Table of Contents

Aim:...........................................................................................................................................3

Regulatory requirements for the polymorphism in us......................................................3

INTRODUCTION............................................................................................................3

DEFINITION OF TERMS: POLYMORPHIC FORMS AND POLYMORPHISM. 3

POLYMORPHISM AND SAMENESS IN ANDAs..............................................................6

CONSIDERATIONS FOR POLYMORPHISM IN ANDAs...............................................6

Regulatory requirements for the polymorphism in Europe..............................................10

Advantages of polymorphism in pharmaceutical industry............................................12

Challenges faced by pharmaceutical industry on polymorphism..................................13

Aim: To prepare and submit various regulatory requirements for the polymorphism in us
Europe and Japan

Regulatory requirements for the polymorphism in us

INTRODUCTION
DEFINITION OF TERMS: POLYMORPHIC FORMS AND POLYMORPHISM
 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 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.

GENERAL PRINCIPLES OF PHARMACEUTICAL SOLID POLYMORPHISM

A. Importance of Pharmaceutical Solid Polymorphism

 Polymorphic forms of a drug substance can have different chemical and physical
properties, including melting point, chemical reactivity, apparent solubility,
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

 There are a number of methods that can be used to characterize polymorphs of a drug
substance. Demonstration of a non-equivalent 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 provide unequivocal proof of polymorphism.
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.

C. Influence of Polymorphism on Drug Substance and Drug Product

1. 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
apparent 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. When there are
differences in the apparent 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).
 Whether drug product BA/BE can be affected by the differences in apparent
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.
 For a drug whose absorption is only limited by its dissolution, large differences in the
apparent 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 apparent solubilities of the various polymorphic forms
are less likely to affect BA/BE. Furthermore, when the apparent 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 product16
and the reference listed drug (RLD), in-vitro dissolution testing is then used to assess
the lot-to-lot quality of the generic drug product.

2. 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 as it relates to
pharmaceutical processing
 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 as it relates to
pharmaceutical processing
 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, and
the solid-state properties of the active ingredient are less likely to affect the
manufacture of the drug product.
 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 to phase conversion, and applied stress

3. Influence on Stability

Polymorphs can have different physical and chemical (reactivity) properties. The most
thermodynamically 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,
POLYMORPHISM AND SAMENESS IN ANDAs
 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." 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. 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.
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, and 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). FDA also
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).

CONSIDERATIONS FOR POLYMORPHISM IN ANDAs

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.

A. Investigating the Importance of Setting Specifications for Polymorphs

Decision Tree 1 provides recommendations on when specifications for polymorphic form 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 apparent solubilities or all
forms are highly soluble. ANDA applicants are expected to have adequate knowledge about
drug substance polymorphs. Information on polymorphism can come from the scientific
literature, patents, compendia, other references, or in some cases, polymorph screening.

B. 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.

C. Investigating the Importance of Setting Specifications for Polymorphs in Drug

Products

Decision Tree 3 provides an approach when considering whether to set specifications for
polymorphs in the drug product. Generally, specifications for polymorphs in drug products
are not necessary if the most thermodynamically 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.
Regulatory requirements for the polymorphism in Europe: follow ICH Topic Q 6 A
because Europe is a one of the member states in ICH

Polymorphic forms: Some new drug substances exist in different crystalline forms which
differ in their physical properties. Polymorphism may also include solvation or hydration
products (also known as pseudo polymorphs) and amorphous forms. Differences in these
forms could, in some cases, affect the quality or performance of the new drug products. In
cases where differences exist which have been shown to affect drug product performance,
bioavailability or stability, then the appropriate solid state should be specified.
 Physicochemical measurements and techniques are commonly used to determine
whether multiple forms exist. Examples of these procedures are: melting point
(including hot-stage microscopy), solid state IR, X-ray powder diffraction, thermal
analysis procedures (like DSC, TGA and DTA), Raman spectroscopy, optical
microscopy, and solid-state NMR.
Note: These decision trees should be followed sequentially. Trees 1 and 2 consider whether
polymorphism is exhibited by the drug substance, and whether the different polymorphic
forms can affect performance of the drug product.

Advantages of polymorphism in pharmaceutical industry

 Preparation of physical stable dosage form
 Influence on solubility dissolution and bioavailability
 Influence on drug product manufacturability
 Influence on stability
 Effect on tableting
Challenges faced by pharmaceutical industry on polymorphism

 How do you know how many forms exist for a drug molecule?
o Structure screening-crystallization tools in lab/HTS
o Computational approach
 How to identify the polymorph-a pure phase or a mixture?
 How to characterize the new polymorphism?
 Patentable polymorphism and new business opportunity