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 sameness6 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  
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys 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. 

  2
  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. 
  3
  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 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, 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, 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.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. 

  4
  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. 

  5
  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. 
  6
  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.  
 
START 
Are there known  
NO 
polymorphs* 
 
with different 
Polymorphic form specifications in both the drug   
apparent 
substance and the drug product are  unnecessary 
solubilities?  
YES 

 
YES 
 
Are all polymorphs 
highly soluble as 
defined by BCS  
criteria?  
NO 

Decision Tree 2 

*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. 
 
 
 
START 
Is there a 
polymorph 
NO 
specification in the 
USP (e.g., melting 
point)?  
YES 
 
Is the polymorph 
specification in the 
NO 
USP relevant and  
Set a new specification for the drug substance  
adequate?  
polymorphic form. 
YES 

Set the same specification for the 
drug substance polymorphic form as   
Decision Tree  3 
in the USP.  
 
 
  9
  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.  
 
START 
Is there sufficient 
concern that a  NO 
polymorph 
A polymorph specification in  
specification in the 
the drug product is unnecessary. 
drug product be 
established?* 
 
YES 

Does drug product 
YES 
performance testing 
Set a specification for drug   
(e.g., dissolution  
product performance testing  
testing) provide 
(e.g., dissolution testing) as a   
adequate controls if 
surrogate for polymorph 
the polymorph ratio  
control in the drug product. 
changes?  
NO 

Set a polymorph specification in  the drug product 
using other approaches,  such as a solid-state characterization method.** 
*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