***Advisory Committee for Pharmaceutical Science, CDER, FDA***

***May 2005***

**Quality-by-Design Approach for Regulatory Decisions: Seeking
Applications for Establishing Drug Dissolution/Release Specifications,
Creating Flexibility for Continuous Improvement and for Assessment of
Therapeutic Equivalence**

**Background**

***Progress on articulating the "desired state"***

Over the past four years FDA initiatives on Process Analytical
Technology (PAT) (1) and CGMP's for the 21^st^ Century (2) have been
developed with the goal of providing a broader systems perspective for
regulatory decision making and to facilitate introduction of new
scientific opportunities for improving the efficiency of pharmaceutical
product development and manufacturing processes. The PAT definition and
principles of *quality-by-design* (QbD) outlined in the FDA\'s PAT
guidance (3) have also been incorporated in the draft *ICH Q8:
Pharmaceutical Development* guideline \[4\]. With this accomplishment,
significant progress was achieved in articulating a shared vision for
the future or the "desired state" in the three regions -- U.S., Europe,
and Japan. This vision was articulated as follows:

-   Product quality and performance achieved and assured by design of
    effective and efficient manufacturing processes

-   Product specifications based on mechanistic understanding of how
    formulation and process factors impact product performance

-   An ability to effect continuous improvement and continuous "real
    time" assurance of quality

This description of the "desired state" aims to enhance the utility of
product and manufacturing process design knowledge and understanding in
regulatory quality assessment process. It is proposed that when product
and process knowledge and understanding are shared with FDA, it can
provide a basis to recognize the level of understanding achieved,
facilitate risk-based regulatory decisions, and provide flexibility for
continuous improvement for companies that have demonstrated an ability
to manage risk to quality \[5\]:

-   Regulatory policies and procedures tailored to recognize the level
    of scientific knowledge supporting product applications, process
    validation, and process capability,

-   Risk-based regulatory scrutiny that relates to the level of
    scientific understanding of how formulation and manufacturing
    process factors affect product quality and performance and the
    capability of process control strategies to prevent or mitigate risk
    of producing a poor quality product.

***Industry Concern "Regulatory Uncertainty"***

To-date, ACPS discussions on the topic of Quality-by-Design (QbD) have
essentially focused on the conceptual framework which the committee
strongly endorsed. Some members of the committee have pointed out that
QbD principles are well established and are being practiced by several
industrial sectors. Discussion with several pharmaceutical companies
suggests these concepts and principles are in practice, to different
degrees, within the pharmaceutical industry. However, industry continues
to express a concern of "delayed approval" if they include
pharmaceutical development information in their regulatory application.
It should be noted that pharmaceutical development information is an
integral part of regulatory applications in Europe; therefore, this
concern, in part, is probably reflecting the challenge of scientific
communication across disciplinary boundaries. Other factors may include
a lack of appreciation on the part of R&D and Regulatory Affairs
departments (generally responsible for regulatory application
submissions) of the challenges faced in day-to-day manufacturing
operations and the substantial amount of wasted resources contributing
to the high costs \[5\].

***Reducing Uncertainty***

From an FDA review perspective, currently available data in new and
abbreviated new drug applications (NDA and ANDA) often do not allow FDA
reviewers to gauge the level of product and process understanding
supporting a proposed product and manufacturing process design.
Therefore, in the current state, regulatory decisions (e.g., setting
specifications) have no choice but to utilize a procrustean decision
approach which is predominantly based on analytical data obtained from
just a few batches (1 bio-batch in the case of ANDA's) used in clinical
trials or bioequivalence assessment. To reduce regulatory uncertainty,
industry should reduce scientific "uncertainty" through information and
knowledge sharing (6).

The FDA has taken the lead to overcome industry concern through a
provision for voluntary submission of pharmaceutical development
information, coupled with a commitment of support for scientific
assessment of this information. This commitment includes among other
things: (a) creating opportunities for scientific discussion (early in
drug development) between an applicant and FDA review staff, (b)
training opportunities for reviewers, (c) recruiting experts in
pharmaceutical science and engineering disciplines, (d) developing a
quality system that will incorporate the concept of "peer review", and
(e) steadily moving towards a question-based quality assessment process.
The PAT Guidance and regulatory process have already been established as
an example of this general approach, which can be expanded to the entire
CMC review process using the ICH Q8 guideline and other tools. The draft
ICH Q8 articulated what should be considered as minimal information in a
pharmaceutical development report and what could be considered as
optional information (3).

***In-depth Discussion on Applications of QbD Conceptual Framework***

The development of illustrative regulatory applications (examples) of
the QbD conceptual framework is an essential next step. Regulatory
decision criteria that relates to establishment of specifications on
critical quality attributes would be an ideal starting point for further
defining QbD. This could be accomplished by outlining key questions that
should be addressed in pharmaceutical development studies and
illustrating how this information can assist in improving the efficiency
and effectiveness of regulatory decisions.

Drug dissolution (or release) for most pharmaceutical products
containing a drug in the solid state is an essential step in delivering
drug molecules to their site(s) of action. Therefore, drug
dissolution/release is a critical quality characteristic that needs to
be controlled throughout the life-cycle of a product. Over the past
three decades, considerable scientific attention has been given to
understanding the mechanism(s) of drug dissolution/release, factors
(e.g., formulation, manufacturing process, and physiologic factors)
affecting drug release/dissolution, and to establishing standardized
methodologies for dissolution testing. The current scientific
understanding and knowledge regarding drug dissolution/release has been
predominantly based on studies on oral drug delivery. For non-oral drug
delivery systems the principles and methods developed are often
generally adopted.

At the end of the 20^th^ Century, we successfully established a
comprehensive regulatory decision system for quality assurance and
control of drug dissolution or release rate characteristics of solid
oral drug products. FDA policy documents currently exist on the topics:
(a) drug dissolution/release specifications from solid oral dosage forms
and establishment of *in vitro to in vivo* correlations (7, 8), (b)
demonstration of drug dissolution/release similarity when formulation
and manufacturing changes have to be made (9), and (c) for waiver of *in
vivo* bioequivalence studies (10). This was accomplished, in part, due
to the dedicated leadership of many FDA staff members, in particular Dr.
Vinod Shah. Furthermore, the ICH Q6A guideline on establishing
specifications has also been developed (11).

Significant opportunities to build upon the current regulatory decision
system and to further improve its effectiveness and efficiency are
afforded by: (a) the ability to utilize pharmaceutical development
information (e.g., ICH Q8) in regulatory decisions and (b) the
availability of new technologies for more effective control of
formulation and manufacturing variables that impact drug dissolution
process, when combined with a comprehensive systems approach to
regulatory quality assessment (e.g., connection CMC review -- Clinical
Pharmacology &Biopharm review -- cGMP inspections).

The development of regulatory decision criteria based on QbD principles
for quality assurance and control of drug dissolution or release rate
may serve as a model to become a milestone in a journey towards the
desired state of pharmaceutical quality in the 21^st^ Century. The QbD
approach to drug dissolution specification can lead to discussions on a
more effective and efficient means of managing post approval formulation
and manufacturing changes. These principles can then contribute to
efficient approaches for establishing therapeutic equivalence of generic
drug products.

**Framing the Discussion**

The challenge posed by Dr. Janet Woodcock (Acting Deputy Commissioner
for Operations FDA) in her paper entitled "The Concept of Pharmaceutical
Quality" (12) essentially frames this discussion. In particular our
planned ACPS discussion will seek to address the following three aspects
of her challenge.

-   *"The scientific challenges facing pharmaceutical manufacturing go
    well beyond the problem of the clinical readout. Despite the slogan
    building quality in, most quality assessment today relies on
    end-product testing. This is a problem in and of itself. In
    addition, many of the tests methods currently being used have severe
    limitations in the modern, mass production environment.*

-   *"..the limits on quality attributes are often chosen empirically to
    ensure production of batches that resemble the batches tested in the
    clinic. However, this approach will only ensure consistent clinical
    performance if the relationship between those limits and the
    clinical outcome is understood. Without this understanding, the
    limits could be overly wide, unnecessarily tight, or completely
    irrelevant to clinical performance. Even worse, other, critically
    important attributes may not be identified, measured and
    controlled."*

-   *".. we must turn to the science of manufacturing and the concept of
    quality-by-design (QbD), which means that product and process
    performance characteristics are scientifically designed to meet
    specific objectives, not merely empirically derived from performance
    of test batches. To achieve QbD objectives, product and process
    characteristics important to desired performance must be derived
    from a combination of prior knowledge and experimental assessment
    during product development. From this knowledge and data, a
    multivariate model linking product and process measurements and
    desired attributes may be constructed. Clinical study would then be
    viewed as confirmatory performance testing of the model."*

***The "Desired State" Directional Vector***

In the current state, regulatory decisions on quality assurance and
control of drug dissolution rate (and many other quality
characteristics) are based predominantly on test data from a relatively
small test sample size; robust estimates of variance (sample and
population) are often not obtained. As a result, the process control
strategy and decision criteria essentially reflect compendial standards.
Compendial standards are intended to be "market standards" since they
have to be applicable to many different manufacturers (i.e., different
formulations and manufacturing processes for the same monograph product)
and, by definition, are absolute -- pass/fail with no room for
uncertainty or risk-based decisions (13). Since these are minimal
standards (sufficient for ensuring quality fit for intended use of a
product), they do not provide an approach to recognize the level of
process understanding and control achieved and, therefore, can not
facilitate continuous improvement in efficiency/productivity.
Furthermore, for a composite physical functionality such as dissolution,
influenced by many physical forces such hydrodynamics, a compendial
standard can sometimes be unfair to some manufacturers; apparatus and/or
test conditions optimally defined for an originator product can impose
constrains on products that follow. In the desired state, where
continuous improvement and innovation are facilitated, relationships
between in-process controls, final product control limits, and
regulatory specifications and/or standards would need to be clearly
understood by all stakeholders. An ability to control a product by
appropriate measurement tools to a degree higher than minimal standards
(minimizes risk of not meeting the minimal standard) should provide both
regulatory and technical flexibility for continuous improvement, but
only if this improved ability to control is not penalized by narrowing
the regulatory acceptance criteria. Tools such as statistical process
control can provide a means to evaluate trends so as to prevent
deviations due to "special causes" (e.g., under CGMP's). A quality
system that reliably ensures this objective can help in justifying
regulatory flexibility for continuous improvement. Since a higher degree
of process understanding and control (e.g., control of variability) is
the critical directional vector towards the "desired state", it may be
useful to visualize this vector as the Z-axis of a three dimensional
object, the X and Y-axis define the plane (i.e., minimal standards) on
which the current state rests. The proposed discussion at the May 2005
ACPS meeting is a re-examination of (inherent assumptions in) current
regulatory policies pertaining to quality assurance of drug dissolution
rate to find means of improving it and create flexibility for continuous
improvement; the relationship of this re-examination to a journey
towards the "desired state" may be illustrated as in Figure 1 below.

Discussions at the May 2005 meeting of the ACPS will predominantly focus
on physical, chemical, and physiological factors and the dissolution
mechanisms underpinning regulatory decisions. It is recognized that
statistical protocols for addressing variability will be an essential
component of the regulatory process; however, the statistical discussion
should be founded on a strong physico-chemical and clinical
pharmacological foundation. Past experience suggests that starting with
statistical discussion and/or predominantly focusing regulatory quality
discussion on development of statistical methodology can often lead to
protracted debates (e.g., the IPAC-RS proposal for a statistical
treatment of delivered dose uniformity).

**Introduction to Topic #1**

The first discussion topic will be on a QbD approach to pharmaceutical
quality assurance and control of drug dissolution or release rate
characteristics of solid oral drug products. Broadly, this discussion
will seek ACPS advice on a regulatory tactical plan for developing a QbD
approach to quality assurance of dissolution rate.

***Considerations for Developing a Tactical Plan***

The proposed approach for developing a tactical plan is to: (a) outline
how structured pharmaceutical development information (pre-formulation
material characterization, formulation development and optimization
efforts using Design of Experiment, etc.) can provide reliable means for
identifying sources of variability and quantifying variability in
pivotal clinical materials (the basis for clinical trial data,
regulatory clinical risk/benefit assessment and approval decision), and
(b) describe why, and how, (contrasting with the current approach)
regulatory assessment and utility of such information can facilitate
establishment of an optimal target value for dissolution rate and
acceptable variability around the target value. The level of quality
assurance and control of drug dissolution rate under the proposed
approach must be higher than what is achieved under the current system.
In addition, it is desirable to seek harmonization with other regulatory
authorities (e.g., the "design space" concept in draft ICH Q8),
specifically the ICH regions. The higher level of confidence should then
be a basis for a flexible regulatory approach (e.g., reducing the need
for prior approval supplement process) to facilitate post approval
changes that improve productivity and reduce variability (continuous
improvement). The key elements of the tactical plan may be categorized
into (a) the measurement system, (b) product design and characterization
(to include characterization of raw materials, and packaging, stability,
and in vivo assessment), and (c) manufacturing process design and its
control strategy.

[Measurement system capability]{.underline}: In the current state,
measurement system variability appears to be controlled by the
instrument design specifications and the method suitability criteria
that are based on testing standard materials -- the calibrator tablets.
There are several official dissolution instruments and calibrator
tablets listed in the US Pharmacopoeia. Selection of an appropriate
instrument for a particular dosage form is, to a large extent, based on
experience. The calibrator tablets are essentially manufactured using
raw materials and manufacturing technologies similar to other tablet
dosage forms; the manufacturing process capability of the calibrator
tablet is essentially confounded in its measurement system capability
(another dissolution apparatus). Furthermore, the quality of some
calibrator tablets has been a concern for several years, and some of
these can exhibit sufficiently large lot-to-lot (and over time within
lot) variability to require adjustment of the goal posts (or criteria)
for dissolution instrument suitability determination (14, 15). In
addition, hydrodynamic variability is also a significant concern that
brings into question the applicability of the calibrator tablet approach
to different dosage forms designs (16 -21).

[Product Design and Characterization:]{.underline} In the current US
regulatory decision system we often only have limited information on
dissolution test results. We utilize this information to seek
association or correlation with *in vivo* pharmacokinetic data on the
same lots. Figure 2 below graphically represents the current approach.
The high degree of uncertainty in this decision system is often a source
of disagreement and debates between FDA and industry (22, 23).

![](media/image1.wmf){width="5.0in" height="3.75in"}

A structured pharmaceutical development report can provide a means to
reduce regulatory concerns and provide a more rigorous scientific
framework for decisions on pharmaceutical quality. A structured approach
could be empirical (e.g., DOE) or can, in some cases, extend to
mechanisms and to first principles. For example, at a recent seminar at
FDA, Professor Richard Braatz (University of Illinois, Urbana-Champaign)
outlined an approach (see Figure 3 below) that is a good illustration of
a structured approach to pharmaceutical development. Such an approach,
we believe, can provide a means to achieve the vision articulated by Dr.
Woodcock:

-   *(QbD), which means that product and process performance
    characteristics are scientifically designed to meet specific
    objectives, not merely empirically derived from performance of test
    batches. To achieve QbD objectives, product and process
    characteristics important to desired performance must be derived
    from a combination of prior knowledge and experimental assessment
    during product development. From this knowledge and data, a
    multivariate model linking product and process measurements and
    desired attributes may be constructed. Clinical study would then be
    viewed as confirmatory performance testing of the model."*

![](media/image2.wmf){width="4.836805555555555in"
height="3.6284722222222223in"}

The essential elements of pharmaceutical development information with
respect to drug dissolution rate may include:

*Drug substance characteristics*: Characterization of solubility,
stability (including mechanism of degradation), ionization, permeability
(including mechanism of absorption) and information on control strategy
for polymorphic form, particle size, moisture content and impurities.
Although much of this information is currently scattered in regulatory
applications, it is anticipated that the pharmaceutical development
section will identify interrelationships among these characteristics and
dissolution rate with an emphasis on which of these are critical.

*Raw materials (excipient) selection criteria* could include
compatibility justification, intended function in a formulation and
characteristics important for these functions, and justification of the
adequacy of the proposed control strategy. Utility of prior knowledge
will be useful, especially with respect to sources of variability (from
manufacturing) and how this knowledge may support proposed control
strategy. Furthermore, development information specifically targeted to
demonstrate the adequacy of the proposed control strategy will provide a
comprehensive view to the regulators.

*Product design considerations* may include anticipated or desired
dissolution mechanism and critical factors based on prior knowledge and
how this information guides product development. Physical and chemical
stability considerations, potential failure modes, and packaging
considerations are an integral part of design considerations. Screening
strategy for experimental product designs, specifically the choice of an
initial dissolution test method for formulation screening and how and
why this method was justified based on drug characteristics and product
design considerations, would be useful to establish a link between the
pharmaceutical development knowledge and characterization of the pivotal
clinical product and thereby support establishment of an acceptable
variability benchmark. As the development process proceeds, what were
the scientific considerations for (a) *in vivo* drug dissolution/release
evaluation and (b) to confirm and/or support postulated *in vivo*
performance (e.g., relative bioavailability, etc.)? A strategic approach
can provide a means to demonstrate/evaluate clinical relevance of a
proposed *in vitro* characterization of clinical trial products and the
proposed control strategy. Pre-formulation and pre-clinical (e.g.,
studies in animal models) characterization may provide additional
supporting knowledge.

Regulatory assessment of pharmaceutical development information should
focus on knowledge/information summarized in the pharmaceutical
development section. To simplify the assessment process and to ensure
sound decisions regarding adequacy of a proposed control strategy (for
the pivotal clinical trial products or bio-batch), demonstration of an
ability to reliably predict (a priori) quality/performance of
experimental and proposed clinical trial product or bio-batch would be
desirable. This ability can be further supported by sound scientific
explanation, based on prior development information, and the observed
performance of products (e.g., characterizing studies, stability
evaluation, and pharmacokinetic evaluation) in various clinical phases.

[Manufacturing process design and its control strategy]{.underline}:
Initial product design considerations, along with a structured approach
to process design, should consider potential product failure modes
(chemical and physical) in developing the process control strategy. Key
questions to be addressed may include: How does a selected manufacturing
process (1) minimize the risk posed by product failure modes identified
(or inherent in its design) and (2) account for and control variability
in the raw materials and variability induced (in material attributes
that relate to quality attributes, e.g., dissolution) likely to be
introduced (likelihood may be derived from prior knowledge) by the
process itself? The failure modes and risk factors often may be
ascertained based on mechanisms of drug dissolution/release and drug
degradation. Characterization of the clinical trial product can
generally provide a means to evaluate the reliability of a proposed
manufacturing process to deliver the intended product design
specifications.

***Specific tactical steps include:***

1.  Develop an alternate regulatory approach to dissolution method
    validation, without the need for an external calibrator tablet, that
    provides for assessment and control of all relevant sources of
    variability in the measurement system. Note that the external
    calibrator tablet approach is not currently utilized in the EU and
    Japan. In this regard, the Japanese perspective on dissolution
    testing (24) addresses variability due to vibration in dissolution
    instruments (25).

2.  As part of Step 1, above, or as an independent step, develop an
    approach to utilize the pivotal clinical trial product or the
    pivotal bio-batch to (1) characterize reproducibility and
    repeatability (e.g., DOE based Gauge R&R for destructive samples) of
    the measurement system and (2) to define criteria when this study
    can also serve to benchmark "acceptable" total variance (product +
    measurement system) in absolute terms as well as in an appropriate
    relation to some appropriate measure of clinical, pharmacodynamic,
    or pharmacokinetic variability. Identify experimental designs and/or
    other information (e.g., from routine production operations) that
    may allow robust estimation of product variance. In conjunction with
    subsequent steps listed below, outline how structured formulation
    development information can support development of a rational Gauge
    R&R protocol and also further assist in reducing regulatory concern
    on benchmarking "acceptable" variability in pivotal clinical trial
    product.

    a.  An ability to define and benchmark acceptable variability in the
        pivotal clinical trial product is important to define
        appropriate dissolution rate specification (acceptance criteria
        or tolerance limits). Certain challenges in the current approach
        for establishing acceptance criteria have been discussed by
        Japanese regulators (24) and others (22).

    b.  Furthermore, with the current confounding of calibrator
        variability, measurement system variability poses other
        significant challenges. For example, the method suitability
        criteria based on the USP 10-mg Prednisone Calibrator tablet
        (Lot O0C056) can be as wide as 27 -- 48 % of dissolution from
        the calibrator, whereas the regulatory decision criteria for two
        products (e.g., pre- and post approval manufacturing change) to
        be considered similar, limits the allowable mean difference to
        about 10 %.

3.  Develop a comprehensive (systems-based) decision tree approach for
    establishing the dissolution specification (assuming availability of
    structured pharmaceutical development information as outlined
    above). Compare the proposed decision tree to the current ICH Q6A
    decisions trees and articulate the advantages and limitations of
    these two approaches.

4.  In conjunction with Step 3, identify and define opportunities for
    utilizing the PAT approach for controlling dissolution rate and
    development of real time quality assurance strategies.

5.  Develop a decision tree for the "design space" concept articulated
    in the draft ICH Q8 (see 23) to minimize the need for regulatory
    [application]{.underline} commitments on process parameters and
    manufacturing options (i.e., in-process controls for appropriate
    material attributes).

6.  For both new and generic drug applications, develop a side-by-side
    comparison of the proposed regulatory decision process with the
    current decision process for dissolution specifications and post
    approval change management. Provide justification and explain why
    the level of confidence (with respect to quality assurance and
    control of drug dissolution rate) under the proposed approach should
    be higher than what is achieved under the current system.

7.  Seek ACPS recommendation at the May 2005 meeting on general
    considerations for identifying and developing statistical analysis
    procedures to support the Steps above.

8.  Based on recommendations of the ACPS at the May 2005 meeting,
    develop a detailed proposal for Steps 1-7 and seek to establish
    consensus on the detailed regulatory decision criteria at a
    subsequent meeting of the ACPS.

9.  Seek harmonization on the approach (Step 8) with other regulatory
    authorities, specifically in the ICH regions.

**[References -- Topic #1]{.underline}**

1.  The PAT Initiative. <http://www.fda.gov/cder/OPS/PAT.htm>

2.  Pharmaceutical cGMPs for the 21st Century - A Risk-Based Approach
    Final Report Fall 2004.
    <http://www.fda.gov/cder/gmp/gmp2004/GMP_finalreport2004.htm>

3.  Guidance for Industry. PAT --- A Framework for Innovative
    Pharmaceutical Development, Manufacturing, and Quality Assurance.
    <http://www.fda.gov/cder/guidance/6419fnl.htm>

4.  ICH Q8: Pharmaceutical Development.
    <http://www.fda.gov/cder/guidance/6672dft.pdf>

5.  Innovation and Continuous Improvement in Pharmaceutical
    Manufacturing. The PAT Team and Manufacturing Science Working Group
    Report. <http://www.fda.gov/cder/gmp/gmp2004/manufSciWP.pdf>

6.  Hussain, A. S. The Process Analytical Technology: A First Step in a
    Journey towards the Desired State. *The Journal for Process
    Analytical Technology*. January 2005.
    <http://www.patjournal.com/main.aspx>

7.  Guidance for Industry: Dissolution Testing of Immediate Release
    Solid Oral Dosage Forms (1997).
    <http://www.fda.gov/cder/guidance/1713bp1.pdf>

8.  Guidance for Industry. Extended Release Oral Dosage Forms:
    Development, Evaluation, and Application of In Vitro/In Vivo
    Correlations (1997). <http://www.fda.gov/cder/guidance/1306fnl.pdf>

9.  Guidance for Industry. Immediate Release Solid Oral Dosage Forms
    Scale-Up and Post approval Changes: Chemistry, Manufacturing, and
    Controls, *In Vitro* Dissolution Testing, and *In Vivo*
    Bioequivalence Documentation (1995).
    <http://www.fda.gov/cder/guidance/cmc5.pdf>

10. Guidance for Industry: Waiver of In Vivo Bioavailability and
    Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms
    Based on a Biopharmaceutics Classification System (2000).
    <http://www.fda.gov/cder/guidance/3618fnl.pdf>

11. ICH Harmonized Tripartite Guideline Specifications: Test Procedures
    and Acceptance Criteria for New Drug Substances and New Drug
    Products: Chemical Substances Q6A.
    <http://www.ich.org/MediaServer.jser?@_ID=430&@_MODE=GLB>

Decision Trees:
<http://www.ich.org/MediaServer.jser?@_ID=431&@_MODE=GLB>

12. Woodcock, J. The Concept of Pharmaceutical Quality. *American
    Pharmaceutical Review*. Nov/Dec 2004.

13. Torbeck, L. D. In defense of USP singlet testing. *Pharmaceutical
    Technology*. February 2005.

14. Foster, T. and Brown, W. USP Dissolution Calibrators: Re-examination
    and appraisal. *Dissolution Technologies*. February 2005.

15. Cox, D. C., Wells, C.E., Furnam, W.B., Savage, T.S., King, A.C.
    Systematic error associated with apparatus 2 of the USP dissolution
    test. II: effects of deviations in vessel curvature from that of a
    sphere. *J Pharm Sci*.1982;71:395-399

16. Qureshi SA, McGilveray IJ. A critical assessment of the USP
    dissolution apparatus suitability test criteria. *Drug Dev Ind
    Pharm*. 1995;21:905-912

17. Qureshi, S. A. and McGilveray, I. J. Typical variability in drug
    dissolution testing: Study with USP and FDA calibrator tablets and
    marketed drug (glibenclamide) product. *Euro. J. Pharm. Sci.* 7:
    249-258 (1999)

18. Kukura, J. Baxter, J. L., Muzzio, F. J*. Inter. J. Pharm.* 279: 9-17
    (2004).

19. McCarthy, L.G., Bradley, G., Sexton, J,C., Corrigan, O. I., Healy,
     A. M. Computational Fluid Dynamics Modeling of the Paddle
    Dissolution Apparatus: Agitation Rate, Mixing Patterns, and Fluid
    Velocities. *AAPS PharmSciTech*. 2004; 5(2): article 31.
    <http://www.aapspharmscitech.org/articles/pt0502/pt050231/pt050231.pdf>

20. Hussain A.S. Biopharmaceutics and Drug Product Quality: Performance
    Tests for Drug Products, A Look Tests for Drug Products, A Look Into
    the Future. USP Annual Scientific Meeting: The Science of Quality.
    September 26--30, 2004, Iselin, NJ.
    <http://www.fda.gov/cder/OPS/BiopharmDPQ.pdf> ).

21. Mirza, T., Joshi, Y., Liu, Q., Vivilecchia, R. Evaluation of
    Dissolution Hydrodynamics in the USP, Peak™ and Flat-Bottom Vessels
    Using Different Solubility Drugs. *Dissolution Technologies.* Feb
    2005.

22. Hofer, J. D., and Gray, V. A. *Dissolution Technologies*, February
    2003

23. Hussain A.S. ICH QD: Pharmaceutical Development, DIA Webinar, March
    30, 2005

24. Kaniwa, N. *Drug Information Journal*. 36: 407-415, (2002).

25. Kaniwa, N., Katori, N., Aoyagi, N., et al. *Int. J. Pharmaceutics*.
    175: 119-129, (1998)

**Introduction -- Topic #2**

Approval of a new drug application (NDA) establishes the intended use
(label) of a product based on an assessment of acceptable
risk-to-benefit ratio. Approval of an ANDA establishes *therapeutic
equivalence* of a generic product to deliver the intended use and
equivalent risk-to-benefit ratio for the reference NDA product. The
decision of *therapeutic equivalence* entails the decision of equivalent
quality, and a similar decision criterion is used for managing post
approval product and manufacturing changes for both generic and
innovator products. These decision criteria may be summarized as follows
(the Orange Book):

> *Drug products are considered to be **therapeutic equivalents only if
> they are pharmaceutical equivalents** **and if they can be expected to
> have the same clinical effect and safety profile when administered to
> patients under the conditions specified in the labeling.** FDA
> classifies as therapeutically equivalent those products that meet the
> following general criteria: (1) they are approved as safe and
> effective; (2) they are pharmaceutical equivalents in that they
> (a) contain identical amounts of the same active drug ingredient in
> the same dosage form and route of administration, and (b) meet
> compendial or other applicable standards of strength, quality, purity,
> and identity; (3) they are bioequivalent in that (a) they do not
> present a known or potential bioequivalence problem, and they meet an
> acceptable in vitro standard, or (b) if they do present such a known
> or potential problem, they are shown to meet an appropriate
> bioequivalence standard; (4) they are adequately labeled; and (5) they
> are manufactured in compliance with Current Good Manufacturing
> Practice regulations.*
>
> *Generic products may differ in certain other characteristics such as
> shape, scoring configuration, drug release mechanisms, packaging,
> excipients (including colors, flavors, preservatives), expiration
> date/time and minor aspects of labeling (e.g., the presence of
> specific pharmacokinetic information) and storage conditions. When
> such differences are important in the care of a particular patient, it
> may be appropriate for the prescribing physician to require that a
> particular brand be dispensed as a medical necessity. With this
> limitation, however, FDA believes that products classified as
> therapeutically equivalent can be substituted with the full
> expectation that the substituted product will produce the same
> clinical effect and safety profile as the prescribed product.*

A generic drug product intended for systemic absorption by the oral
route of administration is considered to be pharmaceutical equivalent to
a reference product only if it contains the same (chemical) active, in
identical amount, and in the same dosage form (e.g., tablet and
capsule). The generic product can differ from its reference product in
several aspects such as its composition (e.g., excipients), design
features such as drug release mechanism, and manufacturing process. *In
vivo* bioequivalence demonstration is necessary for oral drug products
that present \"a known or potential bio -problem\" (criteria based on
prior knowledge and characteristics such as aqueous solubility,
intestinal permeability, etc.). Bioequivalence studies are conducted in
normal healthy volunteers using a cross-over design and are intended to
demonstrate that the 90% Confidence Interval for generic/innovator ratio
of key pharmacokinetic parameters (e.g., C~max~ and AUC) are within
80-125% (acceptance goal post). This same acceptance criteria generally
applies for all oral dosage forms (i.e., a procrustean standard) and is
considered to cover \"worst case\" scenarios. Since this decision
process relies on prior knowledge and limited (analytical)
data/information on a specific product, it essentially is an
\"***uncertainty management***\" process. Its efficiency then is
significantly dependent on the availability of \"generalize-able\"
knowledge. In terms of quality standards, compendial monographs on drug
substance and drug product serve this role and their construction can
have significant impact on regulatory decisions (with respect to
allowable differences in generic products). These standards, standard
test methods (e.g., dissolution test) and the bioequivalence criteria
then define an ***acceptable level of variability***. Achieving and
conforming to these standards is then the characteristics of a generic
drug quality decision system for achieving its goal - approved generic
product is *expected to have the same clinical effect and safety profile
when administered to patients under the conditions specified in the
labeling.* Post approval reports on potential in-equivalence
observations are then monitored.

Table 1: Goal and Characteristics of the Pharmaceutical Quality Decision
System for generic products (e.g., systemic delivery via the oral route
of administration)

+-------------+----------------------+-------------------+-----------+
| Goal:       |                      |                   |           |
| approved    |                      |                   |           |
| generic     |                      |                   |           |
| product is  |                      |                   |           |
| *expected   |                      |                   |           |
| to have the |                      |                   |           |
| same        |                      |                   |           |
| clinical    |                      |                   |           |
| effect and  |                      |                   |           |
| safety      |                      |                   |           |
| profile     |                      |                   |           |
| when        |                      |                   |           |
| a           |                      |                   |           |
| dministered |                      |                   |           |
| to patients |                      |                   |           |
| under the   |                      |                   |           |
| conditions  |                      |                   |           |
| specified   |                      |                   |           |
| in the      |                      |                   |           |
| labeling*   |                      |                   |           |
+-------------+----------------------+-------------------+-----------+
| Char        | Uncertainty          | Variability       | Risk      |
| acteristics |                      |                   |           |
+-------------+----------------------+-------------------+-----------+
| Pha         | Same active,         | Compendial or     | Prior     |
| rmaceutical | identical amount,    | other standards   | Knowledge |
| Equivalent  | same dosage form,    |                   | (NDA)     |
|             | and route of         |                   |           |
|             | administration.      |                   | Post      |
|             |                      |                   | Approval: |
|             | Identity, Strength   |                   |           |
|             |                      |                   | M         |
|             | Quality, Purity.     |                   | onitoring |
|             |                      |                   | program   |
|             |                      |                   |           |
|             |                      |                   | Such as   |
|             |                      |                   | MedWatch  |
|             |                      |                   |           |
|             |                      |                   | Consumer  |
|             |                      |                   | C         |
|             |                      |                   | omplaints |
|             |                      |                   |           |
|             |                      |                   | Th        |
|             |                      |                   | erapeutic |
|             |                      |                   | Ineq      |
|             |                      |                   | uivalence |
|             |                      |                   | Coo       |
|             |                      |                   | rdinating |
|             |                      |                   | Committee |
+-------------+----------------------+-------------------+-----------+
| Need for    | Do not present a     | Compendial        |           |
| Bio         | known or potential   | Dissolution test  |           |
| equivalence | bioequivalence       | method            |           |
| Assessment  | problem. Acceptable  |                   |           |
|             |                      |                   |           |
|             | in vitro standard    |                   |           |
+-------------+----------------------+-------------------+-----------+
|             | Present a known or   | 90% Confidence    |           |
|             | potential bio        | Interval of       |           |
|             | -problem.            | Test/Ref ratio    |           |
|             | Appropriate          | for rate and      |           |
|             | bioequivalence       | extent of         |           |
|             | standard             | absorption in     |           |
|             |                      |                   |           |
|             |                      | 80 -125% range    |           |
+-------------+----------------------+-------------------+-----------+
| Adequately  | Similarity with      | Certain           |           |
| Labeled     | reference label,     | differences due   |           |
|             | medication errors.,, | to changes in the |           |
|             |                      | manufacturer,     |           |
|             |                      | distributor,      |           |
|             |                      | pending           |           |
|             |                      | exclusivity       |           |
|             |                      | issues, or other  |           |
|             |                      | characteristics   |           |
+-------------+----------------------+-------------------+-----------+
| M           | Process Validation   | Deviations, Out   |           |
| anufactured | and Quality System   | of                |           |
| in          |                      | Sp                |           |
| conformance |                      | ecifications,\... |           |
| to CGMP\'s  |                      |                   |           |
+-------------+----------------------+-------------------+-----------+

A QbD approach via pharmaceutical development information can
potentially provide an excellent means to address a number of challenges
previously discussed at ACPS meetings without complete or satisfactory
resolution -- for example: bioequivalence of highly variable drugs,
bio-in-equivalence criteria, pharmaceutical and therapeutic equivalence
of locally acting drug products (e.g., topical drug products). In
addition, further elaboration and extended application of the
Biopharmaceutics Classifications System(BCS)-based waiver of *in vivo*
bioequivalence is essentially an extension of Topic #1 discussions.

At the May 2005 meeting of the ACPS we plan to initiate discussions on
how pharmaceutical development information may facilitate regulatory
decisions on approval of generic drug products. For this initial
discussion, we will briefly outline our thoughts on three topics:

1.  How can pharmaceutical development information help to extend the
    applications of BCS-based waiver of *in vivo* studies for immediate
    release products?

    a.  Backgound -- BCS Workshop Report

2.  How can pharmaceutical development information be utilized to
    address the challenge of highly variable drugs?

    a.  This topic was previously introduced at the April 2004 meeting
        of the ACPS
        <http://www.fda.gov/ohrms/dockets/ac/04/briefing/4034b1.htm>

3.  Establishing therapeutic equivalence of topical products

    a.  Robert Lionberger\'s presentation at the April 2004 ACPS meeting
        (Topical Bioequivalence Update)