three
primary stability batches. Most of the
dissolution, as you can see, ranges
between 5-7
percent.
This is with respect to drug
substance 1
dissolution profile. This is the bio. batch and
you can see these are the three primary
stability
batches and you do not see any discernible
trend
and most of the dissolution ranges
between 5
percent if you compare it to drug
substance 2 prior
to the implement.
Then I would like to conclude
my
presentation with the following
remarks. We were
able to identify probable causes of discrepant and
inconsistent dissolution results for drug
substance
1 and drug substance 2, and recommend
corrective
measures to address the issues. The outcome was
consistent manufacturing process;
acceptable BA/BE
results; stable and consistent release
profiles
without any discernible trend on storage
for both
drug substance and drug substance 2. Dissolution
155
criteria which were set were better
reflective of
the data.
There was a substantial improvement in
the quality of the drug product and there
was a
significant improvement in assurance of
the safety
and efficacy concerns.
However, the case study example
highlighted two significant points. There was a
lack of or poor understanding of the raw
material
properties and manufacturing processes
that were
critical to be controlled for consistent
quality
and thereby desired performance, for
example,
extended-release dissolution of the drug
product.
It also identified inadequate efforts
invested by
the applicant during the drug development
to
understand the causal links of
dissolution
failures.
The case study example stresses
a dire
need for improvement to the existing drug
development efforts to understand the
relationship
between the raw material properties of
formulation
components and critical quality
attributes of the
drug product; the effect of raw material
properties
156
of formulation components on their processibility
for selected manufacturing processes, and
the
effect of manufacturing processes and
associated
critical process parameters on the
critical quality
attributes of the drug product.
I would like to end my talk
with the last
remark that there is no substitute to a
systematic
and scientific approach to drug
development for a
safe, efficacious and quality drug
product. Thank
you.
Questions by Committee
Members
DR. COONEY: Thank you.
There is an
opportunity for questions. Nozer?
DR. SINGPURWALLA: Just a point of
information, you repeatedly used
distribution,
particle size distribution. What particle size
distributions do you use in your
activities?
DR. SHAH: I am not following the
question.
DR. SINGPURWALLA: Particle sizes are
random.
DR. SHAH: Correct.
DR. SINGPURWALLA: They are not the same.
So, they have a probability of
distribution.
DR. SHAH: Yes.
157
DR. SINGPURWALLA: Now, there is a lot of
literature, perhaps not in your business,
on what
should be the distribution of particle
sizes. This
morning we heard the viable distribution
attacked
by my colleague here, but the log normal
distribution is often used as a distribution
of
particle sizes. My question is what distributions
are used in the pharmaceutical industry
for
particle sizes, or is this a completely
different
scenario?
DR. SHAH: I am not sure how to answer
that question, but I will tell you what we
practice
in CMC review. We ask for the applicant to
identify the particle size range in D10,
D15 and
D90.
That means 90 percent of the particles--
DR. SINGPURWALLA: Right.
DR. SHAH: And we ask for the span,
basically the ratio of D10 to D90 divided
by D15
and that gives you where the distribution
lies.
158
Basically, that kind of gives control of
consistency of the particle size
distribution.
DR. SINGPURWALLA: Actually, you answered
my question. What seems to be not there in your
industry is you are just looking at the
percentiles
and if the distributions are skewed one
way or the
other it makes a big difference what they
are when
you simply work with the
percentiles. So, I am
just encouraging you to look into that.
DR. SHAH: I agree.
Thank you.
DR. COONEY: Ken?
DR. MORRIS: I think one of the things
that occurs is that people don't control
the
distributions. They tend to be log normal sort of
in a general sense but people don't intentionally
control this. They usually control to a mean,
which is a real big problem--
DR. SINGPURWALLA: If you control the mean
you start to control the distribution.
DR. MORRIS: Yes, you try to control the
mean but there is no real--and I am not
sure what
historically the reason is for that but
that is
159
sort of the case.
DR. SINGPURWALLA: You need to know what
it is.
DR. MORRIS: But you need to know what it
is.
DR. SINGPURWALLA: You can't control it.
DR. MORRIS: That is right. My question
is do you think that there problem was
control
simply of film thickness or was it
perhaps
incorporation of one of the compounds
into the film
unintentionally during the coating
process?
DR. SHAH: No, that was definitely the
coating process, and this was like black
art in
that they were mixing and matching and
they never
had a handle on the coating process
itself.
DR. HUSSAIN: One point that I think I
wanted to illustrate with this
presentation was
that really to control, to achieve a state of
control, and so forth, you have to get
down to
upstream activities, starting with raw
materials,
and so forth.
The point I also wanted to sort
of
160
emphasize was that just focusing on a
test, even
when you have a correlation, which is
just a
correlation and may not be causal, I
think is that
gap that we are also trying to fill with
focusing
on the CMC part of the manufacturing
controls.
Without that the system really--the
method is
weakened.
So, the quality by design aspect is to
emphasize that part of it. So.
DR. COONEY: I think another dimension
with this particular case is that there
is a
significant amount of complexity because
you are
dealing with multiple products,
complexity both in
the process as well as in the product
itself. This
is I think a particularly good example
where
quality by design can have a greater
impact with
these more complex processes and
products, and the
processes and the products need to be
thought
through together, which is your
point. It is very
clear.
I think we are actually going
to begin
lunch ten minutes early. However, beginning lunch
ten minutes early does not mean that you
get an
161
extra ten minutes for lunch. We will reconvene at
12:50--guess what, you can get an extra
ten minutes
for lunch. We will reconvene at one o'clock.
[Whereupon, at 11:50 a.m., the
proceedings
were recessed for lunch, to resume at
1:00 p.m.]
162
A F T E R N O O N P R O C E E D I N G S
DR. COONEY: If I could have people's
attention, welcome back from lunch. I hope that
everyone appreciated the extra 9.5
minutes that you
had for lunch. It is one o'clock. It is the
opening period for open public
hearing. We have
one presentation for this afternoon by
Will Brown
from USP, and he will speak with us on
USP and
dissolution testing. Thank you.
Welcome
Open Public Hearing
DR. BROWN: Thank you so much, and I would
like to thank the various FDA staff
members for
giving a staff member at USP the
opportunity to
speak before this committee. I am a member of the
staff of the Department of Standards
Development at
USP, and I serve as one of the liaisons
to the
Biopharmaceutics Expert Committee.
This is breaking news. USP reorganizes
itself once every five years, and part of
that
reorganization is the election of the
chair of the
Council of Experts. We have a reelected chair,
Thomas Foster, for the Biopharmaceutics
Expert
163
Committee. You can see on this slide the
membership, and you will see names you
recognize
hopefully.
USP and dissolution--well, we
are terming
dissolution one of the performance tests.
Performance tests currently mean
dissolution or
disintegration test, and by test I mean
part of the
specification. The ICH definition, and it is very
easy to use terms loosely, says that a
specification is a list of tests,
associated
procedures and acceptance criteria. So, that is
kind of the idea of the USP
dissolution. It is
part of the specification. You will find the
public specification in the USP
monograph.
The general dissolution test is
found in
the general chapter, 7-11 on dissolution,
and that
gives a general description of the
techniques that
are available, with the understanding
that those
techniques can be modified. We saw this morning
what the modifications might
represent. They might
represent the appropriate medium or
agitation or
apparatus as determined by the applicant
and the
164
FDA.
Now, the study design that is
embedded in
the dissolution test and the analysis is
in three
stages.
We have a fixed number of samples tested
at each stage and there are acceptance
criteria
again that are determined by the
applicant and the
agency, and then communicated to USP by
what I am
terming the sponsor, who is the same
party as the
applicant.
The general approach is to test
by
attribute. In other words, a product is either
good or bad. It either conforms or it doesn't and
that is a fairly decent approximation and
convenient for application by an
independent
analyst but it doesn't necessarily
address
underlying distributions of performance.
In the USP test by attributes
there is a
control on the spread of the data. By example, at
the S3 level where you tested 24 units
there is a
limit that says that no individual unit
value can
be below Q-25 percent. So, there is an
acknowledgement that there may be an
underlying
165
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
166
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
167
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
168
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
169
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
170
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
171
scale-up from the University of Maryland
batches
that were intended to reproduce the NCDA2
10 mg
prednisone tablet and we have a new batch
in
production. Theophylline beads are calibrated for
apparatus 3, were deleted partially in
response to
requests or concerns by users. And, thank you
very much.
Questions by Committee
Members
DR. COONEY: Thank you.
I would like to
now open up your presentation to
questions from the
committee.
DR. MORRIS: Just one point. I guess if I
sort of put aside for the moment the
specific
hesitation I have about calibrator
tablets, if I
just look at the criteria by which you
would
reproducibly generate a standard for
calibration it
seems to me that the things that are
missing are
not that unattainable. I mean, I think that you
have to have a particle size solid
fraction as
opposed to weight and, you know, the
normal
controls you have on tableting. I don't think
there is solid fraction control in the
calibrator
172
tablets, if I am correct. Art, do you know?
DR. KIBBE: No, and I want to go back and
have a solid cylinder without any
particle size
where you only have dissolution for the
surface.
The point that I was going to make sure I
was right
about is that it is my understanding that
if you
claim a USP product, that product must
meet USP
testing if USP testing is done by
anybody. But it
doesn't require you to do USP testing on
your
product if you have a better way of
controlling the
quality of that product. Isn't that right?
DR. MORRIS: That is correct. That is
clearly stated I think in the Journal of
Medicine.
DR. KIBBE: Right.
So, if I was a company
who was really heavy into PAT and had a
really good
control on my product, once I established
that my
product met USP guidelines for that
product, I
would never have to do that test again
unless I am
challenged.
DR. BROWN: That is correct.
DR. KIBBE: Right.
DR. MORRIS: Can I just ask is solid
173
fraction controlled in the calibrator tablets?
DR. BROWN: I can't speak to the
manufacturing of calibrators but I know
that I have
seen formulas where the solid fraction
beat
particle size. My concern about a disintegrating
dosage form, my personal concern is the
rate of
disintegration and how fast the active is
exposed
to the medium. That is critical and I take your
advice on the solid cylinder. I think that we see
very nice dissolution from salicylic acid
tablets
which, again, are being essentially
remanufactured
and repackaged, and I think will have the
potential
to show some value that we don't
currently extract
from them.
DR. COONEY: Tom?
DR. LAYLOFF: I was going to comment on
Art's question. You know, if you demonstrate that
your product complies and you
cross-validate
against that, then you can enter it in
the columns
because you would say it meets the
specifications
and it is up to someone else to
demonstrate that it
doesn't.
DR. KIBBE: Right.
DR. LAYLOFF: I mean, if you are
challenged you don't have to retest
it. Their
174
challenge has to include the test.
DR. KIBBE: Right, that is what I said. I
mean, as a manufacturer I don't have to
continue to
do this test at all.
DR. LAYLOFF: And if challenged you don't
have to repeat it again. They have to show that it
doesn't comply. The FDA has to go out and seize
it.
DR. COONEY: Marv?
DR. MEYER: In one of your slides on page
three you said inter-laboratory
variability is a
major contributor to the width of
ranges. If so, I
wonder why that is the best way of doing
it. Why
not just have a really good machine in a
really
good laboratory and do it? FDA has a beautiful
guidance on analytical methods for bio.
studies and
they specify variability, and they
specify
precision, and they don't say, well, this
only
applies to University of Tennessee but Pfizer
has
175
to do this and Teva has to do that. They say this
is what works; this is what we will
accept. Why
not have a methodology that doesn't
include inter;
the
inter is their problem it should be the USP
problem.
You should just have a good set of data
and everyone has to match it.
DR. BROWN: One of the things that you see
in dissolution labs is that there are
apparatuses
that have tendencies. I am not sure what
constitutes a really good apparatus. I am not sure
that we have nailed it down even with the
arbitrary
limits that were given in Dr. Buhse's
presentation
this morning. I am not sure what constitutes
active variables in the dissolution. I am not sure
that any of us are. So, I am not sure what that
really good apparatus would be and would
it reflect
reasonable expectations from various
well-manufactured products, apparatus
products.
DR. COONEY: Tom?
DR. LAYLOFF: The dissolution experiment
is not a mystical science
enterprise. Many years
ago we did an 11-lab collaborative study
of FDA
176
labs where we required them to meet the
system
suitability requirement before they
continued the
test.
Now, what that paper said--and this was done
I guess about 1990 maybe, what it said
was that the
between lab results variance was about
2.6 percent;
the within lab was about 1.6, which is
absolutely
consistent with the retrospective study
that was
done by Bill Horowitz over about 50
studies in
AOAC, collaborative studies among
labs. The among
lab results for various analytical
techniques for
pharmaceuticals was 1.6 and the among lab
data was
about 2.6. The ratio is about 1.7. And the
collaborative study for dissolution
testing with 11
FDA laboratories, all required to meet a
suitability requirement, was in the same
range,
which meant that the sample preparation
with the
dissolution medium had the same variance
as
analysis with other techniques.
DR. COONEY: Ajaz?
DR. HUSSAIN: I think the challenge we
face is if inter-lab variability is a
concern,
which I am not sure--and to some extent I
am
177
following what Tom is saying--I don't see
how the
calibrator really does anything. It adds probably
the majority of the variability to that
study. If
we are going to make a calibrator using same
type
of excipients, raw materials with control
of
particle size based on D50 percent and so
forth,
how can that really give us any
information when
the quality of the product being
tested--the real
product might be far superior? That is the
fundamental flaw here.
At the same time, what is the
quality
control strategy for the dissolution
calibrator
tablet?
It is another dissolution test.
So, that
goes in circles. So, that is the challenge we
face.
DR. COONEY: Tom?
DR. LAYLOFF: One other thing, as was
noted previously, the calibrator tablet
isn't
calibrator because you can't use it to
calibrate
anything.
It is a system suitability test tablet.
As Ajaz mentioned, it in itself can be a
moving
target and your product may be less of a
moving
178
target.
If you have good control of your product,
if you do have control over your particle
size,
excipient, polymorph--you control all
those
variables you are home free.
DR. COONEY: It seems to me we are coming
back to a point that we talked about
earlier, and
that is to have clarity in what it is we
want to do
with the test that we are using, and to
make sure
that we are not just simply taking a
methodology
developed at some point in history and
applying it
to meet some regulatory or perceived
regulatory
requirement, and we need to really
understand what
we are testing for; what we want to
measure; and
what is driving the variance in those
measurements.
Are there any further comments
from the
committee? Tom?
DR. LAYLOFF: One comment, it is a
regulatory requirement and people lose
product on
the market because of it. I mean, it is a very
real thing that is out there.
DR. COONEY: Thank you very much. This is
the only presentation we have for the
public
179
period.
Since there are no others we can begin to
go back to the regular agenda. The next
presentation, by Lawrence Yu, is on
establishing
drug release and dissolution
specifications.
Factors Impacting Drug Dissolution
and Absorption:
Current State of
Science
DR. YU:
Good afternoon, everyone. The
assignment today is to talk about the
factors
impacting drug dissolution and
absorption: current
state of the science. This certainly is a big
title.
My talk will cover three aspects, basically
in vitro dissolution testing. I am going
to share
with you some of the limits to oral drug
absorption
which has relevance to in vitro
dissolution, and
finally I want to share with you some
thoughts on
challenges to regulatory evaluation of
dissolution
which have been discussed this whole
morning.
This morning we discussed the
variability
of dissolution testing. We discussed how to set
specifications from a biopharmacist and
pharmacokinetics perspective. We discussed it from
the manufacturing and control
perspective. The
180
question is why are we doing dissolution
testing?
Why do we dissolution testing for almost
all single
solid oral dose drug forms, as well as
the majority
of dosage forms like parenteral dosage
forms?
Let's review the basic process
of oral
drug absorption when a patient takes a
tablet or
capsule.
This tablet or capsule will disintegrate
or dissolve in the stomach. Dissolved and
undissolved drug will be emptied from the
stomach
into the small intestine where
dissolution
continues to occur. The dissolved drug will cross
intestinal membrane, will pass through
the liver
and reach the systematic circulation.
So, from the mass transport
perspective,
look at the processes, the fundamental
processes
going on here. We have gastric emptying, transit,
dissolution, permeation, and
metabolism. These
processes determine the rate and extent
of
absorption, all of which we call
bioavailability.
Because of the significance of
bioavailability with respect to safety
and efficacy
of product, as you can see, dissolution
becomes an
181
essential or critical step, the first
step for drug
absorption. That is part of the reason why.
Another reason why we normally conduct
dissolution
test.
Now, the question is what are
we
measuring? Usually we use the classical equations.
I understand those equations are not
perfect.
Sometimes they do not fit the dissolution
profile
well but they give you a flavor of what
are
critical variables involved with respect
to
dissolution.
We have particle size which we
mentioned
this morning. Basically, particle size effects the
surface area, so surface area affects the
dissolution. The larger the surface area, the
smaller the particle size, the faster the
dissolution.
We have solubility. Now, a number of
factors impact solubility, for example pH
for
ionized compounds. For example, polymorphism
impacts solubility. So, those factors affect
solubility which eventually affect
dissolution.
182
That is why we say the particle size,
polymorphism
sometimes have impact on dissolution.
Finally, there certainly is
bulk media.
Bulk media will determine the pH and pH,
in turn,
impacts the solubility and, again,
impacts the
dissolution. Therefore, if we review the factors
involved, we have particle size; we have
solubility
and certainly bulk solvent.
In terms of utility, normally
we have two
utilities involved, two kinds. Certainly under
each kind there are different kinds of
utilities.
The first is for quality control from
chemistry
manufacturing control perspective. I will give you
an
example here. There are two polymorphic
forms.
The polymorphic II automatically
translates into
polymorphic I, for whatever reason such
as
manufacturing, storage, and so on and so
forth. It
will impact dissolution. So, therefore,
dissolution is a tool for quality
control.
Another utility which we
mentioned this
morning is so-called in vivo performance
evaluation. Now, what I show you here is very
183
beautiful, perfect examples. I have to say we have
a every chance to be successful in
showing level A
in vitro and in vivo correlation. Nevertheless,
this is a real example where one of the
companies
was able to come out with a beautiful
IVIVC which
certainly can be used for waiver in the
future by
current studies, which certainly can be
used for
setting specifications, and so on and so
forth.
But it is not easy. It is a challenge to establish
in vitro and in vivo correlation.
Now, despite its utility for
dissolution,
there are many limitations. When we talk about the
limitations in the CMC or bio. area
dissolution is
always a hot topic because it is so easy to
criticize. For example, you will say the
dissolution is over-discriminating, which
means
that in vitro dissolution you find a
significant
difference and you find no difference at all
in
vivo.
But in some cases you find no difference in
in vitro dissolution, yet, you find a
significant
difference in vivo. So, we call it
over-discriminating.
So, in order to understand
those phenomena
from the perspective of oral drug
absorption, we
have to understand the oral drug
absorption first
184
and particularly the limits to oral drug
absorption. That is what I want to talk about,
limits to oral drug absorption.
First let's review drug
substance factors
and then we will review the drug product
factors,
which is the disintegration. When we review drug
substance we mentioned that particle size
and
solubility are two major factors which
impact the
in vitro absorption and certainly
sometimes, again,
in vivo absorption. So, in order for us to
understand the limits we have to define
what are
the limits here. Yes, we have dissolution but in
vivo absorption certainly involves more
than just
dissolution, as we discussed. In terms of process,
we have transit, gastric emptying. We have
permeation and metabolism.
But from an in vitro
perspective, from in
vivo dissolution perspective what we
define as the
limits to oral drug absorption is
dissolution
185
limited absorption and solubility limited
absorption and permeability limited
absorption.
Now, it is very easy to understand what
is called
permeability limited absorption. It is simply that
the drug across membranes is very, very
slow
compared to other process. That is why it is
called limited.
Now, with dissolution limited
absorption
we have to talk about dissolution so the
dissolution limited absorption seems very
easy to
understand. People ask me very often what is
called solubility limited
absorption. Why do you
distinguish solubility limited absorption
from
dissolution limited absorption? This is because in
the reality setting, especially for drug
discovery
and development, we have to understand
that the
concentration in vivo or in the
gastrointestinal
tract of a patient cannot exceed the
solubility, as
is shown here in the middle. Concentration cannot
exceed solubility. Now, with in vitro dissolution
testing we always have simulated
conditions so,
regardless of the amount of drug, it can
always be
186
dissolved but not necessarily in
vivo. Think about
it, if you dump tons of drug into the
human body,
they are totally saturated and the
concentration
cannot exceed solubility regardless of
how much you
dump into the patient or subject. It is not quite
useful anymore. This is the distinguishing
difference between solubility limited
absorption
and dissolution limited absorption.
Mathematically, with
dissolution limited
absorption we generally refer to particle
size as a
major factor. Solubility limited absorption refers
to solubility. Now, solubility, of course, in turn
impacts dissolution but from an in vivo
perspective, because the concentration
cannot
exceed solubility, that is why we define
solubility
limited absorption. It has clinical implications
with respect to permeability limited
absorption,
solubility limited absorption and
dissolution
limited absorption. Let's look at it.
Theoretically, in order for us to define
under what conditions is dissolution
limited, under
what conditions is solubility limited we
have
187
designed some numbers and we have dose
volume; we
have dissolution time; we have absorbable
dose.
The dose volume is the amount required to
dissolve
the dose.
The dissolution time is minimal time
required to dissolve a single particle
under the
same conditions, while absorbable dose is
the
maximum amount of drug that can be
absorbed under
certain physiological conditions such as
solubility
and transit time.
Based on those parameters, we
can define
under what conditions is dissolution
limited; under
what conditions is permeability limited;
and under
what conditions is solubility limited.
Let's look at the comment
here. For
dissolution limited absorption or for permeability
limited absorption the absolute amount of
drug
increases with the increased dose. So, it is very
simple.
When you require high exposure in vivo
simply give more drug. That is usually the
practice in drug discovery and probably
development, particularly during animal
toxicity
studies.
However, for solubility limited
absorption
the absolute amount of drug absorbed does
not
increase with increase of dosing. That is part of
188
the reason that for solubility limited
absorption
you have to rely on other approaches to
improve
bioavailability, to improve the absolute
amount of
drug absorbed. Very often industry and our fellow
friends in toxicology department they
often give
more and more drug and when they cannot
see high
exposures they ask us why. The reason is that in
many cases it is because the absorption
becomes
solubility limited, therefore, if you
give more and
more drug you cannot see absolute
increase of the
amount absorbed.
In terms of prediction--and
this is the
permeability limited absorption, there is
certainly
fraction of dose absorbed, although
percent of drug
absorbed can be reasonable predicted with
mathematical equations. The data in this slide is
from human permeability but sometimes rat
permeability can be used to give us very
good
results.
K2 cell permeability can be used but does
189
not necessarily give us good results, in
other
words, whether in humans the compound has
high
permeability, can always high
permeability in other
systems, including the rat.
This is another beautiful
example to
determine how particle size impacts
absorption. As
I mentioned, in this theoretical framework
we
define dissolution limited absorption is
because of
particle size so, as you can see, for
digoxin, yes,
it is very poorly soluble; yes, the
solubility is
only 60 mcg/ml. You are actually able to get 100
percent bioavailability. In this case there is no
metabolism, therefore, 100 percent
absorption
equivalent to the bioavailability.
This morning we discussed
particle size
distribution, and I have to tell you that
in
simulation in these slides I simply used mean
particle size. Yes, there is literature out there
using particle size distribution in order
to
understand how particles impact
absorption. In
fact, in my publication we attribute that
at 100
mcg prediction is not that good because
we used
190
mean particle size instead of particle
size
distribution because even though mean
particle is
100 mcg, a number of small particles can
be full
absorbed.
That is part of the reason that you see
higher percent absorption, much higher
than what
has been predicted.
Griseofulvin is a very
classical example.
If you look at 100 mg griseofulvin, the
solubility
is 95 mcg/ml. As you can see, when you give a
higher dose the fraction of dose absorbed
has not
been increased, and part of the reason is
when you
reduce particle size. It explains the utility of
solubility limited absorption.
This is a graph never published
but I
thought I would share it with you because
it is the
interplay of bioavailability, solubility,
permeability and hepatic clearance,
showing in the
drug discovery setting of the drug is
above the
surface.
This means the bioavailability most
likely is lower than 30 percent. Below this, the
bioavailability is most likely above 30
percent.
So, if you want to increase the
bioavailability,
191
depending on where the drug molecule is
located,
you can increase the solubility; you can
increase
the permeability; you can increase
hepatic
clearance and increase the
bioavailability. So,
that is the utility in industry settings.
This is a very brief overview
of how
factors impact the absorption from the
drug
substance perspective. This will give a very brief
overview about the drug product factors
which
impact the absorption. Certainly, the
manufacturing process could impact the
particle
size but I will mainly focus on
disintegration, in
other words, how a tablet disintegrates
and becomes
smaller particles.
In order to illustrate how the
manufacturing process could impact
dissolution, I
will just give you an example here. This is a drug
which is highly soluble and highly
permeable. So,
if you give oral solutions you can see
the Tmax at
about 1.3 hours and it very quickly
reaches the
Cmax, about 13 hours. This is basically the
solution curve.
Now, when you give a different
dosage
form, because of slowing of
disintegration you
could have a different dissolution
profile, slow,
192
medium and fast. When we translate this in vitro
dissolution into in vivo here is the
plasma
concentration profile. Obviously, the slower the
solution translates into lower Cmax and
lower AUC.
Another case is when you have a
different
coating system, this may be dissolved at
different
pHs and in in vitro dissolution we are
able to see
a significant difference and you also see
it in
vitro, as you can see in this slide.
So, those slides basically
illustrate how
the dosage form impacts dissolution,
impacts
absorption. Certainly, there are many factors in
in vitro dissolution that impact, for
example,
manufacturing process, compression force,
and so on
and so forth. Those will impact the dissolution of
a product.
I want to share with you some
thoughts
about challenges or opportunities which
we are
facing today. First of all, when dissolution is
193
very rapid, outcome rate determining
steps, drug
levels in the blood and plasma may not
reflect
dissolution differences at all, as you
can easily
understand. Because dissolution is not limited in
vivo, therefore, in vitro how much
different they
are doesn't matter because you cannot see
it in
vivo from the in vivo perspective. Yet, for
dissolution limited absorption sometimes
we can get
IVIVC and sometimes actually in vivo
fraction
absorbed is not always possible because
of lack of
IV.
For solubility limited
absorption, as well
as permeability limited absorption in
vitro
dissolution will not always reflect into
in vivo
because they are limited by solubility,
because
they are limited by permeability,
therefore, any
difference in vitro may not be translated
into the
in vivo at all. So, we normally call that
over-discriminating.
Now, here we have f2, very
useful,
similarity factors. Usually we use 50 or above
because 50 or above reflects average 10
percent
194
difference or less. I have to say this f2 value
certainly works fine or works well in
most cases
but we can always see a criticism here
because in
some cases the f2 value is not reflected
in vivo
because, as I said, the f2 value is
basically
average 10 percent difference. When you average 10
percent under different limits to
absorption, those
may be reflecting in vivo or may not--may
not see
in vivo situation.
So, as I said earlier in the
discussion of
the presentation, there is a role of
dissolution
for quality control and for in vivo
performance
evaluation. So, the question that comes to my mind
is are these two goals always
consistent? They may
not be.
That presents an opportunity for us.
For
example, under the hydrodynamic
conditions--and we
have a paper from Rutgers University to
show that
Reynolds number for chemical engineering
for 50 rpm
as well as for 100 rpm--under those
conditions we
may see some in vivo/in vitro
correlations. In
fact, the paper suggests we may lower the
rate so
that under laminar flow we could see
significant or
195
more difference in the amount of
dissolution. Yet,
when we go to the lower levels number and
in
laminar flow, even though we may see in
vitro, but
those may not translate in vivo because
in vivo the
hydrodynamics is much more higher, the
Reynolds
numbers--could be a lot higher. In fact, in the
stomach the motility is highest--educated
guess, it
is difficult to see in vitro laminar flow
in the
same situation.
And then there is the
media. The media is
always an issue because in the real
setting we will
evaluate a number of the media and we are
trying to
define the dissolution a significant
difference, or
most of the difference when we select in
vitro
dissolution testing. If you make a survey of some
of poorly soluble drugs, for example,
sometimes we
saw hydrochloride. Sometimes we see pH 7.4
phosphate buffer--these are all
dissolution tests.
The question that comes to us is are
those
dissolution tests or dissolution media
reflected in
vivo?
I have serious doubt that our human
beings--sometimes the pH could be 7.8 in
the
196
stomach or sometimes could be 7.4, or
sometimes the
concentration could be 2 percent or
sometimes could
be zero percent. I think there is a wide spectrum
maybe in vivo. This is true but it may not change
as much as we see in in vitro dissolution
evaluation.
So the question that comes back
is should
these two objectives for dissolution
testing be
separated? I think this is the challenge in front
of us.
We do not have a solution yet but I think
we ought to seriously look at the
possibility and
the value and drawbacks as well as
benefits.
For example, for dissolution
quality
control, hopefully, hydrodynamics and
media are
chosen for reproducibility and detection
of product
changes, for example, particle size
changes; for
example, polymorphic changes. Certainly, design of
in vitro dissolution test and for quality
control
are not constrained by a desire to mimic
in vivo
conditions.
But for in vivo biorelevant dissolution
we
may choose a battery, a number of tests
which
197
pretty much covers what is going on in
vivo in the
human body. So, those tests will, hopefully, get
reasonably good correlations to in
vivo. Yes, FDA
has lots and lots of dissolution
data. Yes, we
have a lot of products approved that have
required
dissolution data. Yet, when we look at dissolution
data and try to transfer those
dissolution data
into knowledge, unfortunately, we almost
get
nothing because every single drug, every
single
product has used similar or even
different
dissolution media. It has been difficult for us to
get to some kind of in vivo/in vitro
correlation
even though we have lots, and lots, and
lots of
data because the difference among in
vitro
dissolution tests almost cannot be
translated in
vivo.
That is the difficulty.
So, in summary, believe me, I
have
discussed in vitro dissolution testing
and
discussed the limits to oral drug
absorption.
Again, the limits to absorption could be
solubility; could be dissolution; and
could be
permeation. We have briefly overviewed the
198
dissolution profile comparison and
discussed the
future role of dissolution with respect
to quality
control and in vivo performance evaluation. Thank
you very much.
Questions by Committee
Members
DR. COONEY: Thank you.
I would now like
to invite questions from the
committee. Ken?
DR. MORRIS:
I guess, Lawrence, one thing
that occurs to me is that really the
distinction
between your dissolution and solubility
limitation
seems to me--or, I guess this is a
question, are
you really differentiating the source of
the
solubility attenuation? In other words, aren't you
really looking at whether or not it is
the activity
coefficient or the lattice energy that is
controlling the solubility?
DR. YU: I guess when we talk about
solubility, certainly there are two
parameters. In
this difference, when we distinguish the
solubility
limited absorption and dissolution
limited
absorption, we infer that solubility is
the
solubility final number, whether it is
caused by
199
lattice energy or not.
DR. MORRIS: But that is not really the
case, is it? Right?
I mean, there is a
distinction. I think it only changes the
terminology; I don't think it changes
your
conclusions but maybe we can talk about
it
off-line.
DR. KIBBE: I follow him a lot better than
where you are going.
[Laughter]
DR. YU: Thank you, Art.
DR. KIBBE: What he is talking about is
absorption and what drives absorption,
and not
dissolution. What drives dissolution is a
different set of parameters.
DR. MORRIS:
I don't think so. If you are
talking about the absolute value--I mean,
you have
the same solubility but different causes
for--
DR. KIBBE: No, he is talking about
different absorption with different solubility.
DR. MORRIS: But that gives you the
differences for the driving force. The driving
200
force is determined by the concentration
or the
activity--
DR. KIBBE: Right.
DR. MORRIS: --no matter what.
DR. KIBBE: What he is saying is that you
have a series of events and if the rate
of
dissolution gets you to a relatively low
solubility
maximum quickly, then the whole thing is
driven by
the limited solubility in terms of
absorption. We
can do the numbers off-line.
DR. MORRIS: Yes.
Yes, I see what you are
saying.
I still think that your dissolution is
solubility limited. It is still just a different
solubility limitation, but we can talk
off-line.
DR. COONEY: Ken, I think the point you
are making relates to one segment of the
possible
space where you are solubility limited.
DR. MORRIS: Yes, for low solubility.
DR. COONEY: Yes.
DR. YU: I guess the solubility limited
absorption as well as dissolution limited
absorption is with respect to in vivo
absorption.
201
You have to look at in vivo absorption
when we talk
about those limits because with in vitro
dissolution evaluation you always same
conditions,
at least based on FDA guidance. Therefore, you
always can see dissolution. But in vivo there is
dissolution going on but think about when
the whole
small intestine is saturated by the drug,
under
this condition we call it solubility
limited
absorption. I don't know if I can explain it to
you better.
DR. MORRIS: I think I understand what you
are saying.
DR. YU: It is just terminology I guess.
DR. COONEY:
Marvin?
DR. MEYER: Lawrence, the dissolution for
quality control is distinct from
dissolution for in
vivo, that comparison. Why have two?
If your
quality control is irrelevant to in vivo,
I don't
see
any particular relevance to it. Let's
say you
want to have something you can detect
changes in
the product, but what if you needed 25
percent
methanol in water to detect a change in
coating
202
thickness, and you needed 10 percent
methanol in
water to detect a change in particle
size, and you
needed some other medium to detect a
change in the
combination of the two and then, all of a
sudden,
you would have three or four dissolution
tests,
none of which may make any difference
when it comes
down to the various product differences
in the in
vivo setting? Why hot just focus in on the
biorelevant dissolution?
DR. YU: Well, I think the question that
comes back is that, first of all, in the
40 years
of dissolution history it is quite
unusual. As I
mentioned, you really need a lot of
laughing,
sunshine and good luck to get in vivo/in
vitro
correlation, and even if you get it today
it may
not exist tomorrow if you change the
formulation a
little bit. That is why the famous words from Ajaz
are that IVIVC is formulation specific.
The question is why do we need to
separate?
What is the value? I guess this
was
presented to you today. What I would argue is the
following, when we talk about in vivo
dissolution
203
testing it is quite complex. It is not so
difficult to do. If you think about it, you have
100 products, or one company has, you use
900
vessels and each and every day you
consume a lot of
acid.
So, if you think about it, those dissolution
tests can be replaced by simple quality
control
dissolution tests of, say, water it is a
worthwhile
effort simply from an economic
perspective and from
a convenience perspective. However, you have to
say whether those tests are sensitive
enough to
detect any significant changes in vitro,
for
example particle size changes,
polymorphic changes,
and so on and so forth. But in vivo dissolution
tests, hopefully, is a fixed battery of
dissolution
tests which pretty much capture what is
going on in
the physiological conditions. Now, whether we
actually can develop those or not we are
waiting to
see.
This is simply a proposal presented to you to
see what you think about it.
DR. HUSSAIN: May I?
I think just to add
to what Lawrence just said, Marvin, the
current
tendency is to use--the phrase
"performance test"
204
was used to some extent--is to capture
all the
other controls that are missing. Let me explain
that.
We currently have a univariate focus on
quality.
What it means is we do all the testing on
the content, rate and everything of the
drug
substance only. But the excipients, distribution,
and so forth, is also relevant. So, dissolution
tests for quality purposes capture all
those
aspects.
Actually, I have an example in my slides
that I could show you later on.
So, that is the current
philosophy of
needing a dissolution test even if it is
not
relevant from an in vivo perspective to
do that. I
think quality by design would say that if
you are
controlling all aspects that are
relevant, then you
may not even need one. I mean, we opened that
possibility to you.
DR. COONEY: Art?
DR. KIBBE: Which is kind of where I
wanted to go. The dissolution testing and a lot of
our terminal testing was developed when
we couldn't
characterize our product
effectively. The easiest
205
way of determining whether your tablet
was hard
enough was to snap it and listen to the
sound of it
cracking it. Friability was you took a handful and
dropped them on the floor, and if none of
them
broke then your tablet was okay. That is where I
started in this business so, hopefully,
we have
come a long way from that.
If we have a process under
control that we
can characterize and we know the factors
that are
affecting the way it performs in vivo
because we
have looked at them with data in people,
then you
say to yourself do I still have to have a
test
which was originally thought of as a
surrogate for
the in vivo performance at all? If so, what is it
getting me in terms of information to help control
my process?
The question I asked USP was,
well, can we
still be USP without doing this
test? Of course,
you can.
You don't need to do this test if you
will eventually pass it whenever you felt
like
doing it.
You could do tests that are much more
useful and instructive in terms of
whether your
206
process is under control. It reminds me of the law
that is still on the books in New York
City that
when the car was invented the requirement
was that
a man walk 20 paces in front of the car
with a red
flag to warn everybody that the car was
coming.
Now if they tried to enforce that law in
New York
he would get run down by the 40 cars that
were
coming.
Perhaps we ought to look at dissolution
testing as the guy with the red flag,
warning us
that we might not be in control anymore
when we
really have much better controls on the
system.
DR. COONEY: Are you suggesting we change
the red to a blue flag?
[Laughter]
DR. KIBBE: I was going to go for Claude
Raines and make the flag invisible.
DR. MORRIS: Actually, it is Kevin Bacon
these days.
DR. KIBBE: That shows you my age, right!
DR. MORRIS: I tried a Claude Raines in
class and nobody knew what I was talking
about. I
guess to that point, if you can
characterize it, I
207
mean sort of looking at statistical
significance
without getting into discussion of
statistics, you
can have a much larger fraction of the
population
sampled during development than you are
going to
ever have when you are doing
manufacturing. So,
once you establish that design space,
then by the
time you get to manufacturing, in
principle you
should never have to do dissolution,
which I am
sure would make everybody a lot happier
if not a
little nervous.
DR. COONEY: Tom?
DR. LAYLOFF: I can see dissolution
testing as a regulatory tool to assure
that the
manufacturer is putting out a product
which
conforms to the specifications, but there
is no
recovery from a failure in dissolution
tests, short
of destroying the batch. I think that there have
been in place for a very long period of
time the
tools to control the processes so that
you can
deliver a product which would meet the
test if
tested.
So, I don't see the dissolution test as a
useful release test because if it fails
that
208
release test you have failed the
lot. It means the
process has failed, everything has
failed. So, I
don't see it as a utility for a release
test. I
see it as a regulatory tool, enforcement
tool
because you can see using that to hammer
somebody
but I can't see it as a release
tool. If you have
to use dissolution testing as a release
tool it
means you don't have everything in
control.
DR. COONEY: I think what we will do is to
move forward to the next
presentation. There is
clearly going to be more conversation and
discussion and that will be most
appropriate after
Ajaz has taken us through his first 16
slides.
[Laughter]
Summary of Tactical
Plan
DR. HUSSAIN: Yes, I will be brief and
just lay out the steps of the tactical
plan and
stop at that point and open this for
discussion. I
do have a number of slides in your
handout which go
on to sort of illustrate some more deeper
part what
we are thinking about and some
illustrative
examples.
But just to summarize, I think what
we are
trying to do is seek your recommendation
on are our
tactical steps outline consistent with
the goals we
209
are trying to achieve? What additional steps, if
any, of changes would you recommend to
improve our
plan?
What additional scientific evidence is
necessary to support development of the
plan when
we come back to you to make the proposal
next time,
hopefully? General considerations for identifying
and developing statistical procedures;
any other
specific recommendations you may have.
Now, the proposed steps are in
one clump
focusing on the measurement system, an
alternate
regulatory approach, suitability of
dissolution
measurement system which will rely on a
rigorous
mechanical calibration and, when
necessary,
measurement of degassing concepts that
Cindy talked
about.
This will be coupled with a
characterization of your clinical pivotal
lot or
the bio. lot in terms of a gauge
reproducibility/repeatability study where
you could
look at how sensitive this formulation is
to
210
conditions of measurement systems such as
degassing, such as operator, such as the
apparatus,
and so forth, in a structured design in
an
experimental way since this is a
destructive
sample, and there are means to do that.
Then we will focus on
developing decision
trees, and I have put them in one
clump. The focus
of the decision tree would be to
establish
dissolution rate specification. I have requested
Lawrence to give you a flavor, just a
flavor of how
we can start thinking from a mechanistic
perspective of setting mechanism-based
specification. He just gave you a snapshot of the
mechanisms that affect absorption. There is a
whole other set of mechanisms that define
the
release of drug from the dosage forms,
and so
forth, and depending on the types of
release
mechanisms so that combination will allow
us to
start thinking about how you approach a
mechanistic-based specification because
that will
drive us to what are the critical factors
that
affect release, and then work around
that.
This is also an opportunity
because often
people are concerned that when you talk
about
mechanism this will restrict--that only
few
211
mechanisms are acceptable. No, I think it actually
says you can have multiple different
mechanisms but
then you will modify your specifications
to that
specific mechanism and not force
companies to one
set of dissolution specifications.
Clearly, I think the
opportunities for
utilizing a control philosophy, quality by
design
and our technologies under the umbrella
of PAT will
replace these methodologies. As I mentioned, the
methodology would be part of the decision
tree. As
part of the decision tree also would be
the level
of process understanding and control to
achieve--
to essentially create a concept of design
space and
how this might be used for post-approval
changes,
the type of changes that Mehul sort of
illustrated
to you, and I will actually pick that up
in my talk
tomorrow and explain that further.
Also, I think it is important
for us to
make sure our decision trees are
compatible and
212
equally open and transparent to all. Therefore, we
would like to develop a side-by-side
comparison of
our decision tree for new and generic
drugs. I
think one of the key aspects would be to
come to
the committee to get an endorsement for
the level
of quality assurance and quality control
confidence
that we will have with our decision trees
and our
control strategy, quality by design,
would be
higher than what the current system
is. To me, it
is a given but I think all of us need to
be
convinced of that.
Today we will specifically seek
recommendations from you on the
statistical
procedures, how do we want to proceed, and
I have a
couple of slides on that. After this meeting we
will get busy and develop a detailed
proposal for a
subsequent meeting for discussion. The timing of
this meeting was very important. We rushed and
tried to get this meeting because, as I
said, this
weekend I go to Brussels and we are
starting a
discussion on decision trees for dosage
forms in
ICH and I needed this discussion behind
me, and the
213
comfort of knowing, arguing and making
the point
because we want to achieve harmonization
in Europe,
Japan, and so forth. So, this meeting and your
recommendations I think will play a part
in our
discussions.
Just to summarize what we
intend to
accomplish with all this--improve our
ability to
identify sources and type of variability,
and to
ensure quality by design. Vibhakar illustrated one
simple example to you. If you only rely on
dissolution, even though you have IVIVC,
a
correlation may not be causal. I think you have to
bring a control system perspective or
control
strategy to assure quality, not just a
test.
Obtain global estimates of variability to
use in regulatory decisions. Our current approach
can be improved. You saw our approach and
opportunities for improvement there. And, we would
like to use this information on variability,
sources of variability in how we set
regulatory
specifications and process controls so
that we
focus on controlling the real source of
variability
214
and, for example, if the concern is that
this
excipient is not uniformly distributed
and that is
important, today the only test we have is
dissolution. If you have other means you can move
in that direction. We also want to use this
information for assessment of adequacy of
proposed
material and manufacturing process
control
strategies.
Facility, assessment and
communication of
technology knowledge transfer and
assurance of
state of control and production
operation--this is
the current big gap between CMC and GMP,
and I
think this will help us to bridge that
gap.
Clearly, the basic philosophy is if you
can
demonstrate a state of control that opens
the door
for continuous improvement flexibility.
The inspiration for the
proposal--there is
not a single thing which is new or unique
in this
proposal.
It is well established and we have
simply borrowed it from other
sectors. The
inspiration was the DMAIC concept of
defined
measure analyzing improvement control of
the Six
215
Sigma concept. So, what we are proposing is in
practice in every other sector,
literally.
But there are many challenges,
and this is
an important challenge that I think we
have
discussed several times, the
pharmaceutical
quality, because of the challenges--the
consumer,
the patients or the physicians cannot
judge
quality--creates some challenges. Now, the key
concepts in Six Sigma are that you need
to know
what is critical to quality attributes,
attributes
most important to the customer. This is the
quality to clinical challenge. It affects failing
to deliver what the customer wants. In this case,
failing to meet your specifications or
deviations
in GMP practices unless these really are
focused on
critical to quality attributes, and so
forth. This
is an opportunity. It is in green. We can get to
more critical variables and focus on
signs rather
than following what our practices have
been.
Process capability, what your
process can
deliver, this is again an opportunity
because the
concern from a CMC review perspective is
that
216
process validation may not be adequate,
and with
the sample size that we have from a USP
market
standard perspective as a release test is
a
significant concern, whether it is right
or not. I
think that is debatable. But the market standards
are perfectly find. In my opinion, I think the USP
market standard is fine. There is nothing wrong
with that. I think the practice of using them as
release tests and as in-process tests,
that is
where the challenge is.
But the challenge I think is
variation,
what the customer sees and feels. We don't know
this so we have to go with what our signs
say and
what the best practices are. Dr. Woodcock, in a
paper, called it market failure because
you cannot
get the feedback from the customer really
unless
there is a dramatic failure.
Stable operation is an
opportunity, and
this is a significant opportunity for
continuous
improvement because the regulatory
agencies around
the world and industries also--corrective
actions,
the only leverage for continuous
improvement--we
217
have to get away from that
mentality. And,
demonstration of stable operations can
provide a
logical and scientifically rigorous way
to
alleviate this concern.
Design for Six Sigma I think is
designing
to meet customer needs and process
capability, and
here the fundamental premise is that you
design
your product for your patient, not for
your
dissolution test. I mean, that distinction really
has to come through. And, many times I think if
FDA is asking the right question we can
make sure
that happens. If FDA doesn't ask the right
question they will design to what FDA
wants, and I
think that is a fundamental
challenge. In some
ways that is a specifications capability
gap that
can exist. So, here are the opportunities and
challenges and I think we have to address
those as
we develop our decision trees.
Step number one is measurement
system
suitability, and this is clearly honing
down on the
target value, the mean value for your
measurement.
It focuses on mechanical and media
factors, but I
218
am not sure it is actually an independent
step so I
have also put step number two, gauge
R&R which is
essentially a qualifying one that you do
once as
part of your approval, using a clinical
pivotal lot
or a bio. lot. Here you have to think about
analysis of variance and the factors that
might
contribute, like apparatus, dissolution
media,
operator, clinical pivotal lot, and this
a
structure design of experiment.
Now, clinical pivotal lot or
gauge R&R has
some considerations. It is not just automatic. It
has to be supported by pharmaceutical
development,
stability and sampling. By stability, here I mean
the process was stable from start to
finish, not
from the conventional stability
perspective also.
It is a statistical control.
Can we also do this for
currently marketed
products is a question mark. Information that
would come from these studies would help
us
facilitate a shift from a deterministic
design
culture because we want to move towards
assessing
variability and using variability. So, this is
219
step two.
This could be an independent step but I
just wanted to sort of repeat that here.
The decision trees--I am not going
to walk
you through in detail of the decision
trees. I do
have some examples later on. How should we
consider moving towards decision
trees? Lawrence
and the Office of Generic Drugs has
started working
on a question-based review process, and
the whole
thing is asking the right questions in a
sequence
that drives you towards quality by
design. So,
clearly, as part of the decision trees is
what are
the
key questions we should be asking, and so
forth.
So, asking the right questions would be a
consideration. Clearly, beginning with the end in
mind, which is the intended use, keep the
focus on
intended use as we develop these
questions.
Systems base, connecting the
key
disciplines and regulatory submission
section--at
the previous advisory committee, as part
of the OPS
Critical Path Initiative, I presented a
proposal on
how to connect different parts of the
section that
will be part of this consideration. Vince Lee
220
actually has started working on that and
I think we
will see how that connects.
We also wish to facilitated
structured
product development process. The traditional trial
and error of one experiment at a time
will not
really cut it. You really need to have a
structured product development. Yet, we do not
want wish to dictate the specific
process. That is
the challenge.
Pre-approval changes and
bridging
studies--on average in a new drug
application there
are three to six bioequivalence studies
done on new
drugs--three to six. Some we don't even review.
If you really look at it, if you leverage
that
information to bring in considerations
that every
experiment you do is a hypothesis you
have so many
opportunities to evaluate that
hypothesis. So,
bridging studies would be a leverage.
The decision trees would be
cumulative in
terms of leading to a decision but also
support use
of prior knowledge. For example, we have wonderful
approaches to predict the impact of
particle size,
221
and so forth. So, as you are in your early part of
development studies you can predict the
impact of
particle size on manufacturability as
well as
dissolution and bioavailability. So, if you have
such a system in place for the next
product that
comes along you will make the prediction
and
evaluate that so you postulate your next
experiment
that you go into in vivo that this is
what I
expect.
Once you do that, you start setting up a
learning system that at some point
becomes very
useful.
That means that we will move
towards a
scientific hypothesis format. I have removed those
slides.
Those slides come later on if you have any
questions.
How do se address the
challenge, the two
challenges of market failure and quality
to
clinical gap? In a sense, one of the challenges I
think we have is we think about risk and
uncertainty and we confuse that, and this
is
again--I learned from this committee and
I will
share with you a table of how we can
separate
222
uncertainty, variability and risk
tomorrow. I
shared it at the training session
yesterday with
some of you.
I think our current assumption
that we
work under is that our methods that we
use are most
discriminating, therefore, risk is
mitigated. So,
if that is the case we are not dealing
with risk;
we are dealing with uncertainty and how
you
approach that opens up a whole new set of
approaches. So, if you are dealing with
uncertainty lack of knowledge is the
challenge.
So, improve the knowledge that leads you
to that.
So, from that basis, product
specification based on
mechanistic understanding provides a
means to
address uncertainty and that will be a
progression
that we will use.
So, if you really look at it,
the way we
set specifications is because of
uncertainty.
Uncertainty management without
pharmaceutical
development information is a
challenge. We focus
on a discriminating test concerned with
in vivo but
without the pharmaceutical development
information.
223
The discriminating part comes from the
method
measurement system. Is it really discriminating
the formulation variables that really
impact?
Sometimes you have a disconnect there.
So, often we have a shotgun
approach. Dr.
DeLuca was sort of raising that question,
why do we
ask for three or four dissolution media
sort of
blindly?
If we had an understanding of what the
physicochemical aspects were, if we knew
what
dissolution media or conditions would be
most
discriminating why would we ask for
more? We
wouldn't.
We shared that. And, the rule of
thumb
that I shared with you, which is a 30
year old rule
which we still do not practice in
industry is when
you have certain acids or bases, however
sensitive
PK is, 4-6 or 3-6, go with the PK8
value. That is
the most discriminating. That is a well
established rule of thumb but we don't
utilize
that.
So, often it is the shotgun
approach, 3-5
different media. We just focus on pH. Now, the
surface tension of the dissolution media
is about
224
70/cm.
The surface tension of the GI fluid is
about 30-50. It makes a big difference. So, why
aren't we doing it at that surface
tension? So, it
opens up all the questions that Lawrence
raised.
In practice, I think the
frequent tendency
is
to utilize 0.1 normal HCL and I illustrated the
concern from the perspective of the
Japanese. If
that is a real concern, then we have to
think about
how to address that.
Quality assurance versus in
vivo relevance
debate, I think that will be part of the
decision
tree process. But one aspect that we have to think
about is mechanistic understanding. We haven't
defined it. And, I am proposing that we will use
the ICH Q6A concept that we have already
accepted,
and here is that concept. For example, this is
section 3.3.2.3 of ICH Q6A, particle size
distribution testing may also be proposed
in place
of dissolution testing when development
studies
demonstrate that particle size is the primary
factor influencing dissolution. So, if you are
able to make that decision for a
parenteral
225
preparation why don't we make that
decision for an
oral preparation? the reason here is because the
parenteral suspension is a
suspension. In a solid
dosage form you have compaction, and so
forth, but
we have technology that can even address
that so
this becomes a meaningful way to move forward.
But, again, as was pointed out, the
particle size
distribution should be well characterized
and well
represented.
So, mechanistic understanding
as a
proposal is that identification and
scientific
justification of causal, physical or
chemical
relationship between pharmaceutical
materials
and/or process factors that impact
quality. Here I
want to draw a distinction. Establishment of
correlation may not be causal. So, we want to be
careful and that is the reason why in the
PAT
guidance we said correlation may not be
sufficient.
We need causality and that is process
understanding.
I think this is a significant
debate and I
think we may be able to achieve it in the
U.S. but
226
it has to occur in this. Specifications equals
standard.
That is the philosophy now. That
is the
reason why release tests are USP market
standard.
Now, this is well ingrained. I would propose we
need to start thinking about changing
that. Market
standards have a value, as Tom pointed
out. Market
standards are fine. You need them from the
perspective that Tom laid out. But then the
release specifications and control
studies should
be different and be risk-based. And this is the
challenge.
So, specifications are
standard.
Non-conformance means you have to reject
or recall
a lot.
Now think about this, most companies have
this but we haven't utilized it. You have to start
thinking about a control limit with a
target value
and an acceptance range around a common
cause of
variability, with special causes of
investigation,
special causes to investigate. So, if you think
about this, one of the reasons why the
concern is
if you start reducing your variability
the
regulators around the world will say you
have
227
narrowed your specification is this
phenomenon
because, if you don't, they may not
investigate and
if there was a special cause that might
be a signal
for something else. So, if you move towards a
control philosophy and if you bridge this
gap
between CMC and GMP this is a way
forward. But,
again, there is no consensus around the
world on
that.
Step six, general consideration
for
identifying and developing statistical
procedure.
In my presentation I also identified the
recent
contribution from the USP. I think it is a step in
the right direction. But it is, again, very
similar to the parametric tolerance
interval test
concept and we have been debating that
for at least
the three years that I have been
involved; I think
it is more than that. And, you will hear a
progress report on that tomorrow from Bob
O'Neill.
This is where I really need the
committee's help. We have to start thinking
differently. Testing a hypothesis on every
production batch is not the right way of
thinking
228
about this when you are in a state of
control. You
are not testing every production batch as
a
hypothesis. The gap between CMC and GMP I think is
validation. Hypothesis testing--my proposal would
be to be limited to the validation part
of it, and
you really test the hypothesis that you
have
transferred the technology appropriately,
and so
forth.
So, specification setting and standards and
hypothesis testing, such as parametric or
non-parametric tolerance interval--and we
have been
working on that. This is a recent hypothesis
structure. There was a recent proposal from our
Office of Biostatistics for
dissolution. It should
be limited as the time of approval and
validation
that our CMC reviewers make that call,
and so
forth.
But then in production you have
to move
towards control. So, you have to start thinking
about control charts of variable, not
attributes,
where you really have a focus and target
value and
risk-based upper and lower limits;
process
capability analysis, not hypothesis testing
on
229
every lot. This is important. This is a very
important principle on which I need your
help.
So, I will stop here. The questions are:
Are the steps outlined consistent? Any additional
steps you might recommend? How should we prepare
to come back to you? What other scientific
evidence is necessary to support
this? General
consideration for identifying and developing
statistical procedures and any other
thoughts or
comments you have on improvements.
Committee Discussion and
Recommendations
DR. COONEY: Ajaz, thank you. I would
like to take some time now for the
committee to
raise questions and discussion. We will probably
break at some point, have a chance to
think things
over and then come back and have more
time for
discussion, especially given the
importance of the
recommendations that you seek us to
make. Nozer,
you had your hand on that button quickly.
DR. SINGPURWALLA: I have had it ever
since he stood up.
[Laughter]
DR. COONEY: The floor is yours.
DR. SINGPURWALLA: Well, I think you have
come a long ways from the last meeting
when I
230
believe there was a discussion on
mechanistic
considerations. What I would like to add is,
Lawrence, you put up a differential
equation.
Remember that? You put up a slide; you put up a
differential equation.
DR. YU: Differential equation, right.
DR. SINGPURWALLA: Now, what struck me
when you put it up is certain
things. The first
thing is you didn't define everything,
which is a
bad way to put up an equation but I won't
punish
you for that.
[Laughter]
But what Ajaz said has some relevance to
what you said. That differential equation you put
up is a mechanistic equation.
DR. HUSSAIN: Yes.
DR. SINGPURWALLA: It is a mechanistic
phenomenon.
DR. HUSSAIN: Yes.
DR. SINGPURWALLA: And there is
variability.
DR. HUSSAIN: Yes.
DR. SINGPURWALLA: And one of the elements
of your equation was the particle
size. We have
had
some discussions here about the particle size
231
not being a variable entity. Therefore, one of the
things I would recommend doing is--you
asked what
additional scientific evidence you
need--I would
encourage you to look at that particular
equation
and make it stochastic so that it becomes
a
stochastic differential equation, and I
would use
whatever knowledge you have about
particle size
distributions, and my colleague from
Pfizer has
given me some clues about what could be
particle
size distribution, and somebody else
also. I would
like to suggest that you merge the two,
the
deterministic, mechanistic equation and
the
particle size equation.
The comments you made about
correlation
and causation are germane and
correct. But the
reason is this, that correlation only
measures
232
linear relationships and is not indexed
by time.
Causation is a time index
phenomenon. If I smoke I
will get lung cancer, assuming that that
is the
causal.
So, there is a time phenomenon.
One of the slides that you put up and
you
quickly slid by is wrong. That hypothesis.
DR. HUSSAIN: As an example--
DR. SINGPURWALLA: That is wrong.
Somebody has to fix it. I wouldn't put it up
again.
DR. HUSSAIN: You have to tell that to Bob
O'Neill tomorrow.
DR. SINGPURWALLA: No way!
[Laughter]
DR. HUSSAIN: Thank God, it was not mine.
DR. COONEY: But, Ajaz, you have been
adequately warned!
DR. HUSSAIN: Yes.
DR. SINGPURWALLA: I will tell you what
the problem with that equation is. You have two
probabilities there. You have the null hypothesis.
You are making hypotheses on
probabilities of
233
certain events.
DR. HUSSAIN: But that is the basis of the
parametric tolerance interval test that
you will
hear tomorrow.
DR. SINGPURWALLA: Maybe I should stay at
home!
DR. COONEY: Ken?
DR. MORRIS: I mean, I think this is
clearly the right track and perhaps
overdue,
hypothesis testing aside for the moment,
but the
question I have is, is it within the
scope of what
we will all jointly do to say that the
dissolution
test, for example, is development
activity as
opposed to a manufacturing control for
either bio.
or control of process development?
The other thing is that if the
decision
tree--I can't remember which one it was
now--where
you had mentioned the design space
section for
development, that is really the whole
enchilada
here.
Right? I mean, in a sense, if we
do that we
have done everything.
DR. HUSSAIN: Right.
DR. MORRIS: With respect to laying out
quality by design development.
DR. HUSSAIN: Yes.
No, I think, Ken, in
234
many ways the decision trees should sort
of focus
on not directing what to do but more in
terms of
what are the key questions that need to
be asked
and direct what the decision should
be. So, that
is the only way we can avoid interfering
with the
development program. We don't want to do that.
So.
DR. COONEY: The use of the decision trees
acknowledges the fact that not all drug
products
behave in exactly the same way--
DR. HUSSAIN: Yes.
DR. COONEY: --in a standard system, and
not all drug products act physiologically
by the
same mechanism.
DR. HUSSAIN: Right.
DR. COONEY: As I understand what you put
forward, these decision trees would allow
you to
have a standard process to develop
methodologies,
but not constrained to always having a
product work
235
the same way.
DR. HUSSAIN: Right.
DR. DELUCA: Your number three there--I
think you developed the first two very
nicely.
Number three, what additional scientific
evidence--you know, once the plan is
outlined, I
think that is the decision tree. Once the plan is
outlined and the steps are rationalized
then, you
know, the additional evidence that is
needed will
surface.
DR. HUSSAIN: Yes.
DR. DELUCA: And I think that will surface
from the decision tree.
DR. HUSSAIN: Yes.
DR. DELUCA: One thing I want to say about
knocking out the dissolution test--
DR. HUSSAIN: We are not; we are not.
DR. DELUCA: No, I know but I am saying,
you know, when you talk about particle
size
distribution in parenterals for a
suspension that
is very straightforward.
DR. HUSSAIN: Yes.
DR. DELUCA: I mean dissolution is going
to be related to particle size.
DR. HUSSAIN: Yes.
236
DR. DELUCA: But you are talking about an
order of magnitude of particle size
distribution
here a lot different.
DR. HUSSAIN: Sure.
DR. DELUCA: I mean, you are in an oral
form and, in fact, I am not even sure
that in the
parenteral size distribution is as
important as
having a minimum particle size. You have to be
below a certain particle size; you have
to get it
through the needle. So, the thing is it has to be
very small and so that makes a difference
and it is
related then, so you don't need to do a
dissolution
test if you have a low enough particle
size. But
with the oral products you have so many
other
factors involved--
DR. HUSSAIN: No, that is the reason I
sort of clarified that I used that as an
example to
construct my statement of what
mechanistic would
be.
But the key aspect was, in a sense, if you are
237
able to achieve a state of control with
some of the
new technologies--in fact, Jerry, at a
science
forum a couple of days back, presented an
imaging
approach to looking at dissolution
prediction. I
didn't mention that to him but it
completely
coincides with the percolation theory
that Hans has
been progressing and just by looking at
that you
could have said that. The purpose of that was to
simply construct a statement of
mechanistic basis
for a decision to move forward. So.
DR. COONEY: Tom?
DR. LAYLOFF: I think it is quite striking
that we are having this discussion
now. You know,
it has been about 30 years since we
started looking
closely at content uniformity and putting
market
standards on that, and looking at
dissolution as a
means to assure bioavailability. It has been 30
years.
And, I think that one of the things that we
have seen is what Cindy was saying, FDA
likes
method 1 and 2; FDA likes content
uniformity
testing, likes dissolution testing. So, the
industry, instead of focusing on quality
systems,
238
directed research and formulas and
production,
actually kept that focus on a 30 year-old
concept
that dealt with the market issues 30
years ago
instead of building the quality systems
that deal
with the present. I am happy to see those other
ones go away and let's go on with quality
systems.
DR. COONEY: Art?
DR. KIBBE: Yes, since we are really deep
into discussing particle size, let me
throw out
that really the key ingredient in
understanding
dissolution is surface area measurements
and not
particle size, and that particle size
distribution
means different things to different kinds
of
formulators at different times and we
have a really
good understanding of the kinds of
particles we
want when we compress a tablet and what
percent of
them are fine, and so on. So, it is a different
game.
One of the issues that comes
into play is
not only does the particle size matter
but if you
have too small a particle size you start
to get
thermodynamic forces acting to cause
aggregates,
239
which give you a larger particle than you
started
out when you measured it the first
time. So, what
I am getting to is that the issue is
complex and
the controls have to be put on for each
system in
each situation, taking into account what
we know
theoretically, and not impose as a
general rule
that just sits on top of everything.
DR. COONEY: Ajaz, one of the
implications, as I understand it, of the
proposal
is that one would develop methods based
around
understanding of the science, the
mechanisms that
are controlling the important
phenomena. This
suggests that the responsibility goes
right back to
the
developer--the developer, CMC and the
manufacturer, cGMP, and you are going to
bring them
together.
But this responsibility goes back to
them to identify what those mechanisms
are as
opposed to simply adhering to a standardized
assay
of some type. This is the implication as I see it,
which will change the way the development
work is
done in the first place.
DR. HUSSAIN: It may change. I think
240
maybe the industry colleagues--
DR. COONEY: That was an invitation, Gerry
and Paul, to respond.
MR. MIGLIACCIO: I mean, it is consistent
with the ONDC restructuring. It is consistent with
getting away from the check-box mentality
of the
CMC section to put the appropriate
science into the
CMC section. So, yes, it is going to change the
way you do things and, hopefully, it will
change
the overall process of reviewing,
approving and
then continuous improvement around our
products.
So, yes, there is no doubt about it.
I guess, since I have the
microphone, why
tactical step two? What is behind your question
around currently marketed products? Because while
quality by design for new products is
starting to
be a reasonably well understood concept,
you cannot
go back redesign a marketed product by
those
principles. There is a lot we can do with
currently marketed products so why did
you say
currently marketed products, question
mark, when it
comes to tactical step two?
DR. HUSSAIN: So, you picked it up! Well,
I think clearly there is a hesitation
there, and
the hesitation comes from the fact that
what we
241
have here--the challenges we have are
destructive
test and the hesitancy is variability of
units in a
pivotal clinical batch to be used is a
key concern.
So this is on the development side right
now. And,
in a sense, what you do is you declare
this as
acceptable. So, in the current scenario our
specifications might be tighter than the
capability
of that and that is the means for
imposing
continuous improvement.
So, the development information
and the
stability of the batch really overcomes
this
hesitation. That essentially is the key here. For
step number two, one of the conditions
that becomes
is for this approach the clinical pivotal
lot or
the bio. lot must be stable--stable, I am
talking
about consistent--and its variation understood
to
the extent that the unit may be sampled
for a
destructive gauge R&R. That is the fundamental
principle of a destructive gauge R&R.
Now, we don't have this
information for
currently marketed products so that was
the reason
for the question mark. Can you overcome the
hesitancy without that? But I did put that, and so
forth, to illustrate that I think we need
to move
in that and do it for those also.
242
Here is an example of what I
mean by
stable process. Is this a stable process? This is
actually real data from a company. A friend of
mine sneaked it to me. So.
The percent
dissolution as a function of
manufacturing time,
and you see that in this case this was
non-homogeneous distribution of an
excipient, which
we never check, was the cause of
this. But most of
these are never caught. We approve those; they are
part of the system. I can show you many examples.
Validation may not always catch this
because the
variation, as Gerry you pointed out, you
learn more
in manufacturing than anything else. So, for the
gauge R&R step two to occur, you will
need to
demonstrate complete stability of this
lot.
DR. COONEY: Paul?
DR. FACKLER: To think about the
implications of what is being discussed
here for
generic products in particular, it is
gratifying to
hear that FDA recognizes that dissolution
parameters really are based on a
formulation and
very often, in fact most of the time,
generic
products have a different set of excipients
than
the brand product that they are
bioequivalent to.
It makes one wonder then why the generic
company
243
would be held to the same dissolution
specifications that the brand product,
with a
different set of excipients and different
formulation, might be held to.
So, I support a revisit of the
whole
dissolution concept and, frankly, it is
something
we have struggled with. We have a bioequivalent
product, for instance, yet can't meet
dissolution
specs based on a different set of
excipients.
DR. HUSSAIN: No, I did allude to that
fact in the background paper that you
might have
seen.
Dissolution specification is such a complex
performance test that depends on many
factors, such
244
as hydrodynamics. If it appropriate for one
formulation design, it may not be
appropriate for
the second. That creates that. In absence of
additional information such as further
development
to understand how the formulation might
behave, we
have very limited choice--I mean, that is
a concern
that you see from the regulatory
side. The way we
approaching it I think we can alleviate
that
concern and actually address that
scenario, and
this is one of the reasons to address
that scenario
too.
So, you are right.
DR. COONEY: Marvin?
DR. MEYER: Ajaz, not being familiar with
this area at all, let me ask a question
anyway.
How easy is it going to be in all cases
or all
complex formulations to develop a total
mechanistic
understanding of the behavior of a given
product,
or will we sometimes have to say, well,
we made a
decent effort; let's go back to the old
dissolution
and whatever?
DR. HUSSAIN: No, I think you will not
have a full level of mechanistic
understanding, and
245
so forth, but if you approach it right
from the
beginning and you start building it so
you
development information really will add
to that.
So, from a control strategy, in most
cases you will
not have complete mechanistic
understanding but
then at least you have enough
understanding to put
in the right controls, and so forth, and
not rely
on one particular test at the end. So, I think it
becomes a combination of the level of
complexity
you have and the degree of uncertainty
you have
that provides a means to say this is the
control
strategy.
So, you have to marry or arrange your
control strategy in light of the
complexity and in
light of the uncertainty that is present
with
respect to the intended use of the
product. So.
DR. MEYER: I can certainly see from a
manufacturing point of view that a total
understanding of the product and the
process would
be great, but it is also great to have a
product on
the market that works.
DR. HUSSAIN: Sure, exactly.
DR. MEYER: So, the agency isn't proposing
246
that ultimately down the line I am sorry,
you
didn't identify--
DR. HUSSAIN: No, no at all.
DR. COONEY: What I would like to suggest
at this point is that we take a break for
20
minutes--this is by design, an extra five
minutes
but this comes with a price. As we think about the
questions that have been put before us,
the six
questions, I would like for the committee
to think
about, as they are sipping their coffee,
particularly questions two and three,
what
additional steps or changes would you
recommend to
improve what has been suggested? And, three, what
additional scientific evidence is
necessary to
support the development and
implementation of the
plan?
The reason for the extra five
minutes is
because I think it is important that we
think about
the impact of the recommendations that we
are going
to address later today, beyond the
discussion, are
there unintended consequences? What are the
impacts that we need to think about, not
that we
247
need to identify them all, but what are
the things
we need to think about as we go
forward? So, for
that an extra five minutes of coffee
break. Let's
reconvene at about 3:12.
[Brief recess]
DR. COONEY: I would like to welcome
everyone back. We have a period now where we can
have a discussion around the questions
that are on
the table. The questions that we have been asked
to consider are summarized on the
screen. What I
would like to do in the next hour
approximately is
to have an open discussion amongst the
committee on
these questions. I would like to get to a point
where we can take a vote as a committee
in terms of
voting either--I will ask the voting
members of the
committee to support the recommendations
of the
committee going forward. I will do that at the
end.
It will be yes, no or abstain. You
will be
given options. The voting members of the committee
will be the committee plus the
consultants that are
here.
But prior to that, I think the
request
248
that we have on the table is a plan that
is laid
out on the slide that is before us that
has a
series of steps. The first, and I think the
central question, is are the tactical
steps
outlined--and these are outlined in
slides 8
through 15 of Ajaz's presentation--are
they
consistent with the goal of quality by
design? I
thought we might begin by talking about
these
tactical steps first, have some
discussion around
that, and then to work through the other
questions
that we have been given. It is particularly
appropriate and important for the
committee members
to take this opportunity and share with
Ajaz and
the rest of the team their ideas and
thoughts, and
it is my understanding that, if these
recommendations are approved, what it
represents is
a step forward; the questions that have
been
outlined will be examined and possibly as
early as
our next meeting specific recommendations
for our
discussion will be brought forward.
With that, let's take a look at
question
one which really revolves around the
tactical
249
steps, slides 8-15, that we have in front
of us.
Then perhaps we can go through these
steps with an
open discussion around them. Ajaz, could you go to
your slide 8, which is tactical step
one? This is
really the first two steps in this
plan. Given the
limitations of the dissolution assay as
currently
practiced, and its relationship or lack
thereof to
therapeutic efficacy and safety, to look
at
alternative suitable methods and
strategies in
order to evaluate the quality of drug
products.
DR. SINGPURWALLA: Let me just get the
ball rolling. Steps one and two essentially
encapsulate what you have in mind in the
boxed
items:
Information collected should facilitate a
shift from the deterministic to a
probabilistic
design culture. That is true for step one and step
two.
And, I don't see any reason why we should not
endorse it. It is the natural thing to do and my
particular position on this is to go
ahead and
endorse it, at least step one and step
two, as I
see it.
DR. COONEY: Let me also put on the table
250
the question are there suggestions,
modifications
that one might make to these steps? We can talk
about that as we go through this as
well. Gerry?
MR. MIGLIACCIO: Yes, I mean, the whole
discussion today and steps one and two
really focus
on dissolution. I guess I thought what we were
trying to get to is a more scientific
measure of
performance, process performance being
the quality
assurance measurement and product
performance being
the in vivo. So, do we need to start with that
decision criteria first, Ajaz? I mean, the
tactical steps are all focused on
dissolution
without saying is it really dissolution
that we
should be talking about.
DR. HUSSAIN: Clearly, I think the
thoughts we had--why is step one the
first step,
and I think that is the key. The way we see it is
the current dissolution test system, as
we use it,
is an essential decision tool during
product
development and for regulatory decisions
so we have
it right now. So, step one and two are overcoming
some of the challenges that we have.
Gerry, what you are
suggesting--we are not
eliminating that target at all and what
we are
doing here is improving upon one tool
that we are
251
using currently, and we anticipate using
currently
and in the future also, improve it and
then also
work on other ones, and other decision
trees that
we are planning will build in aspects
that I think
you are alluding to. So, our thought process of
why is step one the first step is that we
anticipate dissolution testing--that the
methodology will be with us for a long
period of
time, and here the uncertainty with
respect to the
suitability criteria and how we set
acceptance
criteria--there seems to be a disconnect
here and
there is a lot of frustration around
these issues.
So, step one and two combined
address the
immediate need, and also set up a system
which is
more rugged, we can be more confident to
start
building alternate methodologies.
MR. MIGLIACCIO: So, we are really talking
about more scientific approaches to
dissolution.
DR. HUSSAIN: Step one and two, yes.
MR. MIGLIACCIO: I understand gauge R&R
well but I am not an expert. Can you get enough
information out of a gauge R&R on a
single bio.
batch?
DR. HUSSAIN: One of the key aspects that
we are trying to get from this is that in
most
252
simple cases I think we think the study
will not be
a full-blown gauge R&R, and so
forth. We think
that product development information will
guide you
through that. Now, there are elements and there
are arguments out there that you need to
know how
sensitive your particular formulation is
to the
conditions of the dissolution test. So, from that
aspect, I think this will allow us to
gauge the
sensitivity of your formulation, your
particular
formulation to the chosen dissolution
method.
Hopefully, if it is done early you would
remove
that, and so forth. This actually then becomes
simply a study to benchmark
variability. So, that
is the reason I anticipate that for most
simple
cases this may not be an extraordinary
effort
necessary to really do a full-blown gauge
R&R.
MR. MIGLIACCIO: But you don't get the
batch-to-batch variability.
DR. HUSSAIN: Correct, but at least you
benchmark the product and then you could
get
additional benchmarks from your
validation batches,
and so on and so forth.
DR. COONEY: Art?
DR. KIBBE: I agree with my statistician
friend that we probably ought to move
forward, but
253
I think Gerry raised a really important
point, and
I was going to raise it too, that is,
this whole
concept really started several years ago
when we
started really talking about what is the
essential
information we need to know to make sure
that we
have good quality products for the
citizens. That
started with PAT and it kept going. And, this
really is just a natural evolution of the
regulation of the quality of the process
that gives
us pharmaceuticals for sale in the United
States or
anywhere.
So, as long as we, as a
committee, and the
FDA, with you as its spokesperson,
understand that
254
this is just one more small step moving
forward and
not a whole process--I mean, we are not
about
dissolution testing; we are about
eliminating
unnecessary testing and doing the correct
testing
to make sure we have quality
products. That is
one.
Second, the tremendous
variability in
human response to a given drug product is
just like
a thunder cloud on top of a small camp
fire of
dissolution testing. And, if we get better and
better at controlling the process and if
then the
batch is slightly out of that control,
that doesn't
justify not selling that batch because it
is well
within the goal posts that we have been
working
with from the beginning. So, I think we need to
also fold into here the understanding
that as the
process gets under tighter and tighter
control
deviations from that control must be
investigated
and must be understood but aren't
necessarily a
justification for not releasing the
batch. I don't
know how you fold that in. When we start talking
about dissolution as a terminal test,
whether we
255
have surrogate markers that track the
process and
tightly control it, and if we are a
little bit out
we can allow the company to do a quick
extra test
and say, yes, it is still good enough but
we are
going to find out why it is out. If we don't, we
are going to scare off half the companies
from
following us down this path to really
tight control
systems.
DR. HUSSAIN: Your first point is well
made and in the break I was asked to sort
of
summarize that, and you just did that for
me. But
the second point is more
challenging. If your
release test right now is a compendial
test, that
is a market standard. You have no room for
anything there. That is the law. So, that is the
law.
So, how you sort of address that I think is a
much larger issue. In the PAT guidance, if you
recall, we actually suggested in a sense
that there
has to be a way for moving forward and we
created a
system which we call research data so if
it is an
alternate procedure that you are using
that is not
your decision based on your compendial,
you have a
256
way forward under the PAT guidance for
that right
now.
But the point is, in a sense,
for
standards you have to draw the line
somewhere and
compendial standards draw the line. You have to
conform to that. That is the law. So, the whole
strategy then is that I think you have to
move
towards what I would like to sort of
share with
you, a concern that you expressed, and it
is an
important concern--if I can find my
slide--that I
think goes to another dimension.
I think we are moving towards a
state of
control and demonstrating a state of
control is
important but, at the same time, for some
processes
we will never reach the state of assured
statistical control. So, we have to bring a
risk-based decision to that in the sense
of how do
you sort of manage that because every
deviation is
investigated. So, there is an element that we do
intend to discuss, and discuss internally
as well
as I think in workshops, and so forth,
the need to
debate engineering control versus process
control.
257
There is an aspect to that.
DR. COONEY: Art, let me see if I have
heard your point clearly, that is, you
are arguing
or you are suggesting that it is very
important to
think through how this additional
information, how
this different information will, in fact,
be used
from a regulatory perspective.
DR. KIBBE: Yes, I think we have to be
careful, because we can narrow the goal
posts, that
we don't necessarily do it if it doesn't
gain us
anything clinically. We have talked about this
over and over again. The first point I made is
that this is just one more step in a
process that
started several years ago and I think it
is long
overdue, but we shouldn't focus only on
dissolution
as the only thing we are doing because we
are doing
lots of other things too.
The second is that in order to
get the
companies to come along with us, they
can't view it
as an opportunity for the regulatory
agency to
nit-pick them. We talked about that before and I
just wanted to make sure it was kind of
restated
258
for the record. That is all.
DR. COONEY: That is an important point
and that is why I wanted to get clarity,
and it
should be part of the recommendation
going forward.
Ken?
DR. MORRIS: Yes, to your scient point,
Art, and I think this may be a little bit
out of
sequence, in my sort of image the way
things would
ultimately be dissolution in some
form--although I
would argue that there may be better
forms and that
is a different discussion for the next
question, I
guess--that is a develop tool. These are part of
the critical quality attributes that you
want to be
able to build in with enough significance
to have
faith in it. But then you are really in the
position of formulating the process
variables that
are dictated by, hopefully, the first
principles to
determine your design space. Once you have the
design space, then you are taking
advantage of the
PAT guidance and others to do real-time
release,
hopefully, but at least you will be
releasing
within a parameter space that says if I
control to
259
my endpoint, which should be a
manifestation of the
proper attributes, then anywhere in that
design
space that it takes me to get to my
endpoint is
fine, and that is release. You release the product
based on the attainment of the endpoint
as opposed
to a release spec after the fact. The only
criteria are that you are, first of all,
within
your design space and that the design
space has
been developed so that it does accurately
represent
the process.
DR. COONEY: Tom and then Paul and Gerry?
DR. LAYLOFF: Yes, I don't think that we
will see a change in the market
standards, the
limits that are there, because they are
very
appropriate for among lab assessments
within the
statistical bounds that you want to have
for a
release.
But the company release specifications
would be something more like a control
chart I
think where you have the desired in the
center and
then the bracketing on the outside. If you start
drifting away from that you start looking
at kappa,
corrective actions to move it back
down. But if it
260
goes outside those bounds, then you are
probably
going to miss the market standards and if
you miss
the market standards you have marketed an
illegal
product.
But I don't think the market standards
are going to change. If you look the among
laboratory test criteria and the expected
statistics, it is a very rational thing
to do, to
have limits like that.
DR. COONEY: Paul?
DR. FACKLER: I agree.
Of course, I
endorse pursuing examining whether there
is a
better way to deal with dissolution. But I still
think fundamentally we need to ask why
dissolution--is it to hold variability on
the
manufacturing process or is it to assure the
patient that when he takes the product it
is going
to perform the way it is labeled to? We do content
uniformity for exactly that. If the tablet is 10
mg and you find that there are 7-8 mg you
wouldn't
want to release that lot.
On the other hand, you do a
dissolution
test and you are left scratching your
head, saying,
261
well, I know that this dissolution test
has nothing
to do with the way it is going to
dissolve and be
absorbed by the particular patient, yet
you are
forced to scrap the lot. So, really I would
encourage you to keep in mind what the
goal of the
release test is above everything else.
DR. HUSSAIN: Point well taken, and please
keep in mind that the decision trees that
we are
developing will actually address that
aspect. The
key is this, we don't want to go with
one-size-fits-all, like you need a
dissolution test
for everything. That is not the intention. The
decision trees will sort of guide us
through when
it may be needed; when it may be not
needed; and if
it is needed for quality assurance how do
you
approach that; and if it is needed for,
say,
characterization of a product, say,
post-change
like we do in SUPAC, how would we do
that? If you
are using it for biowaiver, as Lawrence
suggested,
can we think about more biorelevant
conditions that
might expand biowaiver decisions for
BCS? So,
those would be the considerations.
So, step one and two are not
intended for
that particular purpose but it sets up
instrument
suitability criteria that makes the
system more
262
stable for us to use, and it also
provides an
experimental approach to start think of
characterizing the variability and doing
more than
just six tablets but characterizing the
variability
to start using that in our
decision-making. So,
step one and two are just for that and
all the
other aspects that you sort of mentioned
are for
decision trees where we want to capture
that. So,
that is how we want to approach it.
DR. COONEY: Gerry?
MR. MIGLIACCIO: Yes, I want to go back to
Ken's comments. Ken is always a visionary.
Unfortunately, the vision is a ways out.
DR. MORRIS: Yes, six weeks.
[Laughter]
MR. MIGLIACCIO: We might all be in
rocking chairs by that time. But, you know, he has
raised a good point which I think an industry
perspective needs to put out there, and
that is,
263
you know, coming in with greater
understanding of
product to process to come up with better
performance measurements will work if,
when we are
sitting down and discussing these with
the agency,
it is not just that plus the layer of the
traditional dissolution test and the
traditional
this and the traditional that. If this is just
layering on more and more, then no
company will
invest the resources to do it. We will do it
internally. We will have our internal controls
because that process understanding makes
us more
efficient, more effective, but this
process will
stop--Art has hit it right on the head,
there has
to be an understanding that by coming in
with this
we have to take a new path and not be
mired in
history.
DR. MORRIS: If I can comment just real
quickly, I think the other thing is that,
from the
agency side, adding another layer isn't
going to
win any friends on the agency side
either. Right?
You guys can speak for yourself but I
think they
are already stressed to the limit.
DR. HUSSAIN: No, I think we clearly
understand that, and the key is, in a
sense, if we
keep holding on to things which may not
be adding
264
value and keep adding more the system
doesn't work.
So, the decision tree will have to
capture a
process which says these are the key
questions that
we need to address and this is how we
will control
this.
If your control strategy meets that, for a
new product you might have a completely
different
set of specifications which are
non-traditional.
But keep in mind that if you already have
approved
products you have those locked in and if
you have a
compendial you have those locked in. So, the
future of specifications and controls
could be very
different. So, we have to balance the two as we go
along.
DR. COONEY: Nozer?
DR. SINGPURWALLA: Ajaz, I am going to
comment on this slide.
DR. HUSSAIN: Please.
DR. SINGPURWALLA: There is no need to
debate.
While this is a fictitious issue raised by
265
some of my statistician colleagues about
10, 15
years ago, what they did is if you have
engineering
control then there is no need to do
statistical
process control. Engineering control essentially
achieves control for you.
DR. HUSSAIN: Yes.
DR. SINGPURWALLA: This was some kind of
an article written by some of my
colleagues, not
necessarily friends, in journals, trying
to make a
distinction, and the distinction is
completely
fictitious. So, I don't think you should spend too
much time debating this. I think engineering
control has elements of stochasticity in
it and
that is about it. So, I would just not bother with
this question any more.
DR. HUSSAIN: I appreciate that because I
expect this to be a debate in the
committee, and
the way I think we have constructed the
QA
guidelines, especially how to define
that, we
actually have approached it from an
engineering
perspective. But I do have to put it on the table.
DR. COONEY: Mike?
DR. KORCZYNSKI: As most of you know,
pharmaceutical companies are very
conservative in
nature and as long as the dissolution
testing
266
appears in the USP, even though the USP
may say one
can use alternative methods, I think
there is going
to be a major reluctance to abandon
dissolution
testing.
It was already mentioned that a lot of
the emergent technologies, in fact, are
sort of
relegated to segments of the process, not
necessarily the total process. So, somewhere I
would think some type of guidance
document could be
available that cites opportunities
relative to
dissolution testing, and maybe begin to
provide a
bridge and have companies begin to think
that, yes,
they can abandon the method if they use
these
potential alternatives that are cited.
DR. COONEY: Gerry?
MR. MIGLIACCIO: Yes, speaking for the
innovators, you know, where there is no
USP
monograph that we are dealing with, we
obviously
can come up with any performance method
that is
appropriate that I think many companies
and FDA are
267
evaluating. I mean, the PAT guidance gives us the
open door to evaluate these, and there
are a number
of them under evaluation now. None of them have
proven out but I don't think it is going
to be that
much longer before they are. And then, I don't
know that we need guidance. I think the instrument
manufacturers will sell it for us. Once they
understand that the methodology and the
equipment
that they are providing is a surrogate
for
dissolution, I think they will be out
there
marketing it very aggressively to the
entire
industry.
DR. COONEY: Mike?
DR. KORCZYNSKI: Well, I think large
innovative companies all basically have
the
wherewithal to develop their own emerging
methodologies and PAT systems, but there
are many
smaller companies that would look for
guidance
prior to, say, abandoning a USP
methodology. You
know, we heard the words that, oh well,
one can do
an alternative test but there is the
reality of the
field inspector who may interpret that if
you are
268
USP labeled you should be following the
USP test.
That is why I think some companies we be
real
reluctant to abandon that testing.
DR. HUSSAIN: One aspect is, I mean, we
are not asking for abandoning, and so
forth. We
want to sort of move towards an
appropriate control
or measurement that is relevant for that. I mean,
that is the whole intention. So, I think I have
some hesitation to use the word
abandon. That is
not the discussion. I completely understand I
think the concern of the field and I
think this is
one of the gaps which we are addressing
as we are
moving along.
One of the bullets in Cindy's
was training
and I think one of her jobs after this is
to put
together a training program for our field
inspectors, and so forth, and Mehul and
others I
think are really--I think the CMC and GMP
aspect,
especially in how the quality assessment
system is
involved in ONDC decisions. ONDC decisions have to
be shared with their colleagues and
inspectors.
So, I think we are putting a systems
perspective to
269
address all of these concerns so I think
we do
understand the concerns there.
DR. COONEY: I think the specific point
being made here is one of being sure that
there is
adequate communication of the work
product of this
group to the broader community. It doesn't
necessarily need to be a guidance but
certainly
adequate communication so that it can be
used.
DR. HUSSAIN: One of the reasons for
putting a tactical plan--I mean, we could
have
taken our time and brought a proposal to
the
advisory committee but we felt that we
wanted to
bring the tactical plan to engage and
actually have
the committee debate and discuss
this. When we do
bring a proposal, I think most of the
committee
will at least have been engaged in
discussing this
among themselves.
DR. COONEY: So far we have focused on the
tactical plan steps one and two, although
we really
have moved into three through five, which
are the
decision trees, as well. Without necessarily
curtailing discussion on any of those, I
would like
270
to consider step six in your plan, which
is general
considerations for identifying and
developing
statistical procedures. I wonder if any one on the
committee might have any commentary on
this point.
DR. SINGPURWALLA: Yes.
DR. MEYER: While he is formulating his
Bayesian response could I just say your
proposed
steps, page two, and six bullets so I
presume the
last one was number six.
DR. HUSSAIN: No, those are sort of
specific tactical, and the others are
this meeting,
ICH and so forth.
DR. MEYER: Anyway, with respect to page
two, the sixth one, from a committee
member
perspective I think that would be an
excellent way
to present whatever you choose to change,
side-by-side comparison of new and
generic, and why
the old wasn't as good as the new, and
how you are
not really layering one thing on top of
another but
you are replacing one thing with the
other. It
would be extremely helpful I think to
present the
information that way.
DR. HUSSAIN: Yes. Sorry,
I think my
slide had a different number.
DR. SINGPURWALLA: Getting back to step
271
six--
DR. HUSSAIN: This one?
DR. SINGPURWALLA: Yes, on page eight. It
seems reasonable in the sense that in
principle
what has been outlined is very
reasonable. We may
have to disagree on details and detail
steps. I
think you want to use control charts for variables
and not attributes. That makes sense. You lose
information when you use attribute
data. Process
capability analysis, yes. You don't want to test
every lot. You don't want to focus attention on a
piece by piece; you want to look at the
broader
picture.
Yes, you need tolerance intervals.
How
you are going to get them is a different
matter.
And, maybe there are other things that
you may want
to throw in which don't come to my mind
immediately, but I don't see why this is
not a
reasonable step so, again, I would
endorse it.
DR. HUSSAIN: Well, I think the challenge
272
is significant. This is the fundamental aspect
because tomorrow you have a proposal to
actually do
hypothesis testing on every batch, and we
have been
discussing that for the last three and a
half
years.
DR. SINGPURWALLA: What is the alternative
to not testing every batch?
DR. HUSSAIN: No, I think as our CMC
reviewers are finalizing the
specifications, and so
forth, and then if you need a hypothesis,
that is
where it occurs. But then imposing a hypothesis
test on every production batch and then
deciding
whether you met the hypothesis completely
negates
the systems of GMP philosophy which says
this is
validated and under control. So.
But the
parametric tolerance interval test is
exactly doing
that.
So, that is the reason I think this sort of
comes back. Gerry, do you see that point?
DR. MORRIS: I don't know if it matters,
you were talking before, you know, that
it is hard
to meet Short's criteria but there are
more
advanced SPC or engineering control
techniques than
273
those I guess older ones.
DR. HUSSAIN: See, the control chart and
the limits are connected to the
hypothesis, and so
forth.
They are not disconnected. But
then you
are approaching it very definitely, the
philosophy
and the system that you have to put in
place is a
different system as opposed to hypothesis
testing.
DR. MORRIS: That is what I am saying, if
you used a more sophisticated control
system or
whatever you want to call it--a filter,
doesn't
that suffice?
DR. HUSSAIN: It should. We can discuss
that as we debate that.
DR. SINGPURWALLA: I am presuming that
that is encompassed as general
vocabulary.
DR. HUSSAIN: Yes.
DR. SINGPURWALLA: You know, even though
it is called engineering, there is a lot
of
probabilistic thinking behind that. So, I endorse
those.
If these techniques are becoming
old-fashioned, as my colleague says and
he is
right--
DR. MORRIS: Long-standing.
DR. SINGPURWALLA: Yes, long-standing, I
think it is time to look at other things.
274
DR. COONEY: Are there any other comments
on this first question which is on slide
two, that
is, the tactical steps which are outlined
in slide
three of Ajaz's presentation? I think embodied in
part of that are the questions on
additional steps
that you would recommend to improve the
plan and
additional scientific evidence. I think we have
already made a number of suggestions to
that end.
DR. HUSSAIN: In particular, I just want
to repeat what I think my understanding
has been.
One aspect was that I think we have
focused on
decision trees and really the science
will evolve
from decision trees. In one aspect, one proposal
was from Cindy, the calibration,
mechanical
calibration conditions that we are using
in our lab
is what we are using and that will be a
recommendation to industry to use the
same one. Is
that sufficient or does Cindy need
additional
information to make her case for
that? You could
275
think about it that way also.
DR. MORRIS: I mean, I think my opinion is
already pretty clear but I just don't see
the
calibrator tablets as being value
added. So, to
that end, I would say the alternative
then is to
have a far more rigorous mechanical
calibration, a
real gauge R&R in the sense of the
word as you
proposed it.
DR. HUSSAIN: In addition, we are doing a
gauge R&R study for a couple of
products that we
are evaluating. So, I think we will bring an
example of a gauge R&R, a real-life
example.
DR. BUHSE: I think Ajaz was making the
point--some of you asked what would you
do with a
gauge R&R? You know, it is a destructive test.
How would you carry it out? And, I think that is
what we are trying to figure out in our
lab by
doing a few of them and kind of seeing
what we get
and seeing how many tablets you actually
have to
run, etc., etc., to try to get a feel for
how much
work it would actually be to do something
like
this.
DR. HUSSAIN: Right, and since we are
using a commercial product we hope
to--because in a
destructive test, when the sample is
destroyed the
276
selection of your reference material,
which is your
clinical lot, really has to be very
carefully
thought out and planned out and the
conditions
under which you judge that they are
acceptable.
That goes hand in hand with our approval
decision
anyway.
But we are using a commercial material to
do
this so I think it will raise some aspects and I
think we will learn something about that.
DR. COONEY: Gerry?
MR. MIGLIACCIO: Well, since you ask the
question on calibrated tablets, after the
last
industry study, which was in the background
material, the one remaining issue is
vibration. Do
you feel in the FDA labs that that is now
well
understood and controlled?
DR. BUHSE: We actually measure vibration
and we feel that we have a control over
it
definitely, yes. We can measure it without having
to use a calibrator tablet.
MR. MIGLIACCIO: So, I think we all agree
that if we had a reasonable measure of
vibration
and could control it that the calibrator
tablets
aren't necessary.
DR. COONEY: Art?
DR. KIBBE: Just a quick point, even if
277
you didn't, the one that we are using as
a tablet
calibrator we would have to redesign
that, and I
think we are far better off with
engineering
parameters in the long run.
One point, we never should feel
married to
any test.
I mean, many, many years ago the test
for quality of digitalis whole leaf was
the pigeon
death test where we injected a pigeon
with a
macerated solution of whole leaf
digitalis until it
died and then we rated the number of
units of
digitalis efficacy on that. We clearly don't do
that today. Perhaps the dissolution test as a
quality control test ought to go with the
pigeon
death test.
DR. COONEY: Paul?
DR. KIBBE: See if you can follow that!
DR. COONEY: That is a tough one to
follow!
DR. FACKLER: I just want to remind
everyone of the difficult position the
generic
industry is in with USP requirements imposed. You
know, part of what we do is try to obtain
FDA
approval but we are also bound to USP
specifications. So, I would again encourage FDA to
work as closely with USP as possible to
get both
278
organizations aligned such that we are
not in a
position where we can satisfy one and not
satisfy
the other. The whole industry is really at a loss.
DR. HUSSAIN: Gary, do you want to
respond?
DR. BUCHLER: Thanks, Ajaz.
We certainly
can discuss with USP revising the
requirements so
they are in line with our new paradigm
that we want
to set up for quality. Clearly, we do have a
relationship with USP and I think we know
a few
people over there so we should be able to
discuss
things with them.
DR. LAYLOFF: A couple of things, first of
279
all, the industry can submit methods to
the USP and
submit changes to the USP. That is one option. I
don't think it should be FDA. If FDA is very
concerned that a method is not suitable
to protect
the consumer, the public health, then the
FDA could
issue a standard and override the
USP. They have
done that in the past. So, if the FDA has grave
concern about protecting public health
they can go
over, but the industry can submit
changes. You
said you have a product that fails the
dissolution
but is bioequivalent to the
innovator. It means
that the dissolution test is not a good
surrogate
and you should submit an alternate one.
DR. FACKLER: And we do that. The problem
is the timing involved in getting a USP
monograph
changed, and waiting for that often puts
us at
tremendous disadvantage economically.
DR. LAYLOFF: You can also get from the
USP a letter waiving that requirement
pending an
option.
DR. MORRIS: Can I ask what is the impact
if calibrator tablets were deemed to be
unnecessary
280
by FDA? You would still have to use them? Is that
what you are saying?
DR. HUSSAIN: Well, I think that is a GMP
issue and I think we have other options
of a
compliance policy guide. So, there are a number of
mechanisms to think about that. I think the words
we chose were very carefully chosen, an
alternate
method.
In my description of the vector for
desired state anything we do should
conform to the
current standards in a sense. I think we are
trying to achieve a level of quality so
that when
tested with minimal standards there
should not be
an issue.
So, that is the basic premise on which
we have developed the tactical plan. It says an
alternate procedure. So, that is an option too.
DR. COONEY: If there are no further
questions or comments from the committee,
what I
would like to do is to consider moving
forward with
a recommendation from the committee to
the FDA that
the proposed regulatory tactical plan, as
described
in slide two, be adopted and moved
forward,
recognizing that our responsibility is to
make a
281
recommendation to the FDA, it will then
be
considered by the FDA as to how it actually is
implemented.
I would also suggest that, in
addition to
the tactical plan, as described in slide
two--
DR. HUSSAIN: This one?
Right?
DR. COONEY: No, that plan and then, in
addition, the proposed steps in slide
three are
incorporated in this recommendation.
I have heard from this
discussion six
other additional points and I will just
read these
quickly, acknowledging that this is one
step in
quality by design, not just a focus on
dissolution
testing.
That one needs to think through how the
information will be used in both
manufacturing and
regulation. That it is important to keep in mind
the ultimate goal of the release test,
which is the
patient.
The implementation plan needs to consider
the impact on the manufacturer and the
regulator.
That may be redundant with the point I
made above.
To develop a suitable communication
strategy for
the work to be done, and to also work
through the
282
implications to the generic products with
respect
to USP requirements. These are additional factors
that I have heard out of the conversation
this
afternoon.
DR. HUSSAIN: I think the next page, page
four, had one more step which Prof. Singpurwalla
really commented on. So, we will include that in
your recommendation. Developing detailed procedure
and harmonization--these are part of our
tactical
plan but not necessary for discussion at
this
stage.
So, if you would include this as part of
your recommendation?
DR. COONEY: So, the request is to embrace
the content of slides two, three and
four?
DR. HUSSAIN: Yes.
DR. COONEY: The procedure that we should
follow for a vote--we will go around the
table and
we will begin with Art and I will fill in
the last
step.
You have three options, yes, no or abstain.
DR. KIBBE: Never give me three choices;
it is too hard on me. Yes.
DR. COONEY: Marv?
DR. MEYER: Yes.
DR. SINGPURWALLA: Yes.
DR. COONEY: Carol?
283
DR. GLOFF: I am supposed to vote?
DR. COONEY: Yes.
DR. GLOFF: Yes.
DR. DELUCA: Yes.
DR. MORRIS: Yes.
DR. COONEY: Mike?
DR. KORCZYNSKI: Yes.
DR. SWADENER: Yes.
DR. COONEY: Cynthia?
DR. SELASSIE: Yes.
DR. COONEY: Tom?
DR. LAYLOFF: Yes.
DR. COONEY: My vote is also yes.
Therefore, we have 11 yes, zero no and
zero
abstentions for the vote. Wonderful!
Thank you
all for your input and your
discussion. The next
piece will be by video conference or
teleconference. It is scheduled for 4:30. We are
hopeful that we can get Jurgen on the
line before
284
that.
But would anybody object if I gave you a
ten-minute break? Ken has to stay here and work, a
10-minute break for everyone else while
we set up
the teleconference.
[Brief recess]
Clinical Pharmacology
Subcommittee Report
(via teleconference)
DR. COONEY: We are about to begin the
final part of today's program. Jurgen Venitz I
think is on line.
DR. VENITZ: Yes, I am here.
DR. COONEY: I believe that you can hear
everything that is said into a
microphone.
DR. VENITZ: That is correct.
DR. COONEY: So, if anyone wishes to speak
please turn your microphone on. I also understand
that we have a set of slides with your
name on
them.
They are showing up on the screen, and I
would invite you to begin.
DR. VENITZ: Thank you for giving me the
opportunity to discuss on behalf of the
Clinical
Pharmacology Subcommittee what transpired
at our
285
last meeting.
As you can tell from the first
slide, this
committee provides expertise to the
parent Advisory
Committee for Pharmaceutical Science on
exposure-response modeling, pediatric
clinical
pharmacology and pharmacogenetics.
The next slide shows you the
topics which
were discussed at our most recent meeting
in
November of last year. We had five topics being
discussed, one being an update on the
progress the
subcommittee had made. Then we spent a
considerable amount of time on
pharmacogenetic
testing of irinotecan, followed by a
discussion on
drug-drug interaction potential
assessment; a
tribute to Lewis Sheiner and, on the second
day
discussed the role of biomarkers and
surrogate
markers.
As you can tell, those slides
are more
explicit than my usual summary, the
reason being
that... [speaker phone problems;
inaudible]...exposure-response and
simulation
guidances where the committee was having
an impact
286
were used internally within the OCPB and
continue
to have an impact on labeling recommendations. He
also told us that discussion
of...[inaudible]...risk assessment that
had been
going on for about two years were on
hold, the
reason being there was no consensus
internally and
externally as to how to come up with an
acceptable
way for setting up ...[inaudible].
On the next slide he also
shared with us
that the [inaudible]...decision tree was
continued
to be used within FDA and there was a
research
project going on within OCPB that was
trying to
assess different [inaudible]...in
children and how
to assess and revise the pediatric
decision tree.
The next slide...
[inaudible]...in using
pharmacogenetic testing for TMP, an
enzyme involved
in the metabolism
of...[inaudible]...labeling
language to include that testing in 2003
and at the
time, meaning as of end of 2004,
negotiations
between the FDA and the sponsors were
ongoing to
analyze labeling language that would at
least
recommend a test for TMPT. [Inaudible].
On the next slide, Dr. Lesko
shared with
us that at the end-of-phase 2a meeting
initiative
that he undertook late in 2003 was
ongoing and that
287
a guidance was being developed and should
be coming
out this year.
Lastly he told us that a
QT-liability
discussion that has been going
on...[inaudible]...discussions were going
on within
the agency to...[inaudible]...clinical
study
designs and analyses.
The second part, as I mentioned
before was
the role of pharmacogenetic testing for
irinotecan.
[Inaudible]...Rahman, Dr. Parodi with
respect to
Pfizer, and Dr. Ratan was invited as the
consultant
to discuss...[inaudible].
Irinotecan is an oncological
agent. It is
currently approved and used for first-and
second-line treatment of colorectal
cancer. Like
most cancer drugs, it is limited in its
use by
major clinical toxicities, primarily
neutropenia
that cases infection and diarrhea. On the other
hand, CPT-11
has...[inaudible]...pharmacokinetics.
288
The drug is just a
prodrug...[Inaudible]...metabolized by
SN-38. This
metabolite, SN-38 is further metabolized
by an
enzyme called UGT1A1, which forms inactive
glucuronide. The peculiarity about this enzyme,
UGT1A1, is that it is subject to
pharmacokinetic...[inaudible]...has an
allele
called 7/7 that is prevalent
in...[inaudible]...to
form glucuronide. However, there are
other enzymes,
such as CYP3A4 and other transporters
such as P-gp
that are involved in irinotecan PK as
well. Their
significance clinically is unknown as
yet.
What was known at the time of
the meeting
was that SN-38 as the active metabolite
was
associated with the *28 genotype. So,
patients...[inaudible]...also have higher
exposure
of active metabolite, which is what you
would
expect.
Furthermore, systemic experience to this
metabolite...[inaudible]...namely,
neutropenia.
The risk of grade 4 neutropenia was felt
to be 9.3
for patients that have 7/7 genotype. So,
patients...[inaudible]...to develop very
severe
289
neutropenia. The second limiting toxicity,
diarrhea, was less clearly associated
with the
genotype. [Inaudible]...label irinotecan
with certain known risk
factors...[inaudible]...responsible for
neutropenia, in particular, age, prior
abdominal/pelvic radiation, low
performance status
and increased bilirubin. So, the discussion or the
vote the committee was asked to take was
can we use
UGT1A1 genotype as a risk factor that
would then
lead to a relabeling
of...[inaudible]. So, we were
presented with a summary of clinical
studies that
dealt with that issue. So, across four clinical
trials--the information on the next slide
shows you
that the odds ratio for patients that
have 7/7 gene
variant--the odds for neutropenia were
raised from
2.5 to 16.7. So, obviously those patients were at
significantly increased risk of
developing
neutropenia. On the other hand, diarrhea,
as I
said, was much less clearly associated
with this
genotype.
The limitations for all those
studies were
290
the fact that they were not designed to
assess the
strength of the genetic association. Nevertheless,
Pfizer presented the committee, on the
next slide,
with a table that gives you the estimated
performance battery for this test. The sensitivity
of this test in those four clinical
studies would
be 22 percent, however, the specificity
would
expected to be 95 percent. This means that you
would expect negative fixed value of 83
percent.
This really means that if you take
somebody and
somebody does have this allele there is
an 83
percent chance that this individual would
not
develop neutropenia. On the other
hand...[inaudible]...would be a patient
that has
this neutropenia and does have the
genotype. There
is a 50 percent chance of that. This is shown as
an overall incidence of neutropenia of
about...[inaudible].
This was further elaborated on
by...[inaudible] ...and he shared with
the
committee that in his estimation without
pharmacogenetic testing 100 percent of
the patients
291
were treated and 10 percent of those
developed
severe neutropenia. On the other hand, if this
test is implemented, only 90 percent of
patients
treated only 5 percent would develop
severe
neutropenia. So, the test
actually...[inaudible]...many patients
would be
tested in order to protect...[inaudible].
Now, there were some concerns
raised
during the discussion about a role and
implications
of...[inaudible]. The first was that current
studies were really limited in assessing
the
strength of association between the
negative
clinical outcome of neutropenia and the
UGT1A1 *28
genotype. Pfizer also indicated to us
that ongoing
clinical trials may help identify other
variants,
other than UGT
...[inaudible]. Currently, there is no validated
algorithm for dosing that would allow us
to adjust
the doses after PG testing has been
performed.
And, there was some concern that if you
reduced
irinotecan...[inaudible].
The committee was asked to
vote.
292
[Inaudible]... that this 7/7 genotype is
associated
with a higher risk of neutropenia and, as
you can
tell, the committee unanimously agreed
with that.
The second statement or the second
question put to
us was that 7/7 genotype was associated
with a
higher risk for acute or delayed
diarrhea. The
committee didn't believe that there was
sufficient
evidence to support that. The most important vote
was the last where we were asked does *28
PG
testing have adequate sensitivity and
specificity,
and the committee voted 9 in favor and 3
abstentions.
During the discussion there
were some
comments by the committee to include PG
testing in
the label even though...[inaudible]. We noted that
there is lack of information in the
current label
about the dosing regimen, which is not
unusual. We
were...[inaudible]...that lower doses as
a result
of the test may actually allow patients
to stay on
drug...[inaudible]...as opposed to
discontinuing
treatment because of neutropenia. We realized,
however, that additional clinical testing
may be
293
needed to establish and validate a
modified dosing
regimen.
And there was some discussion about
bilirubin which, as I mentioned before is
a UGT1A1
substrate, as a potential safety marker
in addition
to the pharmacogenetic testing.
The second topic for discussion
on the
first day dealt with the issue about drug
interactions. You can tell
...[inaudible]...starting with Dr. Huang,
followed
by Gottesdiener, Lacluyse and Reynolds
from OCPB as
well.
The issues here were around the update of
the DDI guidance. In particular, we were
asked...[inaudible]...in vitro transfer
studies;
how to integrate in vitro enzyme
induction studies,
and whether there should be a requirement
for
inhibitor/impairment in vivo studies.
[Inaudible]...and also eliminated by the
kidney.
Then the question is should you study
this drug in
patients who have...[inaudible]...as well
as have a
genetic variant of 2D6 enzyme that makes
them poor
metabolizers.
You can see in the next slide
that we were
294
basically...[inaudible]...and the
committee was
asked to vote in favor or against.
[Inaudible]...that has shown in vitro not
to have
inhibition of 1A2, 2C9, 2C19 and 2D6 and
3A. Is
there a need for an in vitro study? And, the
committee pretty much unanimously agreed
that there
wasn't any need to do an in vivo
study. So, in
vitro would predict the in vivo.
The next question, if you have
an NME that
is a P-gp inhibitor in vitro should there
be a
requirement or should there be a
follow-up in vivo
interaction study with a known P-gp
substance?
Again by majority the committee was in
favor of
doing an in vivo study as a result of in
vitro
demonstrated inhibition.
The next question was a little
more
complicated. So, here the NME, the new molecular
entity, is a P-gp substrate and a 3A4
substrate,
and the question was is there a need to
do an in
vivo interaction study with a drug like
ritonavir
which inhibits both P-gp as well as 3A4,
and again,
by a smaller margin, the committee voted
in favor
295
of that.
The next question related to an
NME that
is a P-gp substrate and not a 3A4
substrate.
Should there be an in vivo study
specifically to
look at P-gp inhibition and the
committee, with a
very slim margin, voted in favor.
Then we moved on to new
cytochrome P54
enzyme tests. The question was put to us would the
committee recommend in vivo drug
interaction
studies for CYP2B6, 2B8 and for this
UGT1A1 enzyme,
and the committee was virtually unanimous
in favor.
then we moved along to look at
transporter systems,
such as OATP and MRP, and we were asked
would we
recommend in vivo drug interaction
studies and, as
you can tell, the majority of the
committee was
opposed to that, the main reason being
that we
didn't think that science would really
allow us to
draw any mechanistic conclusions from in
vivo drug
interaction studies.
Then we moved to in vitro
induction and
its predictive value. We were asked if an in vitro
induction study for a new molecular
entity has more
296
than 40 percent ...[inaudible]...positive
control
should an in vivo study be done. The committee, by
majority, voted against that.
The next question was if there
was in
vitro demonstration of lack of that,
there is no
need for any in vivo studies...[inaudible],
and the
committee felt evidence exists currently
so...[inaudible]...by majority.
[Inaudible]...should inhibitor in vivo
studies be
recommended to actually do that and the
committee,
by virtually unanimous vote, voted
against it.
Then we moved to the second day
of our
meeting.
That was started with a tribute to Dr.
Sheiner. That was given by Blaschka who
is at
University of California at San
Francisco. Lew
Sheiner, as some of you may
know...[inaudible]...worked as a
consultant for a
long time. He was known as a seminal researcher
and teacher in the area of PK/PD
exposure-response
and pharmacometrics, and a lot of terms
and
approaches that he developed still are
being used
quite extensively--learn and confirm
cycles in drug
297
development; the role of empiricism
versus
mechanistic approaches, and the issue of
frequentists versus Bayesian
statisticians. He
also developed what is called
"Sheiner's rules"
that deal with the certainty of knowledge
that is
used or required.
[Inaudible]...the role of biomarkers,
surrogate markers and regulatory
decision-making.
These presentations, starting with Dr.
Woodcock of
CDER, Dr. Wagner, from Merck on behalf of
PhRMA,
and Dr. Blaschke.
Dr. Woodcock led a discussion,
and I guess
it was more a...[inaudible]...than it was
a
discussion but she shared with us
biomarkers
indicate biological processes and/or the
pharmacological responses to therapeutic
intervention. So, anything that changes as a
result of these or the drug is considered
to be a
biomarker. On the other hand, clinical endpoints
measure how patients feel, function or
survive and
are related to outcomes such as efficacy
and/or
this of a drug. [Inaudible]...somewhat in between.
298
So, those can be measured and are
intended to
replace clinical endpoints for efficacy
and
toxicity.
Dr. Woodcock shared with us in
her talk
that the rational use of those biomarkers
can,
indeed, accelerate the drug development
process and
the internal decision-making
within...[inaudible]...as well as
regulatory
decision-making within the FDA. She also pointed
out that biomarkers can provide a
mechanistic
bridge between preclinical studies that
is
typically...[inaudible]...and the
clinical test
which is typically quite empiric. However, in
order for this to really have an impact,
a new
business model needs to be developed that
allows
biomarkers to be developed in parallel
with drug
development as part of a commercial
enterprise.
[Inaudible]...and are rarely
met in a
strict statistical sense. She pointed out future
clinical endpoints may not be a
univariate as we
currently use them
but...[inaudible]...and that
biomarkers may help get away from a mean
analysis
299
to a responder analysis...
[inaudible]...pave the
way for this individualization and
personalization
of...[inaudible]...in clinical testing as
well as
post-market.
Her presentation was followed
by Dr.
Blaschke who did review use of HIV viral
load
as...[inaudible]. He pointed out the validation of
those surrogate markers required
sensitive assays
to detect...[inaudible]...as well as
mechanistic
models about disease progression, both
qualitative
as well as intellectual.
He pointed out that biomarkers
need to be
causal path. That means they have to be
mechanistically... [inaudible] and
proximal to the
disease endpoint in order to provide
confirmatory
evidence to support the efficacy of new
molecular
entities.
The last presentation was Dr.
Wagner's
presentation which, as I mentioned
before, spoke on
behalf of the work group that PhRMA put
together do
deal with this issue of biomarkers and
surrogate
markers.
He reviewed what is called
300
"fit-for-purpose" qualification
of biomarkers,
meaning the extent of qualification of a
biomarkers
depends on its intended use. He reviewed four uses
for it.
The first one would be the exploratory
use.
So, here the biomarker is used as a research
tool and, obviously, the requirements in
terms of
qualification are relatively minor.
The next level of qualification
would be a
demonstration of purposes So, those would be
biomarkers that are likely or emerging as
useful
biomarkers.
The next level would be
characterization.
So, here you are using known or
established
biomarkers to assess exposure-response
relationships and mechanism of action,
for example.
The highest level of qualification would
obviously be surrogacy so here the
biomarkers would
become a surrogate marker and would
substitute for
clinical endpoints. That would obviously require
the highest level of qualification.
Dr. Wagner did lament the lack
of
nomenclature in the biomarker area. He spoke of
301
the need for collaboration between
PhARMA, FDA, NIH
and academia on two issues, number on,
what are the
most useful biomarkers to pursue that
might, in the
long run, provide a payoff and, more
importantly,
how to decide what evidence can be used
and how it
can be used to accept biomarkers and
surrogate
markers as part of a
regulatory...[inaudible], and
he also mentioned some of the hurdles
associated
with extensive use of biomarkers such as
incentives, intellectual property rights
and
funding.
[Inaudible]...that the discussion of
markers would continue in one of the next
meetings.
And, that is all I have to report.
Questions by Committee
members
DR. COONEY: Thank you very much. We have
an opportunity for questions from the
committee.
Ajaz?
DR. HUSSAIN: Jurgen, thanks for reporting
the subcommittee report. I think Prof. Nozer left
before you mentioned the Bayesian aspect
so you
missed that.
One question I had was I think
in the work
we are doing also from a risk-based
perspective
utility functions really have to be
discussed and
302
we need to start thinking about
that. What are the
challenges that you are facing that has
started
that discussion?
DR. VENITZ: Well...[inaudible]...there
was no consensus on not only how to come
up with a
uniform rating scale but also a process
to follow
because you have to be involve all
stakeholders--patients, clinicians,
sponsors,
regulatory individuals--in designing a
process
before you can get
utility...[inaudible]...results.
So,
that is the reason why he told us that for the
time being that initiative has been put
on hold. I
didn't get the sense that it was fatally
wounded as
much as they were trying to reassess what
to do
internally.
DR. HUSSAIN: One more comment that I
have, Jurgen, usually you are here but I
think one
opportunity you have is if you really
looked at the
PAT guidance and what you are doing in
clinical
303
pharmacology has a lot of commonality,
and the
biomarkers, surrogacy and so forth I
think comes to
the same level of discussion in terms of
fundamentals to alternate testing and
control
strategies that we are developing. So, keep that
in mind, and maybe have some discussion
on the
commonality and how we might approach
things that
might be useful at some future point.
DR. VENITZ: I would agree with that and I
would add, as was mentioned in the
tribute that was
given to Dr. Sheiner, his approach, which
I think
is very pertinent to the PAT approach as
well, is
how much weight do you give empiric
evidence by
testing and testing over again, and how
much do you
give to mechanistic understanding whether
it is a
manufacturing process or whether it is
the
pathogenicity of disease. That is really what the
dilemma is. As I mentioned before, the
frequentists would just do things over
and over
again if you are willing to make any
mechanistic
assumptions. Of, if you are more on the
mechanistic side you might be willing to
make
304
certain assumptions without having to
empirically
repeat experiments and just base your
confidence on
the reproducibility of the test.
DR. HUSSAIN: Thank you.
DR. COONEY: Thank you. Jurgen, the good
news and the bad news at the end of the
day is that
it is the end of the day. Cynthia?
DR. SELASSIE: Jurgen, I have a question
for you.
Do increased levels of P-gp result in
greater levels of neutropenia? Does it impact it
in any way?
DR VENITZ: As far as I know, there are no
clinical studies. All we know is that G-pg seems
to be involved in the kinetics of
irinotecan.
Whether... [inaudible] is a very
difficult question
at this stage to answer. The only thing we know is
that UGT1A1 has been shown to be
associated with
neutropenia. None of those tests have proven to be
clinically relevant...[inaudible]... any
association between neutropenia levels of
irinotecan and those
genetic...[inaudible]. So,
right now the answer is we do not know.
DR. COONEY: Thank you.
I think we have
reached the end of our discussion,
looking at the
way the people are sitting around the
room. Thank
305
you very much for the summary and the
update.
DR. VENITZ: Good luck.
I am sorry that I
couldn't be there.
DR. COONEY: Thank you.
We will look
forward to you joining us next time.
DR. VENITZ: Okay.
Bye, bye.
DR. COONEY: I think we can adjourn the
meeting unless anyone else has anything
pressing.
Everyone looks like they are ready to
adjourn!
Thank you all very much. I look forward to seeing
you tomorrow morning.
[Whereupon, the proceedings
were adjourned
at 4:42 p.m., the reconvene at 8:30 a.m.,
Wednesday, May 4, 2005.]
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