MEMORANDUM

TO: Members, Advisory Committee for Pharmaceutical Science

FROM: Ajaz S. Hussain, Ph.D.

> Deputy Director, Office of Pharmaceutical Science

Date: 10 April 2002

RE: 7 - 8 May 2002 Meetings of the Advisory Committee for Pharmaceutical
Science

Dear ACPS Members,

We look forward to meeting you in May 2002 to discuss several important
scientific topics. The first day of the meeting will primarily focus on
two biopharmaceutics topics; regulatory recommendations on
bioequivalence studies under fed conditions and approaches for expanding
the regulatory applications of the Biopharmaceutics Classification
System. Also, on the first day we will share with you our thoughts on
discipline-specific subcommittees.

The second day of this meeting will focus on PAT Subcommittee (progress
report and next steps), follow-up discussion on rapid microbial testing
(should this topic be made part of the PAT subcommittee), PQRI
recommendations on blend uniformity analysis, and a new \"awareness\"
topic on polymorphism.

A brief summary of these topics and issues for discussion along with
background information is attached. I hope this will help you in
formulating your advice to us on these topics.

See you in May.

**[Summary of the discussion topics:]{.underline}**

**Future Sub-committees**

Discipline specific sub-committees, under ACPS, are being considered as
a means to expand the range of scientific expertise needed to address
the wide range of scientific questions that arise within the Office of
Pharmaceutical Science. We plan to discuss this concept with you.

-   Proposal to form discipline specific subcommittees under ACPS

-   Clinical Pharmacology

-   Pharmacology/Toxicology (NCSS)

-   Microbiology

-   Manufacturing (PAT)

-   Others (?)

**Draft Guidance: Food Effect BE Studies**

The draft guidance on food effect bioavailability and bioequivalence
studies is the subject of this discussion. We plan to focus this
discussion on the following questions on bioequivalence (BE)
implications of the recommendation in this draft guidance.

1\. With regard to waiver of *in vivo* fed bioequivalence (BE) studies
in Abbreviated New Drug Applications (ANDAs) for BCS Class I drugs/drug
products:

1.  To what extent does the committee feel that the literature, in-house
    and original research data provide sufficient evidence to support
    the claim that fed BE studies are unnecessary?

> \[Note: We have recently completed our research studies (in
> collaboration with Univ. Tennessee) in which we assessed
> bioequivalence between generic drug products (model drugs studied:
> metoprolol (BCS-Class I; first pass metabolism), propranolol
> (BCS-Class I; first pass metabolism) and hydrochlorthiazide (BCS-Class
> III)) under fed conditions. These products were found to be
> bioequivalent.\]
>
> 1.2. If additional evidence were needed to support the waiver of *in
> vivo* fed BE studies for BCS Class I drug/drug products, what form of
> evidence would be desirable?

2\. With regard to using confidence intervals and a criterion to claim
bioequivalence between fasted and fed states for new drugs and between
fed states for generic drugs (relative to reference products):

> 2.1 To what extent does the committee feel that the issue of food
> effects can be treated as a lack of equivalence question?
>
> 2.2 To what extent does the committee feel that a 90% confidence
> interval with boundaries of 80-125% are appropriate to make a claim of
> bioequivalence?
>
> 2.3 What alternative approaches would the committee suggest to
> demonstrate bioequivalence in the fed state?

**Biopharmaceutics Classification System - Next Steps**

**Background: Scientific Basis for Current BCS Based Biowaivers**

The FDA/CDER's BCS guidance (9/2000) document provides a means for
justifying biowaivers for rapidly dissolving products (85% in 30 minutes
in 900 ml of 0.1 N HCl, 4.5 pH and 6.8 pH media, in USP I or II) of
highly soluble (highest dose strength soluble in 250 ml in pH 1-7.5
range) and highly permeable (extent of absorption equal to, or greater
than 90%) drugs that are not considered to exhibit a *Narrow Therapeutic
Range*.

The high permeability plus high solubility attributes are utilized in
this guidance to minimize risk of bio-in-equivalence due to solubility
or permeability limited absorption processes. Low permeability drugs
exhibit incomplete absorption from small intestine and, therefore, small
intestinal residence time of these drugs (dissolved) is considered
critical. Relatively minor differences in the time needed for complete
*in vivo* dissolution of low permeability drugs can potentially reduce
the time available for their absorption during small intestinal transit.

The rapid dissolution (in three different pH conditions) and built-in
profile similarity criteria are to ensures that dissolution *in vivo* is
not likely to be rate limiting and minimal differences in product
disintegration time (to minimize the likelihood of differences in
gastric emptying) are observed between the pre- and post change
products. The multi-media dissolution is recommended to account for
observed physiologic (and pathologic) variability in gastric fluid pH
and gastric emptying process. Since the time of drug administration
(during bioequivalence studies and use by patients) is not synchronized
(and should not be for practical reasons) with the gastric motility
pattern, gastric emptying in some subjects could occur almost
immediately after administration. In such cases dissolution would occur
in small intestine following emptying. If one of the two products being
compared exhibits a different dissolution rate (compared to the other
product) in intestinal pH then the effect of variable gastric emptying
on *in vivo* dissolution may not be a truly random phenomenon. This may
increase the likelihood of bio-in-equivalence when only a single *in
vitro* dissolution condition (e.g., 0.1 N HCl) is used to compare two
products. The multi-media dissolution criteria are intended to minimize
this possibility.

The permeability attribute of drugs plays a significant role in the
request for biowaivers. In addition to reasons stated above,
permeability contributes to the development of "sink condition" for *in
vivo* drug dissolution*.* Drug dissolution *in vitro* in a relatively
large volume, 900 ml, is likely to be a better emulation of *in vivo*
dissolution process of a highly permeable drug. High permeability
attribute also reduces the probability of excipient affecting
bioavailability due to an effect on gastrointestinal membranes and/or
motility.

**Focus of Discussion:**

The current guidance has been criticized as being \"too conservative\"
with respect to its application for biowaivers. FDA staff and invited
guests will present to you some proposals on how to expand the
applications of BCS.

Questions for the Committee:

(1) Should the Agency consider expanding the application of BCS based
    biowivers to rapidly dissolving conventional (IR) products of Class
    III (high solubility and low permeability) drugs? If so, what
    evidence should the agency collect to justify this extension?

(2) Should the Agency consider expanding the application of BCS based
    biowivers of conventional (IR) solid oral products of Class II (low
    solubility and high permeability) drugs that exhibit similar in
    vitro dissolution? If so, what evidence should the agency collect to
    justify this extension?

**Process Analytical Technology**

Two presentations are planned:

1\. PAT Subcommittee report (Tom Layloff)

2\. Progress report and next steps (Ajaz Hussain)

[Accomplishments to Date]{.underline}

Following the November 2001 FDA Science Board and ACPS meetings the
following has been accomplished:

1.  Formation of CDER-ORA Steering Committee on PAT

> Membership: Douglas Ellsworth (Director, New Jersey District Office,
> ORA), Mike Olson (Director, Field Science, ORA), Joe Famulare
> (Director, Division of Manufacturing and Product Quality, CDER), Frank
> Holcombe (Associate Director for Chemistry, Office of Generic Drugs,
> CDER), Moheb Nasr (Acting Director, Office of Testing and Research,
> CDER), Yuan-yuan Chiu (Director, Office of New Drug Chemistry, CDER),
> Ajaz Hussain (Chair).

Two parallel tracks identified for facilitating PAT.

> The first track will develop general guidance on PAT to provide a
> regulatory process for PAT based submissions and to articulate
> regulatory expectations for both review and inspection. The
> information necessary for this guidance will be obtained from industry
> and academic experts on the FDA\'s PAT Subcommittee under the Advisory
> Committee for Pharmaceutical Sciences.
>
> The second track will encourage companies to submit their PAT based
> applications. A CDER-ORA (Review-Inspection) team approach will be
> utilized to work with these companies to address questions as they
> arise, so as to minimize \"regulatory uncertainty. " We are very
> pleased to report that as of March 8, 2002, two US companies have
> officially requested meetings with FDA to discuss their planned PAT
> based submissions.

2.  PAT- Subcommittee

> In response to our Federal Register notice we received over 60
> applications from industry and academia to serve on this subcommittee.
> The members were selected to represent the key scientific and
> engineering disciplines necessary for PAT. In addition, four working
> groups were created to have focused discussions on the following
> topics: (1) Benefits and Regulatory Hurdles, (2) Process and
> Analytical Validation, (3) Product Development, and (4) Chemometrics.
> The first meeting of this subcommittee was held on 25-26 February
> 2002. This was a very successful meeting and very useful information
> was collected.

3.  Field Trips

> Several companies invited FDA staff to visit their facilities and to
> discuss the PAT initiative. We visited Bristol-Myers Squibb Company in
> New Jersey, Pfizer in Friberg (Germany) and AstraZeneca in Plankstad
> (Germany). Both the German plants have PAT based manufacturing systems
> in place. The AstraZeneca plant is currently completing their
> validation studies (for German Authorities) on a complete PAT based
> system for production of tablets of two very potent drugs.

[Planned Next Steps]{.underline}

1.  Establish a CDER-ORA PAT team for joint review/inspection of PAT
    based submissions. We are planing to identify four reviewers and
    four inspectors to be part of this first team. These individuals
    will then be trained on PAT systems.

2.  Develop a training (and certification) program of the PAT
    Review-Inspection Team.

3.  Expand FDA research efforts to understand issues related to PAT
    based applications.

4.  Develop the proposed general guidance on PAT following the second
    meeting of the PAT-Subcommittee. Publish draft for comments and
    input.

5.  Public workshops on PAT.

**Rapid Microbial Testing - Update**

Is the PAT program sufficiently broad to address the general issues
related to the introduction of rapid microbial testing?

**Blend Uniformity**

At the previous meeting of the ACPS we introduced this topic to you. We
have now received the official recommendation from the PQRI and wish to
discuss these with you prior to adopting or incorporating these in our
revised guidance document. The questions for the ACPS considerations
are:

> Do you consider the PQRI proposal appropriate for inclusion in a
> planned revised FDA guidance? If no, please suggest modifications or
> improvements.
>
> If yes, should the proposed stratified sampling and analysis plan be
> applicable [only]{.underline} for the bioequivalence batch and
> validation batches?
>
> If the proposed stratified sampling and analysis plan is limited only
> to bioequivalence and validation batches, how should adequacy of mix
> be ensured for routine production batches?
>
> Should the planned revised FDA guidance only focus on generic drugs or
> should it be a general guidance (i.e., for both new and generic
> drugs)?
>
> (Note - our current thinking is that this is a science issue and not
> just limited to generic drugs. Therefore, we believe the guidance
> should apply to both generic and new drugs).

**Regulatory Issues related to crystal habits - polymorphism**

This topic will be presented to you as an \"awareness\" topic to seek
your input to identify and frame the key questions. This topic plus the
\"awareness\" topic on \"physical\" stability, discussed at the previous
meeting, are in preparation for an in-depth discussion at a subsequent
ACPS meeting.

FDA staff and invited experts will provide an overview on regulatory
issues related to polymorphism. These presentations will cover
regulatory issues related to characterization, setting specification for
a new drug candidate (ICHQ6A guidance), and impact on approval of
generic drugs.