Guidance for Industry 

ANDAs: Pharmaceutical 

Solid Polymorphism 

Chemistry, Manufacturing, and Controls Information 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

July 2007 

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) 

July 2007 

OGD 
TABLE OF CONTENTS 

I. INTRODUCTION..............................................................................................................................................1

II. DEFINITION OF TERMS: POLYMORPHIC FORMS AND POLYMORPHISM ...................................2

III. GENERAL PRINCIPLES OF PHARMACEUTICAL SOLID POLYMORPHISM..............................2

A. IMPORTANCE OF PHARMACEUTICAL SOLID POLYMORPHISM ...........................................................................2

B. CHARACTERIZATION OF POLYMORPHS.............................................................................................................2

C. INFLUENCE OF POLYMORPHISM ON DRUG SUBSTANCE AND DRUG PRODUCT.................................................3

1. Influence on Solubility, Dissolution, and Bioavailability (BA) and Bioequivalence (BE)..........................3

2. Influence on Manufacturing of the Drug Product ......................................................................................4

3. Influence on Stability..................................................................................................................................5

IV. POLYMORPHISM AND SAMENESS IN ANDAs....................................................................................5

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

A. INVESTIGATING THE IMPORTANCE OF SETTING SPECIFICATIONS FOR POLYMORPHS........................................6

B. SETTING SPECIFICATIONS FOR POLYMORPHS IN DRUG SUBSTANCES ...............................................................6

C. INVESTIGATING THE IMPORTANCE OF SETTING SPECIFICATIONS FOR POLYMORPHS IN DRUG PRODUCTS........7

ATTACHMENT 1 – DECISION TREE 1.................................................................................................................8

ATTACHMENT 2 – DECISION TREE 2.................................................................................................................9

ATTACHMENT 3 – DECISION TREE 3...............................................................................................................10
Contains nonbinding recommendations 

Guidance for Industry1

ANDAs: Pharmaceutical Solid Polymorphism 

Chemistry, Manufacturing, and Controls Information 

This guidance, represents 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. 

I. INTRODUCTION2

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 substance4 exists in polymorphic forms.5 

Specifically, this guidance provides: 

• FDA recommendations on assessing sameness

6

 when the drug substance exists in 

polymorphic forms. 

•

 

Decision trees that provide recommendations on monitoring and controlling polymorphs 

in drug substances and/or drug products.7

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 

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 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 used interchangeably. 5

 The terms polymorphic forms and polymorphs are synonymous and are used interchangeably in this 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. 

1
Contains nonbinding recommendations 

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 

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.8

 

• 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.9

 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 

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,10 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.11 Demonstration of a nonequivalent structure by single crystal X-ray diffraction is 

 

8

 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. 9

 SR Byrn, RR Pfeiffer, and JG Stowell. Solid-State Chemistry of Drugs. 2nd Edition, SSCI, Inc., West Lafayette, 

Indiana, 1999. 

10 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. 11 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. 

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Contains nonbinding recommendations 

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.12 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).13 

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. In this context, the Biopharmaceutics Classification System (BCS)14, 15 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 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. 

 

12 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. 

13 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.” 

14 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. 

15 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. 

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Contains nonbinding recommendations 

Upon demonstration of in-vivo bioequivalence between the generic drug product16 and the 

reference listed drug (RLD),17 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. 

 

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.18 

The effect of polymorphism on pharmaceutical processing also depends on the formulation and 

the manufacturing process.19 For a drug product manufactured by direct compression, the solidstate 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, and the solid-state 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, spraydrying, 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.20 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 when drug product 

BA/BE has been demonstrated. 

 

16 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. 

17 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). 

18 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. 

19 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. 

20 SR Vippagunta, HG Brittain, DJW Grant. "Crystalline solids," Adv. Drug Del. Rev. 48:3-26, 2001. 

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Contains nonbinding recommendations 

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,21 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 

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.22 

When a United States Pharmacopeia (USP) monograph exists for a particular drug substance, 

standards for identity generally refer to the definition (e.g. 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.23 

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."24 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. 

 

21 See footnote 18. 

22 See preamble to the 1992 final rule (57 FR 17958; April 28, 1992). 

23 See footnote 22. 

24 See footnote 22. 

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Contains nonbinding recommendations 

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.25 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). 

V. 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. 

The following sections describe each of the decision trees. 

A. Investigating the Importance of Setting Specifications for Polymorphs 

Decision Tree 1 provides recommendations on when specifications for polymorphic form(s)26

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 

 

25 See 505(j)(4) of the Act and 21 CFR 314.127. 

26 See footnote 7. 

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Contains nonbinding recommendations 

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. 

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. 

7
Contains nonbinding recommendations 

ATTACHMENT 1 – DECISION TREE 1 

Decision Tree 1 Investigating whether to set specifications for polymorphs for solid oral 

and suspension dosage form products. 

Are all polymorphs 

highly soluble as 

defined by BCS 

criteria? 

Are there known 

polymorphs*

with different 

apparent 

solubilities? 

Polymorphic form specifications in both the drug 

substance and the drug product are unnecessary 

START 

Decision Tree 2 

YES 

NO 

YES

NO 

*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. 

8
Contains nonbinding recommendations 

ATTACHMENT 2 – DECISION TREE 2 

Decision Tree 2 Setting specifications for polymorphs in drug substances for solid oral and 

suspension dosage form products. 

Is the polymorph 

specification in the 

USP relevant and 

adequate? 

Is there a 

polymorph 

specification in the 

USP (e.g., melting 

point)? 

Set a new specification for the drug substance 

polymorphic form. 

START 

Set the same specification for the 

drug substance polymorphic form as 

in the USP.

YES

NO

NO

YES 

Decision Tree 3 

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Contains nonbinding recommendations 

ATTACHMENT 3 – DECISION TREE 3 

Decision Tree 3 Investigating whether to set specifications for polymorphs in drug 

products for solid oral and suspension dosage form products. 

Does drug product 

performance testing 

(e.g., dissolution 

testing) provide 

adequate controls if 

the polymorph ratio 

changes? 

Is there sufficient 

concern that a 

polymorph 

specification in the 

drug product be 

established?* 

Set a specification for drug 

product performance testing 

(e.g., dissolution testing) as a 

surrogate for polymorph 

control in the drug product. 

START 

Set a polymorph specification in the drug product 

using other approaches, such as a solid-state characterization method.**

YES 

NO 

YES 

NO 

A polymorph specification in 

the drug product is unnecessary. 

*In general, there may not be a concern if the most thermodynamically 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. 

10