Issues of Polymorphism and Abbreviated New Drug Applications

21CFR 314.92 (a)(1) addresses drug products which may be suitable for
filing as an abbreviated new drug application (ANDA), and reads in part
" Drug products that are the same as a listed drug....For determining
the suitability of an abbreviated new drug application, the term "same
as" means identical in active ingredients(s), dosage form, strength,
route of administration, and conditions of use..."

The existence of different physical forms of a drug substance has
provided a basis for arguments concerning drug substance identity and
suitability for use in drug products approved under 505(j) of the
Federal Food, Drug, and Cosmetic Act. The arguments, for the most part,
relate to the requirements for "sameness" that such products must meet.
Additional issues relate to the characteristics of drug products that
are manufactured using different physical forms of a drug substance.

Monographs that appear in the United States Pharmacopeia (USP) are
relevant to FDA's consideration of an ANDA drug product. Such monographs
are one source of specifications for each drug substance and drug
product on such matters as identification, dissolution, and assay.
Because by regulation, USP is recognized as an official compendium, the
monograph drug substance and drug product nomenclature may serve as the
"official" or "established name". Restrictions on physical form, either
in the monograph description or by specific test (such as crystallinity)
can affect the use of the established name.

For drug substances or drug products that are not subject to USP
monographs, there may still be constraints on the use of other forms of
the drug substance, such as product labeling or patents. In such cases,
identity or sameness arguments might be based on differences in physical
characteristics of the drug substance forms, leading to potential
differences in drug product performance.

A variety of legal and scientific positions, based on these and other
topics, have been raised as arguments that certain ANDAs can not be
shown to meet "sameness " requirements and therefore are not approvable.
Alternative arguments propose that specific testing requirements be
imposed as conditions of approval.

Although the attached citizen petition response is directed at only one
product, the discussion addresses several different topics and is
instructive of the various legal and scientific issues raised.

F. Holcombe, Jr. / 4/8/02

Agency Position on Polymorphism and Abbreviated New Drug Applications

For a generic drug product to be regarded as having the same active
ingredient under section 314.92(a)(1), the drug substance in a proposed
generic drug product need not have the same physical form as the drug
substance in the reference listed drug. FDA states in its *Approved Drug
Products With Therapeutic Equivalence Evaluations* (*Orange Book*) that
the Agency considers drug products containing different polymorphs of
the same drug substance to be pharmaceutically equivalent. The *Orange
Book* describes pharmaceutical equivalents as, among other things,
containing the same active ingredient(s). Therefore, FDA regards
different polymorphs of a drug substance as the same active ingredient.

Also, the *Guideline for Submitting Supporting Documentation in Drug
Applications for the Manufacture of Drug Substances*, issued February
1987, in discussion of the relationship of solid-state drug substance
forms to bioavailability, notes the following:

> Some drug substances exist in several different crystalline forms
> ("polymorphs"), due to a different arrangement of molecules in the
> crystal lattice, which thus show distinct differences in their
> physical properties. The same drug substance may also exist in a
> noncrystalline (amorphous) form. These various forms differ in their
> thermodynamic energy content, *but not in composition*.

As the Guideline points out, the polymorphic form of a drug substance
can affect the dissolution and bioavailability of drug products. Thus,
it is possible that a difference in physical form of the active
ingredients might prevent a proposed generic drug from being
bioequivalent to the reference listed drug (thus barring approval of the
ANDA). However, this difference in bioequivalence would not mean that
the generic and reference listed drug products contained different
active ingredients; it would mean that the *drug products* would *not*
be the \"same.\" If however, the drug product had been shown to be
bioequivalent to the reference listed drug, in addition to meeting other
requirements, the drug product would be considered to be the same, and
could be approved.

Reprints from the Orange Book, USP, and CDER Drug Substance Guideline
providing additional information are attached.

F. Holcombe, Jr. / 4/8/02