Guidance for Industry

**ANDAs: Pharmaceutical Solid Polymorphism**

**Chemistry, Manufacturing, and Controls Information**

***DRAFT GUIDANCE***

**This guidance document is being distributed for comment purposes
only.**

Comments and suggestions regarding this draft document should be
submitted within 90 days of publication in the *Federal Register* of the
notice announcing the availability of the draft guidance. Submit
comments to Dockets Management Branch (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All
comments should be identified with the docket number listed in the
notice of availability that publishes in the *Federal Register*.

For questions regarding this draft document contact Andre S. Raw (301)
827-5758.

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**December 2004**

**OGD**

Guidance for Industry

**ANDAs: Pharmaceutical Solid Polymorphism**

**Chemistry, Manufacturing, and Controls Information**

*Additional copies are available from:*

*Office of Training and Communication*

*Division of Drug Information, HFD-240*

*Center for Drug Evaluation and Research*

*Food and Drug Administration*

*5600 Fishers Lane*

*Rockville, MD 20857*

*(Tel) 301-827-4573*

*http://www.fda.gov/cder/guidance/index.htm*

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**December 2004**

**OGD**

# I. INTRODUCTION [1](#i.-introduction) {#i.-introduction-1 .TOC-1 .unnumbered}

# II. DEFINITION OF TERMS: POLYMORPHIC FORMS AND POLYMORPHISM [2](#ii.-definition-of-terms-polymorphic-forms-and-polymorphism) {#ii.-definition-of-terms-polymorphic-forms-and-polymorphism-2 .TOC-1 .unnumbered}

# III. general principles of pharmaceutical solid polymorphism [3](#iii.-general-principles-of-pharmaceutical-solid-polymorphism) {#iii.-general-principles-of-pharmaceutical-solid-polymorphism-3 .TOC-1 .unnumbered}

## A. Importance of Pharmaceutical Solid Polymorphism [3](#a.-importance-of-pharmaceutical-solid-polymorphism) {#a.-importance-of-pharmaceutical-solid-polymorphism-3 .TOC-2 .unnumbered}

## B. Characterization of Polymorphs [3](#b.-characterization-of-polymorphs) {#b.-characterization-of-polymorphs-3 .TOC-2 .unnumbered}

## C. Influence of Polymorphism On Drug Substance And Drug Product [3](#c.-influence-of-polymorphism-on-drug-substance-and-drug-product) {#c.-influence-of-polymorphism-on-drug-substance-and-drug-product-3 .TOC-2 .unnumbered}

### 1. Influence on Solubility, Dissolution, and Bioavailability (BA) and Bioequivalence (BE) [3](#influence-on-solubility-dissolution-and-bioavailability-ba-and-bioequivalence-be) {#influence-on-solubility-dissolution-and-bioavailability-ba-and-bioequivalence-be-3 .TOC-3}

### 2. Influence on Manufacturing of the Drug Product [4](#influence-on-manufacturing-of-the-drug-product) {#influence-on-manufacturing-of-the-drug-product-4 .TOC-3}

### 3. Influence on Stability [5](#influence-on-stability) {#influence-on-stability-5 .TOC-3}

# IV. POLYMORPHISM AND *SAMENESS* In ANDAs [5](#iv.-polymorphism-and-sameness-in-andas) {#iv.-polymorphism-and-sameness-in-andas-5 .TOC-1 .unnumbered}

# V. CONSIDERATIONS FOR Polymorphism in andas [6](#v.-considerations-for-polymorphism-in-andas) {#v.-considerations-for-polymorphism-in-andas-6 .TOC-1 .unnumbered}

## A. Investigating the Importance of Setting Specifications for Polymorphs [7](#a.-investigating-the-importance-of-setting-specifications-for-polymorphs) {#a.-investigating-the-importance-of-setting-specifications-for-polymorphs-7 .TOC-2 .unnumbered}

## B. Setting Specifications for Polymorphs in Drug Substances [7](#setting-specifications-for-polymorphs-in-drug-substances) {#b.-setting-specifications-for-polymorphs-in-drug-substances-7 .TOC-2 .unnumbered}

## C. Investigating the Importance of Setting Specifications for Polymorphs in Drug Products [7](#c.-investigating-the-importance-of-setting-specifications-for-polymorphs-in-drug-products) {#c.-investigating-the-importance-of-setting-specifications-for-polymorphs-in-drug-products-7 .TOC-2 .unnumbered}

# ATTACHMENT 1 -- DECISION TREE 1 [8](#attachment-1-decision-tree-1) {#attachment-1-decision-tree-1-8 .TOC-1 .unnumbered}

# ATTACHMENT 2 -- DECISION TREE 2 [9](#attachment-2-decision-tree-2) {#attachment-2-decision-tree-2-9 .TOC-1 .unnumbered}

# ATTACHMENT 3 -- DECISION TREE 3 [10](#attachment-3-decision-tree-3) {#attachment-3-decision-tree-3-10 .TOC-1 .unnumbered}

**Guidance for Industry**[^1]

**ANDAs: Pharmaceutical Solid Polymorphism**

**Chemistry, Manufacturing, and Controls Information**

*This draft guidance, when finalized, will represent the Food and Drug
Administration\'s (FDA\'s) current thinking on this topic. It does not
create or confer any rights for or on any person and does not operate to
bind FDA or the public. You can use an alternative approach if the
approach satisfies the requirements of the applicable statutes and
regulations. If you want to discuss an alternate approach, contact the
appropriate FDA staff. If you cannot identify the appropriate FDA staff,
call the appropriate number listed on the title page of this document.*

> *If you plan to submit comments on this draft guidance, the following
> suggestions will help expedite FDA review of your comments:*

-   *Clearly explain each issue/concern. You may include a proposed
    revision for FDA consideration, along with a rationale or
    justification for the revision.*

-   *Identify specific comments by line numbers.*

-   *If possible, use the pdf version of the document.*

-   *If possible, e-mail an electronic copy (Word) of the comments you
    have submitted to the docket to cummingsd@cder.fda.gov.*

# I. INTRODUCTION[^2] {#i.-introduction .unnumbered}

Chemistry, manufacturing, and controls (CMC) information must be
submitted to support the approval of an abbreviated new drug application
(ANDA).[^3] This guidance is intended to assist applicants with the
submission of ANDAs when a drug substance[^4] exists in polymorphic
forms.[^5] Specifically this guidance provides:

-   FDA recommendations on assessing *sameness*[^6] when the drug
    substance exists in polymorphic forms.

```{=html}
<!-- -->
```
-   Decision trees that provide recommendations on monitoring and
    controlling polymorphs in drug substances and/or drug products.[^7]

If you plan to submit an application in the Common Technical Document
(CTD) format, you may refer to the International Conference on
Harmonisation (ICH) guidance, *Common Technical Document --- Quality:
Questions and Answers/Location Issues,*[^8] which is available on the
Internet at www.fda.gov/cder/guidance/index.htm. You may refer to
Section III.A.3.1, *Polymorphism*, of that guidance to find the
suggested placement of information related to polymorphism that is
important to include when submitting applications in the CTD-Q format.

FDA's guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency's current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# II. DEFINITION OF TERMS: POLYMORPHIC FORMS AND POLYMORPHISM {#ii.-definition-of-terms-polymorphic-forms-and-polymorphism .unnumbered}

We recommend that ANDA applicants investigate whether the drug substance
in question can exist in polymorphic forms. Polymorphic forms in the
context of this guidance refer to crystalline and amorphous forms as
well as solvate and hydrate forms, which are described below.[^9]

-   Crystalline forms have different arrangements and/or conformations
    of the molecules in the crystal lattice.

-   Amorphous forms consist of disordered arrangements of molecules that
    do not possess a distinguishable crystal lattice.

-   Solvates are crystal forms containing either stoichiometric or
    nonstoichiometric amounts of a solvent.[^10] If the incorporated
    solvent is water, the solvate is commonly known as a hydrate.

When a drug substance exists in polymorphic forms, it is said to exhibit
polymorphism.

# III. general principles of pharmaceutical solid polymorphism {#iii.-general-principles-of-pharmaceutical-solid-polymorphism .unnumbered}

## A. Importance of Pharmaceutical Solid Polymorphism {#a.-importance-of-pharmaceutical-solid-polymorphism .unnumbered}

Polymorphic forms of a drug substance can have different chemical and
physical properties, including melting point, chemical reactivity,
apparent solubility,[^11] dissolution rate, optical and mechanical
properties, vapor pressure, and density. These properties can have a
direct effect on the ability to process and/or manufacture the drug
substance and the drug product, as well as on drug product stability,
dissolution, and bioavailability. Thus, polymorphism can affect the
quality, safety, and efficacy of the drug product.

## B. Characterization of Polymorphs {#b.-characterization-of-polymorphs .unnumbered}

There are a number of methods that can be used to characterize
polymorphs of a drug substance.[^12] Demonstration of a nonequivalent
structure by single crystal X-ray diffraction is currently regarded as
the definitive evidence of polymorphism. X-ray powder diffraction can
also be used to support the existence of polymorphs. Other methods,
including microscopy, thermal analysis (e.g., differential scanning
calorimetry, thermal gravimetric analysis, and hot-stage microscopy),
and spectroscopy (e.g., infrared \[IR\], Raman, solid-state nuclear
magnetic resonance \[ssNMR\]) are helpful to further characterize
polymorphic forms.

##  {#section .unnumbered}

## C. Influence of Polymorphism On Drug Substance And Drug Product  {#c.-influence-of-polymorphism-on-drug-substance-and-drug-product .unnumbered}

###  {#section-1 .unnumbered}

### Influence on Solubility, Dissolution, and Bioavailability (BA) and Bioequivalence (BE)

The solid-state properties of a drug substance can have a significant
influence on the solubility of the drug substance. Since polymorphic
forms differ in their internal solid-state structure, a drug substance
that exists in various polymorphic forms can have different aqueous
solubilities and dissolution rates.[^13] When there are differences in
the solubilities of the various polymorphic forms, we recommend that you
focus on the potential effect such differences can have on drug product
bioavailability (BA) and bioequivalence (BE).[^14]

Whether drug product BA/BE can be affected by the differences in
solubilities of the various polymorphic forms depends on the various
physiological factors that govern the rate and extent of drug absorption
including gastrointestinal motility, drug dissolution, and intestinal
permeability. In this context, the Biopharmaceutics Classification
System (BCS)[^15]^,^ [^16] provides a useful scientific framework for
regulatory decisions regarding drug substance polymorphism.

For a drug whose absorption is only limited by its dissolution, large
differences in the solubilities of the various polymorphic forms are
likely to affect BA/BE. On the other hand, for a drug whose absorption
is only limited by its intestinal permeability, differences in the
solubilities of the various polymorphic forms are less likely to affect
BA/BE. Furthermore, when the solubilities of the polymorphic forms are
sufficiently high and drug dissolution is rapid in relation to gastric
emptying, differences in the solubilities of the polymorphic forms are
unlikely to affect BA/BE.

Upon demonstration of in-vivo bioequivalence between the generic drug
product[^17] and the reference listed drug (RLD),[^18] in-vitro
dissolution testing is then used to assess the lot-to-lot quality of the
generic drug product. Drug product dissolution testing frequently
provides a suitable means to identify and control the quality of the
product from both the bioavailability and physical (stability)
perspectives. In particular, inadvertent changes to the polymorphic form
that may affect drug product BA/BE can often be detected by drug product
dissolution testing.

##   {#section-2 .unnumbered}

### Influence on Manufacturing of the Drug Product

Drug substance polymorphic forms can also exhibit different physical and
mechanical properties, including hygroscopicity, particle shape,
density, flowability, and compactibility, which in turn may affect
processing of the drug substance and/or manufacturing of the drug
product. Since an ANDA applicant should demonstrate that the generic
drug product can be manufactured reliably using a validated process, we
recommend that you pay close attention to polymorphism and crystalline
habit as they relate to pharmaceutical processing.[^19]

The effect of polymorphism on pharmaceutical processing also depends on
the formulation and the manufacturing process.[^20] For a drug product
manufactured by direct compression, the solid-state properties of the
active ingredient will likely be critical to the manufacture of the drug
product, particularly when it constitutes the bulk of the tablet mass.
On the other hand, for a drug product manufactured by wet granulation,
the solid-state properties of the active ingredient are often masked by
the resultant granulation, therefore, such properties of the active
ingredient are less likely to affect the manufacture of the drug
product. In the context of the effect of polymorphism on pharmaceutical
processing, what is most relevant is the ability to consistently
manufacture a drug product that conforms to applicable in-process
controls and release specifications.

Polymorphic forms of the drug substance can undergo phase conversion
when exposed to a range of manufacturing processes, such as drying,
milling, micronization, wet granulation, spray-drying, and compaction.
Exposure to environmental conditions such as humidity and temperature
can also induce polymorph conversion. The extent of conversion generally
depends on the relative stability of the polymorphs, kinetic barriers
for phase conversion, and applied stress.[^21] Nonetheless, phase
conversion generally is not of serious concern, provided that the
conversion occurs consistently, as a part of a validated manufacturing
process where critical manufacturing process variables are well
understood and controlled and where drug product BA/BE has been
demonstrated.

### Influence on Stability

Polymorphs can have different physical and chemical (reactivity)
properties. The most stable polymorphic form of a drug substance is
often chosen during development based on the minimal potential for
conversion to another polymorphic form and on its greater chemical
stability. However, a metastable form can be chosen for various reasons,
including bioavailability enhancement. Since an ANDA applicant must
demonstrate that the generic drug product exhibits adequate
stability[^22] we recommend that you focus on the potential effect that
a polymorphic form can have on drug product stability. Nonetheless,
because drug product stability is affected by a multitude of other
factors, including formulation, manufacturing process, and packaging, it
is the stability of the drug product, and not stability of the drug
substance polymorphic form that should be the most relevant measure of
drug quality.

# IV. POLYMORPHISM AND *SAMENESS* In ANDAs {#iv.-polymorphism-and-sameness-in-andas .unnumbered}

Section 505(j)(2) of the Act specifies that an ANDA must contain, among
other things, information to show that the active ingredient in the
generic drug product is the \"same as\" that of the RLD. Under section
505(j)(4) of the Act, FDA must approve an ANDA unless the agency finds,
among other things, that the ANDA contains insufficient information to
show that the active ingredient is the same as that in the RLD. FDA
regulations implementing section 505(j) of the Act provide that an ANDA
is suitable for consideration and approval if the generic drug product
is the \"same as\" the RLD. Specifically, 21 CFR 314.92(a)(1) provides
that the term \"same as\" means, among other things, \"identical in
active ingredient(s).\" The drug substance in a generic drug product is
considered to be the same as the drug substance in the RLD if it meets
the same standards for identity.[^23]

When a United States Pharmacopeia (USP) monograph exists for a
particular drug substance, standards for identity generally refer to the
definition (i.e. chemical name, empirical formula, molecular structure,
description) at the beginning of the monograph. However, FDA may
prescribe additional standards that are material to the *sameness* of a
drug substance.[^24]

Polymorphic forms of a drug substance differ in internal solid-state
structure, but not in chemical structure. In the context of *sameness*
of active ingredient(s) in the preamble to the 1992 final rule, FDA
specifically rejected a proposal that would have required an ANDA
applicant to show that the active ingredient in its generic drug product
and the active ingredient in the RLD \"exhibit the same physical and
chemical characteristics, that no additional residues or impurities can
result from the different manufacture or synthesis process and that the
stereochemistry characteristics and solid state forms of the drug have
not been altered.\"[^25] Therefore, differences in drug substance
polymorphic forms do not render drug substances different active
ingredients for the purposes of ANDA approvals within the meaning of the
Act and FDA regulations*.*

In addition to meeting the standards for identity, each ANDA applicant
is required to demonstrate that, among other things, the drug product
exhibits sufficient stability and is bioequivalent to the RLD.[^26]
While the polymorphic form can affect drug product stability and
bioequivalence, these performance characteristics are also dependent on
the formulation, the manufacturing process, and other physicochemical
properties (e.g., particle size, moisture) of both the drug substance
and formulation excipients. Thus, using a drug substance polymorphic
form that is different from that of the RLD may not preclude an ANDA
applicant from formulating a generic drug product that exhibits
bioequivalence and stability. Therefore, the drug substance in the
generic drug product need not have the same polymorphic form as the drug
substance in the RLD.

Over the years, FDA has approved a number of ANDAs in which the drug
substance in the generic drug product had a different polymorphic form
from the drug substance in the respective RLD (e.g., warfarin sodium,
famotidine, and ranitidine). Also, FDA has approved some ANDAs in which
the drug substance in the generic drug product differed in solvate or
hydrate forms from the drug substance in the corresponding RLD (e.g.,
terazosin hydrochloride, ampicillin, and cefadroxil).

# V. CONSIDERATIONS FOR Polymorphism in andas  {#v.-considerations-for-polymorphism-in-andas .unnumbered}

The decision trees shown in Attachments 1 to 3 provide ANDA applicants
with a suggested process for evaluating the importance of and approaches
to setting specifications for polymorphic forms in solid oral drug
products and oral suspensions. Although the conceptual framework adopted
by these decision trees is based primarily on the potential for
polymorphic forms to affect drug product BA/BE, we recommend that you
still consider the influence polymorphic forms may have on the ability
to manufacture the drug product and on the stability of the drug
product.

The following sections describe each of the decision trees.

##  {#section-3 .unnumbered}

## A. Investigating the Importance of Setting Specifications for Polymorphs {#a.-investigating-the-importance-of-setting-specifications-for-polymorphs .unnumbered}

Decision Tree 1 provides recommendations on when specifications for
polymorphic form(s)[^27] for the drug substance and/or the drug product
may be appropriate. Polymorphs are unlikely to have a significant effect
on BA/BE when all forms have the same solubilities or all forms are
highly soluble.

[]{.mark}

ANDA applicants are expected to have adequate knowledge on drug
substance polymorphs. Information on polymorphism can come from the
scientific literature, patents, compendia, other references, or in some
cases, polymorph screening.

## Setting Specifications for Polymorphs in Drug Substances 

Decision Tree 2 provides an approach for setting specifications for
polymorphs in the drug substance when at least one form is known to have
low solubility based on the BCS. If relevant and adequate specifications
for polymorphs are included in the USP, ANDA applicants may adopt these
specifications for the drug substance polymorphic form. Otherwise, we
recommend that a new specification for the drug substance polymorphic
form be established.

##  {#section-4 .unnumbered}

## C. Investigating the Importance of Setting Specifications for Polymorphs in Drug Products {#c.-investigating-the-importance-of-setting-specifications-for-polymorphs-in-drug-products .unnumbered}

Decision Tree 3 provides an approach when considering the importance for
setting specifications for polymorphs in the drug product. Generally,
specifications for polymorphs in drug products are not necessary if the
most stable polymorphic form is used or if the same form is used in an
approved product of the same dosage form. However, since manufacturing
processes can affect the polymorphic form, we recommend that you use
caution if a metastable form is used.

[]{.mark}

Drug product performance testing (e.g., dissolution testing) can also
generally provide adequate control of polymorph ratio changes that can
influence drug product BA/BE for poorly soluble drugs. In such
instances, setting specifications for polymorphs in the drug product
would generally not be considered important for ensuring adequate
product performance. Only in rare cases would we recommend setting
specifications for polymorphic forms in drug products.

+-----------------------------------------------------------------------+
| # ATTACH                                                              |
| MENT 1 -- DECISION TREE 1 {#attachment-1-decision-tree-1 .unnumbered} |
+-----------------------------------------------------------------------+

*Decision Tree 1* Investigating the importance of setting specifications
for polymorphs for solid oral and suspension dosage form products.

\*We recommend that you consider only those polymorphs that are likely
to form during manufacture of the drug substance, manufacture of the
drug product, or while the drug substance or drug product is in storage.
See footnote 7 in this guidance document.

+-----------------------------------------------------------------------+
| # ATTACH                                                              |
| MENT 2 -- DECISION TREE 2 {#attachment-2-decision-tree-2 .unnumbered} |
+-----------------------------------------------------------------------+

*Decision Tree 2* Setting specifications for polymorphs in drug
substances for solid oral and suspension dosage form products.

+-----------------------------------------------------------------------+
| #  {#section-5 .unnumbered}                                           |
|                                                                       |
| # ATTACH                                                              |
| MENT 3 -- DECISION TREE 3 {#attachment-3-decision-tree-3 .unnumbered} |
+-----------------------------------------------------------------------+

*Decision Tree 3* Investigating the importance of setting specifications
for polymorphs in drug products for solid oral and suspension dosage
form products.

\*In general, there may not be a concern if the most stable polymorphic
form is used or the same form is used in a previously approved product
of the same dosage form.

\*\*Drug product performance testing (e.g., dissolution testing) can
generally provide adequate control of polymorph ratio changes for poorly
soluble drugs, which may influence drug product BA/BE. Only in rare
cases would polymorphic form characterization in the drug product be
recommended.

[^1]: This guidance has been prepared by the Office of Generic Drugs
    (OGD) in the Office of Pharmaceutical Science (OPS), Center for Drug
    Evaluation and Research (CDER) at the Food and Drug Administration
    (FDA).

[^2]: Although issues relating to polymorphic forms may be relevant for
    issues relating to new drug applications (NDAs), this guidance only
    addresses polymorphic forms in the context of ANDA approvals.

[^3]: See 21 CFR 314.94 (a)(9); see also section 505(j)(4)(A) of the
    Federal Food, Drug, and Cosmetic Act (the Act).

[^4]: For the purposes of this guidance the terms *drug substance* and
    *active ingredient* are use interchangeably.

[^5]: The terms *polymorphic forms* and *polymorphs* are synonymous and
    are used interchangeably in this draft guidance.

[^6]: Refer to Section IV for more information.

[^7]: This guidance is intended to help industry with the most common
    types of polymorphs. A drug substance may exist in many polymorphic
    forms, but some forms may be rare and not likely to form. For
    example, in one approved drug product, the drug substance can exist
    in at least twenty polymorphic forms, but in reality only a subset
    of polymorphic forms has the potential to develop under the process
    conditions used to manufacture the drug substance and drug product.
    Therefore, we recommend that you consider only those polymorphs that
    are likely to form during manufacture of the drug substance,
    manufacture of the drug product, or while the drug substance or drug
    product is in storage.

[^8]: This guidance is intended to clarify location issues for
    information submitted to FDA in the CTD format as described in the
    guidance for industry, M4Q *CTD-Quality (CTD-Q)*, August 2001. The
    *CTD-Q* provides recommendations for applicants preparing the
    *Common Technical Document for the Registration of Pharmaceuticals
    for Human Use* for submission to FDA.

[^9]: Guidance for industry, Q6A *Specifications: Test Procedures and
    Acceptance Criteria for New Drug Substances and New Drug Products:
    Chemical Substances,* International Conference on Harmonisation
    (ICH), December 2000.

[^10]: SR Byrn, RR Pfeiffer, and JG Stowell. *Solid-State Chemistry of
    Drugs*. 2^nd^ Edition, SSCI, Inc., West Lafayette, Indiana, 1999.

[^11]: Apparent solubility refers to the concentration of material at
    apparent equilibrium (supersaturation). Apparent solubility is
    distinct from true thermodynamic solubility, which is reached at
    infinite equilibrium time.

[^12]: H Brittain. \"Methods for the characterization of polymorphs and
    solvates.\" In HG Brittain (ed.) *Polymorphism in Pharmaceutical
    Solids*. Marcel Dekker, Inc., New York, 1999, pp. 227-278.

[^13]: HG Brittain and DJW Grant. \"Effect of polymorphism and
    solid-state solvation on solubility and dissolution rate.\" In HG
    Brittain (ed.) *Polymorphism in Pharmaceutical Solids*. Marcel
    Dekker, Inc., New York, 1999,

    pp. 279-330.

[^14]: Bioavailability (BA) is defined in 21 CFR 320.1(a) as "the rate
    and extent to which the active ingredient or active moiety is
    absorbed from a drug product and becomes available at the site of
    action.\" Bioequivalence (BE) is defined in 21 CFR 320.1(e) as "the
    absence of a significant difference in the rate and extent to which
    the active ingredient or active moiety in pharmaceutical equivalents
    or pharmaceutical alternatives becomes available at the site of drug
    action when administered at the same molar dose under similar
    conditions in an appropriately designed study."

[^15]: GL Amidon, H Lennernas, VP Shah, and JR Crison. \"A theoretical
    basis for a biopharmaceutic drug classification: the correlation of
    in vitro drug product dissolution and in vivo bioavailability,\"
    *Pharm. Res*. 12:413-420, 1995.

[^16]: LX Yu, GL Amidon, JE Polli, H Zhao, M Mehta, DP Conner, VP Shah,
    LJ Lesko, M-L Chen, VHL Lee, and AS Hussain. \"Biopharmaceutics
    Classification System: The scientific basis for biowaiver
    extension.\" *Pharm. Res.* 19:921-925, 2002.

[^17]: The term *generic drug product* refers to a new drug product for
    which approval is sought in an ANDA submitted under section 505(j)
    of the Act.

[^18]: See 21 CFR 314.3 (b) (providing that *reference listed drug*
    means the listed drug identified by FDA as the drug product upon
    which an applicant relies in seeking approval of its abbreviated
    application).

[^19]: Section 505(j)(4)(A) provides that FDA must approve an ANDA if,
    among other things, the methods used in, or the facilities and
    controls used for, the manufacture, processing, and packing of the
    drug are adequate to assure and preserve its identity, strength,
    quality, and purity.

[^20]: DA Wadke, ATM Serajuddin, and H Jacobson. \"Preformulation
    testing.\" In HA Lieberman, L Lachman, and JB Schwartz (eds.)
    *Pharmaceutical Dosage Forms: Tablets* (Vol. 1). Marcel Dekker,
    Inc., New York, 1989,

    pp. 1-73.

[^21]: SR Vippagunta, HG Brittain, DJW Grant. \"Crystalline solids,\"
    *Adv. Drug Del. Rev.* 48:3-26, 2001.

[^22]: See footnote 19.

[^23]: See preamble to the 1992 final rule (57 FR 17958; April 28,
    1992).

[^24]: See footnote 23.

[^25]: See footnote 23.

[^26]: See 505(j)(4) of the Act and 21 CFR 314.127.

[^27]: See footnote 7.