TO: Members, Advisory Committee for Pharmaceutical Science

FROM: Ajaz S. Hussain, Ph.D.

Deputy Director, Office of Pharmaceutical Science, CDER, FDA

Date: October 29, 2001

RE: Topics for discussion at the November 2001 ACPS meeting

Dear ACPS Members,

We look forward to meeting you on 28 and 29 November 2001. Dr. Vincent Lee will serve as the Chairperson. Several newly appointed members are joining this committee New members to the committee are Dr. Marvin Meyer and Dr.Arthur Kibbe. Two prospective members will be attending, Dr. Lemuel Moye and Dr. Patrick Deluca.

Five topics were selected for discussion at this meeting and a brief outline of the key issues is provided in the background information packet.

The following three chemistry topics are scheduled for discussion on November 28, 2001.

    1. Review of the PQRI proposal on blend uniformity analysis
    2. Approaches for improving assurance of physical (e.g., dissolution rate) stability of drug products
    3. Work plan for the Process Analytical Technology Sub-committee of the ACPS

Towards the end of day some time has been set aside for you to discuss, in a closed session, approaches for improving the effectiveness and impact of this committee.

On November 29, 2001 the discussion will focus on two biopharmaceutics topics.

    1. Dermatopharmacokinetic method for assessing bioequivalence of topical dermatological products.
    2. Regulatory applications of "individual" bioequivalence



Issues: Summary

Draft Blend Uniformity Guidance

In August 1999, a draft guidance document was issued requesting blend uniformity testing data on those generic drug products for which USP requires content uniformity analysis. This draft guidance received a number of comments from industry. In general, questions were raised on the need for blend uniformity testing on every production batch, technical difficulties for collecting "representative" blend samples using sampling-thieves, and the proposed acceptance criteria being tighter than the acceptance criteria for the end product content uniformity.

The Product Quality Research Institute initiated a project to address the science and technical issues underlying the blend uniformity analysis. The PQRI Blend Uniformity Working Group under the direction of Dr. Tom Garica and Dr. Garth Boehm developed a proposal to address these issues. This proposal and the draft Guidance document are included in the background information packet.

The FDA is planning to issue a revised draft guidance document following its review and analysis of the PQRI recommendations. The final PQRI recommendations are anticipated following the ACPS meeting in November.

Issues for discussion:

    1. Is the current PQRI proposal appropriate for inclusion in a planned revised guidance?
    1. If no, please suggest modifications or improvements that would be necessary prior to any regulatory application.
    2. If yes, should the proposed stratified sampling and analysis plan be applicable for the bioequivalence batch and validation batches, or should it also be applicable for routine commercial batches of drug products.
    3. 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?
    1. Although the PQRI proposal did not address "On-line" and "At-line" methods for assuring adequacy of mix or content uniformity, these methods are currently available and can significantly reduce the sampling and analytical burden. Should these methods be considered for inclusion in the revised guidance

Approaches for ensuring physical stability

This is an "awareness" topic that we wish to bring to your attention. No specific questions are being posed at this time. The discussion is intended to focus on scientific aspects of ensuring physical stability of drug products. For the last several years compromised physical stability (e.g., changes in dissolution rate) has been a frequent reason for product recalls. Accelerated stability testing programs do not necessarily provide relevant information regarding the potential for physical changes and we currently have to rely of long term stability data to establish expiry dates. To facilitate discussion we plan to present a couple of case studies.

Process Analytical Technologies (PAT)

During this session we will update you on the FDA Science Board discussion on PAT and also on the status of applications received to date for the ACPS Subcommittee. The goal of the discussion is to define the objectives and work-plan for the PAT Subcommittee.


Issue #1. Does the dermatopharmacokinetic (DPK) approach that studies drug disposition over time in the stratum corneum, provide a viable method for determining bioavailability and/or bioequivalence of topical dermatologic products?

Issue #2. To be suitable as a regulatory method, a technique should provide similar conclusions between laboratories that are experienced at performing the method. Does dermatopharmacokinetics show an appropriate level of between-lab consistency?

Issue #3. Ideally a regulatory method should not be so difficult or complex that it can only be performed by one or two experts in the field. Is DPK a method that can be set up in any testing laboratory? What is the time, effort and cost involved in setting up this technique so that the method can be properly validated and performed?

Individual Bioequivalence

Over the years, assessment of bioequivalence (BE) has generally been made based on the comparison of averages between the test and reference formulations. Since early 1990s, the concept of individual BE has been promulgated by several articles in the literature for consideration to include comparisons of both means and variances. The individual BE was proposed to ensure that an individual could be switched from the reference product to the test product with unchanged efficacy and safety. After evaluating the various methodological approaches, the US Food and Drug Administration (FDA) published a preliminary draft guidance in 1997 and a draft guidance in 1999 on the proposed criteria and statistical methodology for public comments.

Despite all the advantages of the individual BE approach, a number of comments on both draft guidances expressed concerns about the new criteria. These comments were presented and resolution to the concerns was sought at several public workshops and conferences. The issues were also discussed at the Expert Panel and Advisory Committee for Pharmaceutical Science (ACPS) meetings.

After careful consideration of all the recommendations from the ACPS and Expert Panel as well as public comments, the Agency in 2000 issued a final guidance for industry entitled Bioavailability and Bioequivalence Studies for Orally Administered Drug Products General Considerations. In this guidance, the Agency recommends non-replicated BE study designs for most orally administered immediate-release drug products and replicated BE study designs for modified-release dosage forms. The guidance maintains the average BE criterion while allows the option for a sponsor to provide rationale a priori for using another criterion to declare BE, e.g., the individual BE criterion for highly variable drug products.

Discussion Topic 1

Is it reasonable and appropriate for FDA to use average bioequivalence (ABE) for market access, unless there is a compelling reason not to, for an interim period of another year until a final decision is made to use individual bioequivalence (IBE) for market access?

Discussion Topic 2

The Advisory Committee is asked to comment on the proposal that if the FDA were to use IBE for market access (when there is a compelling reason not to use ABE) during the interim period, the following conditions would apply (below).

-- The sponsor declares IBE for data analysis a priori in BE study protocol

-- A heterogeneous population is enrolled in the study

-- The mean Test/Reference ratio is constrained to +/- 15%

-- There are no significant subject-by-formulation interaction, SxF (> 0.15)

-- The study includes at least 24 subjects

-- The study passes the IBE criterion

Discussion Topic 3

Are there scientific, technical or other reasons not to continue with the recommendations in the General BA/BE Guidance to a) conduct replicate design studies for modified release dosage forms and for highly variable drugs, and b) to use a heterogeneous study population (at least 40% male and female subjects, and/or young and elderly subjects)?

Discussion Topic 4

The Advisory Committee is asked to comment on plans for further research programs and projects associated with the use of ABE and IBE to allow comparison of bioavailability measures and to arrive at a final conclusion and recommendation on IBE.