# Advisory Committee for Pharmaceutical Science

> **April 13-14, 2004**
>
> The Advisory Committee for Pharmaceutical Science of the Food and Drug
> Administration, Center for Drug Evaluation and Research met on April
> 13-14, 2004, at the Advisors and Consultant Staff Conference Room,
> 5630 Fishers Lane, Rockville, Maryland. Art Kibbe, Ph.D, chaired the
> meeting.
>
> **Advisory Committee for Pharmaceutical Science Members (voting):**
>
> Arthur H. Kibbe, Ph.D., Charles L. Cooney, Ph.D., Patrick P. DeLuca,
> Ph.D., Melvin V. Koch, Ph.D., Meryl H. Karol, Ph.D. (April 13 only),
> Marvin C. Meyer, Ph.D., Cynthia R.D. Selassie, Ph.D, Marc Swadener,
> Ed.D., Nozer Singpurwalla, Ph. D., Jürgen Venitz, M.D., Ph.D.
>
> **Advisory Committee for Pharmaceutical Science Consultants
> (voting):**
>
> Gordon Amidon, Ph.D., M.A., Judy Boehlert, Ph.D., Thomas Layloff,
> Ph.D. (April 13 only)
>
> **Acting Industry Representative (non-voting):**
>
> Paul H. Fackler, Ph.D.
>
> **Industry Representative (non-voting):**
>
> Gerald Migliaccio
>
> **Guest Speakers:**
>
> Leslie Benet, Ph.D., Laszlo Endrenyi, Ph.D., Charles DiLiberti, M.S.
>
> **FDA Guest Speakers**:
>
> Ali Afnan, Ph.D., Dale Conner, Pharm.D., Barbara Davit, Ph.D., Sam
> Haidar, Ph.D., Ajaz Hussain, Ph.D., Chris Joneckis, Ph.D., Robert
> Lionberger, Ph.D., Robert O'Neill, Ph.D., Brian Riley, Ph.D., Nakissa
> Sadrieh, Ph.D., Donald Schuirmann, M.S., Chris Watts, Ph.D., Keith
> Webber, Ph.D., Helen Winkle, Lawrence Yu, Ph.D.
>
> **FDA Participants:**
>
> Gary Buehler, R.Ph.
>
> **Open Public Hearing Speakers:**
>
> **April 13, 2004:**
>
> Parrish M. Galliher, Troy J. Logan, Leo Lucisano, Robert Mattes
>
> **April 14, 2004:**
>
> Dr. Jeffrey A. Staffa, Consillium, LLC (paper submission only)
>
> These summary minutes for the April 13 and 14, 2004 of the Advisory
> Committee for Pharmaceutical Science of the Food and Drug
> Administration were approved on \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_.
>
> I certify that I attended the April 13 and 14, 2004, meeting of the
> Advisory Committee for Pharmaceutical Science of the Food and Drug
> Administration meeting and that these minutes accurately reflect what
> transpired.
>
> \_\_\_\_\_\_//S//\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
> \_\_\_\_\_//S//\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
>
> Hilda F. Scharen, M.S. Art Kibbe, Ph.D.
>
> Executive Secretary Chair
>
> The Committee received an update from the Clinical Pharmacology
> Subcommittee, and on the formation of a Working Group for Parametric
> Tolerance Interval Test for Dose Content Uniformity, and discussed the
> following: Process Analytical Technology (PAT) -- Next Steps, PAT
> Applications for products in the Office of Biotechnology Products
> (OBP), Bioequivalence of Highly Variable Drugs, Bioinequivalence,
> Topical Bioequivalence. A topic awareness presentation was made on
> Nanotechnology. The members and the invited consultants were provided
> the background material from the FDA prior to the meeting.
>
> Art Kibbe, Ph.D. (Committee Chair), called the meeting to order at
> 8:30 a.m. on April 13, 2004. The Committee members, consultants, and
> FDA participants introduced themselves. The conflict of interest
> statement was read into the record by Hilda Scharen, M.S. The agenda
> proceeded as follows:
>
> **[Day 1: Tuesday, April 13, 2004]{.underline}**
>
> Introduction to Meeting Helen Winkle
>
> OPS Update Director, Office of Pharmaceutical Science
>
> **Pharmaceutical Quality for the 21st Century** (OPS), CDER, FDA
>
> Subcommittee Reports

Clinical Pharmacology Jürgen Venitz, M.D., Ph.D.

> Chair, Clinical Pharmacology Subcommittee
>
> **Parametric Tolerance Interval Test** Ajaz Hussain, Ph.D.
>
> **for Dose Content Uniformity** Deputy Director, OPS, CDER, FDA
>
> Moving Forward \-- An Approach for Resolution Robert O\'Neill, Ph.D.,
> FDA
>
> Committee Discussions and Recommendations
>
> *Break*
>
> **Process Analytical Technology (PAT) --** Ajaz Hussain, Ph.D.

####### Next Steps 

Finalizing PAT Guidance Chris Watts, Ph.D., FDA

> Standards Development Ali Afnan, Ph.D., FDA
>
> Rapid Microbial Methods Bryan Riley, Ph.D., FDA
>
> Committee Discussions and Recommendations
>
> *Lunch*
>
> **Open Public Hearing**
>
> Leo Lucisano, Regional Director, CMC Regulatory Affairs,
> GlaxoSmithKline
>
> Parrish M. Galliher, Founder, President and CEO, Xcellerex, LLC
>
> Troy J. Logan, Pharmaceutical Segment Manager, Siemens Energy &
> Automation
>
> Robert Mattes, Laboratory Instrumentation Scientist, Foss-NIR Systems
>
> **PAT Applications for products in the Office of Biotechnology
> Products** Keith Webber, Ph.D., FDA
>
> **Overview and Issues**

Christopher Joneckis, Ph.D., FDA

> Charles Cooney, Ph.D.
>
> Massachusetts Institute of Technology
>
> Melvin Koch, Ph.D.
>
> University of Washington
>
> Tom Layloff, Ph.D.
>
> Principal Program Associate
>
> Management Sciences for Health

*Break*

Committee Discussion and Recommendations

The meeting was adjourned at approximately 4:30 p.m. on April 13, 2004.

Art Kibbe, Ph.D. (Committee Chair), called the meeting to order at 8:30
a.m. on April 14, 2004. Hilda Scharen, M.S., read the conflict of
interest statement into the record. The agenda proceeded as follows:

**[Day 2: Wednesday, April 14, 2004]{.underline}**

**Bioequivalence of Highly Variable Drugs** Lawrence Yu, Ph.D., FDA

Why Bioequivalence of Highly Variable Drugs Charles DiLiberti, M.S.,
Barr Labs, Inc.

is an Issue? .

Highly Variable Drugs: Sources of Variability Gordon L. Amidon, Ph.D.,
University of Michigan

Clinical Implications of Highly Variable Drugs Leslie Benet, Ph.D.,
University of California, San Francisco

Bioequivalence Methods for Highly Variable Drugs Laszlo Endrenyi, Ph.D.,
University of Toronto

######## Break 

Bioequivalence of Highly Variable Drugs: Case Studies Barbara Davit,
Ph.D., FDA

FDA Perspectives Sam Haidar, Ph.D., FDA

Bioequivalence of Highly Variable Drugs Q & A Dale Conner, Pharm.D., FDA

Committee Discussion and Recommendations

######## Lunch

Open Public Hearing: No speakers

**BioINequivalence -- Concept and Definition** Lawrence Yu, Ph.D., FDA

Statistical Demonstrations of BioINequivalence Donald Schuirmann, M.S.,
FDA

######## Break 

BioINequivalence Q & A Lawrence Yu, Ph.D., FDA

Committee Discussion and Recommendations

**Update \-- Topical Bioequivalence** Lawrence Yu, Ph.D., FDA

Establishing Bioequivalence of Topical Dermatological Products Robert
Lionberger, Ph.D., FDA

**Future Topics - Nanotechnology** Nakissa Sadrieh, Ph.D., FDA

Conclusion and Summary Remarks Ajaz Hussain, Ph.D., FDA

***[Questions to the Committee]{.underline}**:*

*Topic #1: Parametric Tolerance Interval Test (PTIT) for Dose Content
Uniformity of Aerosol Products*

**Evaluate this proposal for the formation of a working group under ACPS
supervision**

**Recommend improvements necessary for realizing the group\'s goals and
objectives**

**Recommend reporting requirements and a timeline for completing this
project**

*The Committee agreed on the proposal for the formation of a working
group under the supervision of the Advisory Committee for Pharmaceutical
Science. The Committee accepted the outlined process for how the working
group will function and the proposed timelines. The committee emphasized
the importance of clinical representation on this working group, as this
is the essence of risk based management.*

######### Topic #2: PAT Applications for Products in the Office Of Biotechnology Products in OPS/CDER and in the Center for Biologics Evaluation and Research (CBER) 

1.  **What technologies are available now to evaluate the
    characteristics of protein products in real time during
    manufacturing?**

*The Committee agreed it is difficult to judge how well the developed
tools are applied. The members felt that this was an important question,
as it relates what is being made to its therapeutic efficacy and safety.
The Committee argued that asking the right questions and understanding
what is to be known will drive the creation of new technologies.*

2.  **What tools would allow us to understand the manufacturing process
    better?**

*The Committee emphasized that data collection/mining is important.
However, the members felt that a correlation of cause/effect and
critical thinking about the analytical data are crucial.*

3.  **What processes in biological drug manufacturing would benefit the
    most from implementation of PAT?**

*The members recognized that variability control is key. The committee
suggested that the goal is to identify how much variation is allowed at
each critical step, while still maintaining a good product.*

4.  **For processes or products that do not currently allow direct
    product quality monitoring, what other strategies do you recommend
    for product quality control in addition to control of in-process
    parameters?**

*The Committee agreed that critical thinking needs to be applied to
understanding what needs to be measured and what we know about the
product. The members added that can be measured may not be helpful and
it is important to find the technology to measure what is needed.*

5.  **What additional elements should be incorporated in a training and
    certification program for reviewers and inspectors of biotechnology
    PAT applications?**

*The Committee felt there is a need to emphasize critical thinking and
problem solving in the training. In addition, the members felt it was
important to incorporate the science of uncertainty and its
quantification in the training programs. Also, the committee agreed that
the PAT Guidance is a framework, applicable to any manufacturing and
will apply to the Office of Biotechnology Products; not originally part
of the initial training and certification activities.*

######### Topic #3: Bioequivalence of Highly Variable Drugs 

######### **1. ACPS is requested to provide advice on the following issues:**

**That "highly variable drugs or drug products can be defined as those
exhibiting intra-subject variability of 30% CV or greater in AUC or
Cmax."**

*The Committee suggested the need to understand where the variability
originated. The members added that prior knowledge of all biostudies may
help set more appropriate specifications to make decisions.*

**2. Comment and recommendations on two approaches for addressing the
challenges:**

1.  **Expand bioequivalence limits from 80-125%, and restrict the mean
    T/R difference, e.g., ± 20? What information is necessary to
    properly set these new confidence interval limits?**

2.  **Reference Scaling: Scale current bioequivalence criterion based on
    the reference variability in each study and restrict the mean T/R
    difference as above.**

*The Committee emphasized that Highly Variable (HV) drugs focus on HV
drug product. The members emphasized there is an undue reliance on the
use of confidence intervals to make decisions, thus a paradigm shift is
in order.*

*The members agreed that the use of reference scaling and good
scientific methods could reduce the variability in the short term.
However, in the long term, the Committee felt a Decision Tree would be
useful in understanding what the problem is, as well as the real
fundamentals i.e. physical and chemical parameters. The Committee added
that the role of decision trees is not merely an understanding of a
problem, but a necessary step for making coherent, science based
decisions. In conclusion, the Committee agreed that a limit on the point
estimate should also be used along with reference scaling.*

*Topic #4: The Concept and Criteria of BioINequivalence*

1.  **Does the ACPS agree with the distinction between demonstrating
    bioINequivalence and failure to demonstrate bioequivalence?**

*The Committee felt that there was a need to separately define
bioINequivalence, not just as failure of the bioequivalence test. The
members argued it was important to focus on the clinical relevance with
the therapeutic index. The Committee discussed both Area under the Curve
(AUC) and Cmax as metrics important for bioequivalence and
bioINequivalence.*

2.  **Does the ACPS recommend a preferred method for evaluating the
    three pharmacokinetic parameters for bioINequivalence?**

-   **If bioINequivalence is demonstrated for any one pharmacokinetic
    parameter, then bioINequivalence is demonstrated for the products.**

-   **BioINequivalence must be demonstrated for all three
    pharmacokinetic parameters for bioINequivalence to be demonstrated
    for the products.**

-   **There should be one pre-selected pharmacokinetic parameter used
    for bioINequivalence testing. If so, which one?**

-   **The three pharmacokinetic parameters should be evaluated for
    bioINequivalence with statistical corrections to the level of
    significance for each parameter in order to maintain an overall
    significance level of 0.05.**

*The Committee agreed on a general understanding of bioINequivalence to
move forward recognizing it is not a simple matter. In addition, the
members felt this is an important concept, especially how it applies to
the entire regulatory scenario. There was no consensus at this point as
to a final criteria pertaining to the three pharmacokinetic parameters.*

*In addition, the members' felt that the criteria used for approving
bioequivalence is very good. However, the Committee felt that the
criteria used to define bioINequivalence is very difficult, with the
criteria and confidence interval both needing to be outside the
boundary.*

*In conclusion, the committee agreed that these discussions will force
people to ask questions of why a product is bioequivalent and will lead
to mechanistic understanding.*

The meeting was adjourned at approximately 4:15 p.m. on April 14, 2004.