Sameness  Evaluations  
in  an ANDA     
Active Ingredients  
Guidance for Industry  
 
 
 
 
 
 
 
DRAFT GUIDANCE 
 
 
  This guidance document is being distributed for comment purposes only.  
 
Comments and suggestions regarding this draft document should be submitted within 60 days of  
publication in the  Federal Register  of the notice announcing the availability of the draft  
guidance.  Submit electronic comments to  https://www.regulations.gov. Submit written  
comments to the Dockets Management  Staff (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 (CDER)  Susan Levine  240-402-7936.  
 
 
 
 
U.S.Department of Health and Human Services  
Food and Drug Administration  
Center for Drug Evaluation and Research (CDER)  
 
November 2022  
Generic  Drugs  
   
 
Sameness  Evaluations  
in an ANDA     
Active Ingredients  
Guidance for Industry  
 
 
Additional copies are available from:  
Office of Communications,  Division of Drug Information   
Center  for Drug Evaluation and Research  
Food and Drug Administration  
10001  New Hampshire Ave.,  Hillandale Bldg., 4th  Floor   
Silver Spring, MD 20993-0002   
Phone:  855-543-3784 or  301-796-3400; Fax:  301-431-6353  
Email:  druginfo@fda.hhs.gov   
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S.Department of Health and Human Services  
Food and Drug Administration  
Center for Drug Evaluation and Research (CDER)  
 
November 2022  
Generic  Drugs  
  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
 
TABLE OF CONTENTS  
 
 
 
I.   INTRODUCTION.............................................................................................................  1  
II.   BACKGROUND  ...............................................................................................................  1  
III.   ACTIVE INGREDIENT SAMENESS EVALUATIONS  .............................................  3  
A.   General Considerations for Determining the Active Ingredient  ............................................... 4  
B.   Active Ingredient Sameness Considerations in Certain Drug Products ................................... 5  
1.  Synthetic Peptides ............................................................................................................................ 5  
2.  Complex Mixtures ............................................................................................................................ 6  
C.   Characterization of the Active Ingredient  in  the Drug Product ................................................ 7  
D.   Additional Recommendations ....................................................................................................... 9  
  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
1   Sameness Evaluations in an ANDA    Active Ingredients  
2   Guidance for Industry1  
3    
4    
5   This draft guidance, when finalized, will represent the  current thinking of  the  Food and Drug 
6   Administration (FDA or Agency) on this topic.  It does not  establish  any rights for any person and is not 
7   binding on FDA or the public.  You can use an alternative approach if  it  satisfies the requirements of the 
8   applicable statutes  and regulations.   To  discuss an alternative approach, contact the FDA staff  responsible  
9   for this  guidance  as listed on the title page.   
10    
11    
12    
13    
14   I.   INTRODUCTION  
15    
16   This guidance is intended to assist applicants preparing an abbreviated new drug application 
17   (ANDA)  by providing recommendations on demonstrating sameness2  between  the active 
18   ingredient in a proposed generic drug product3  and  its  reference listed drug  (RLD)4  as required  
19   under section 505(j)(2)(A)(ii)  of the  Federal  Food, Drug, and Cosmetic Act (FD&C Act)  (21 
20   U.S.C. 355(j)(2)(A)(ii)) and FDAs  regulations  in   314.94(a)(5) (21 CFR  314.94(a)(5)).    
21    
22   In general, FDAs guidance documents do not establish legally enforceable  responsibilities.  
23   Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
24   as recommendations, unless specific regulatory or statutory requirements are cited.   The use of  
25   the word should  in Agency guidance means that something is suggested or recommended, but  
26   not required.  
27    
28    
29   II.   BACKGROUND  
30    
31   The Drug Price Competition and Patent Term Restoration Act of 1984 (Public Law 98-417)  
32   (Hatch-Waxman  Amendments) created an  approval pathway for generic drug products under  
33   which applicants  can submit an ANDA under  section 505(j) of the FD&C Act.  An ANDA relies  
34   on the Agencys previous finding of safety and effectiveness  for an  RLD  and, as a result, may be  
 
1  This guidance has been prepared by the Office  of Generic Drugs in the Center  for Drug Evaluation and Research  at 
FDA.  
  
2  For purposes of this guidance, the term  sameness  is used to describe the requirement that  a drug product proposed 
in an ANDA have  the same active ingredient as the drug product it references.  See section II of this guidance for  
more information.    
 
3   314.3(b) (21 CFR 314.3(b)). A  drug product  is a finished dosage form, e.g., tablet, capsule, or solution, that  
contains a drug substance,  generally, but  not necessarily, in association with one or  more  other ingredients.      
 
4   314.3(b). A  reference listed drug  is the listed drug identified by FDA as the drug product upon which an 
applicant relies in seeking approval of its ANDA.  
1  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
35   approved without submission of the same type and extent of information that is  required for 
36   approval of  a new drug application  (NDA)  submitted  under section 505(b)  of the FD&C Act.5  
37    
38   Among other things, an ANDA must contain information to show that the active ingredient of  
39   the proposed generic  drug product is the same  as that of the RLD.6,7,8   FDAs regulations  
40   provide that the term same as means, among other things, identical in active ingredient(s).9   
41   Active ingredient  is defined as:  
42    
43   [A]ny  component that is  intended to furnish pharmacological activity or other direct  
44   effect  in the  diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect  
45   the structure  or any function of the body of  man or  other animals.  The term includes 
46   those components that  may  undergo chemical change  in the  manufacture of  the drug 
47   product and be present in the drug product  in a modified form  intended to furnish the  
48   specified activity or  effect.10,11  
49    
50   The preamble of the proposed rule implementing the  Hatch-Waxman  Amendments states that  
51   [a]ctive ingredient in  this context means the active ingredient in the finished drug product prior  
52   to its administration.12   FDA recommends that applicants evaluate active ingredient sameness  
53   using the active ingredient  as it exists  in the  drug product  (i.e.,  in the  finished dosage  form).13   
54   Accordingly, applicants should fully evaluate the potential for changes in or to the active  
55   ingredient  during the  manufacturing process  of the drug product.    
56    
 
5  Compare section 505(j)(2)(A) of the  FD&C Act with section  505(b)  of the FD&C Act.    
 
6    314.94(a)(5).    
 
7  If the active ingredient in an applicants proposed generic drug product cannot  be demonstrated to be the same as  
the active ingredient in the RLD by using the information and data that may be submitted in an ANDA, the proposed 
drug product should not be submitted for approval in an ANDA.  See section 505(j)(2)(A)(ii) and 505(j)(4)(C) of the  
FD&C Act;  see also  the guidance for industry Determining Whether to Submit an ANDA or a 505(b)(2) Application  
(May 2019), at page  8. We update guidances  periodically. For the most recent version of a guidance, check the FDA  
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.     
 
8  An applicant may submit a suitability petition to FDA requesting permission to submit an  ANDA for a  proposed 
generic drug product that differs from an RLD in that it has one different active ingredient in a fixed-combination 
drug product. See section 505(j)(2)(C) of the FD&C Act and 21 CFR 314.93.    
 
9  21 CFR 314.92(a)(1).  The regulation states in part that [f]or determining the suitability of an abbreviated new  
drug application, the term  same as means identical in active ingredient(s), dosage form,  strength, route of  
administration, and conditions  of use, except that conditions  of use for which approval cannot be  granted because of  
exclusivity or an existing patent may be omitted.  
 
10   314.3(b).  
 
11  This guidance uses the term active ingredient, as defined in the regulations (21 CFR 314.3(b)), which pertains  to 
both human and animal drugs, and components that may undergo a chemical change during manufacturing and be  
present in a modified form intended to furnish the specified activity or effect.  
 
12  54 FR 28872 at 28881 (July 10, 1989).  
 
13  See footnote 3.  
2  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
57   FDA will refuse to  approve an ANDA  if  the ANDA contains insufficient information to show  
58   that,  among other things, the active ingredient  of the proposed generic drug product  is the same 
59   as that of the RLD.14   Accordingly, the ANDA applicant is responsible for providing sufficient  
60   information to demonstrate that the proposed generic drug product is  the same as the RLD  
61   with respect to the active  ingredient.   For fixed-combination drug products, i.e., drug products  
62   with more than one active  ingredient, the recommendations in this guidance  apply to each active 
63   ingredient.    
64    
65    
66   III.   ACTIVE INGREDIENT  SAMENESS EVALUATIONS  
67    
68   FDA has broad discretion to determine whether an ANDA applicant has submitted information 
69   sufficient for the  Agency to reasonably conclude that the  proposed generic  drug products active 
70   ingredient is the same as  the  active ingredient  of the RLD.15   The statutory provisions outlining 
71   the contents of an ANDA do not describe the type  or amount of information that an ANDA  
72   applicant must submit to  demonstrate  sameness.  In the preamble to the  final rule that  
73   implemented  the Hatch-Waxman Amendments  (1992 Final Rule), FDA specifically  declined to 
74   require that  applicants show active ingredient sameness by demonstrating that their active  
75   ingredients  exhibit the same physical and  chemical characteristics [as the RLDs], that  no 
76   additional residues or impurities can result from the different manufacture  or synthesis process;  
77   and that the  stereochemistry  characteristics and solid state forms of the drug have not been 
78   altered.16   Instead, FDA adopted a more flexible approach  in  assessing whether a proposed 
79   generic drug product contains the same active ingredient as that of the RLD.17   
80    
81   The preamble to the  1992 Final Rule indicated that FDA will consider an active ingredient to be  
82   the same as that of the RLD  if it meets the same standards for identity.  In  most cases, these  
83   standards are described in the U.S. Pharmacopeia  [(USP)].18   If there is no USP identity 
84   standard for  an active ingredient in an official monograph, FDA  recommends  an applicant  
85   establish the identity of the active ingredient by using appropriate  analytical methods (e.g., high-
86   performance liquid  chromatography, titration, etc.).   In other  cases,  FDA  may prescribe 
87   additional standards that are material to the ingredients sameness.19   FDAs determination of  
88   active ingredient sameness is based on relevant scientific information and is made as to the  
89   individual  active ingredient(s)  presented  in the proposed drug product.  
90    
 
14  21 CFR 314.127(a)(3).  
 
15  See generally  Serono Laboratories, Inc.  v.  Shalala, 158 F.3d 1313 (D.C. Cir. 1998).  
 
16  57 FR  17950 at 17958-17959 (April  28, 1992).  
 
17  Id. at 17959; see also letter from Janet Woodcock to J. Michael Nicholas (April 16, 2015), Docket No. FDA- 
2015-P-1050, at page 7  (denying citizen petition  from Teva Pharmaceuticals).     
 
18  57 FR  17950 at 17959.  
 
19  Id.  
3  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
91   Section III.B. of this guidance discusses  how FDA generally intends to evaluate the sameness of  
92   the active ingredient in  certain  proposed generic drug products  compared to the active ingredient  
93   in the RLD.  
94    
95   A.   General Considerations  for Determining  the  Active Ingredient  
96    
97   To assist prospective applicants in evaluating and demonstrating sameness, this section provides  
98   general  information on  active ingredient  sameness  issues that FDA generally intends to 
99   consider.     
100    
101   This guidance provides  recommendations on establishing the identity of an active ingredient to 
102   demonstrate  active ingredient  sameness.  As part of the identity of an active ingredient,  we 
103   generally consider the chemical form of  an active ingredient  to be the entire molecule, including 
104   those portions of the molecule that cause the drug to be an ester  or  salt.   For the evaluation of  
105   sameness, the identity  of  the active ingredient may also  encompass  noncovalent derivatives  (such 
106   as a complex, chelate,  or clathrate, with some limitations described below)  of the molecule  as  it 
107   exists in the  drug product  (i.e.,  in the finished dosage form20).   Instances where a complex,  
108   clathrate,  or chelate of an active ingredient may  or may  not  be part of the  chemical form of the  
109   active ingredient  are discussed  in section  III.C.  
110    
111   The same active ingredient  can  exist in  more than one  physical form, such  as polymorphs21  or  
112   co-crystals.22,23   Polymorphs are different crystalline forms of the same  active ingredient; they 
113   differ in internal solid-state structure but not in chemical structure.  This may include solvate  or 
114   hydrate  forms  (also known as pseudopolymorphs) and amorphous forms.  Co-crystals are 
115   crystalline materials composed of two or more  different moleculesthe active  ingredient  and co-
116   crystal formers  (coformers)in a defined stoichiometric ratio within the same crystal lattice that 
117   are associated by nonionic and noncovalent bonds.   Co-crystals  may  be viewed as a special case 
118   of solvates and hydrates, wherein the  coformer is not a solvent (including water)  and is typically 
119   nonvolatile.   In general,  differences  in physical  form will not prevent a prospective ANDA  
 
20  See  314.3(b) (definition of  drug  product).  
 
21  See the guidance for industry ANDAs: Pharmaceutical Solid Polymorphism: Chemistry, Manufacturing, and 
Controls Information  (July 2007) (Polymorph Guidance).  
 
22  See the guidance for industry  Regulatory Classification of Pharmaceutical Co-Crystals  (February 2018) (Co-
Crystals Guidance).  
 
23  We note that the Polymorph  Guidance uses the terms  drug substance  and active ingredient  interchangeably  
(Polymorph Guidance at page  1, footnote 4) and that the Co-Crystals Guidance uses  the term  active pharmaceutical  
ingredient  in  place of  active ingredient.   Though this guidance does distinguish between active ingredient and active  
pharmaceutical ingredient, the concepts articulated in the Polymorph Guidance and the Co-Crystal Guidance apply  
to the discussion here  on active ingredient, as defined and used throughout this document.  
4  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
120   applicant from demonstrating active ingredient sameness  between the active ingredient in the  
121   ANDA drug product and the RLD.24  
122    
123   B.   Active Ingredient  Sameness Considerations  in  Certain Drug Products  
124    
125   1.   Synthetic Peptides25  
126    
127   In general,  FDA considers any amino acid polymer composed of 40 or  fewer amino acids to be  a  
128   peptide  regulated under the FD&C Act, rather than a protein regulated under the Public Health 
129   Service Act.26   Currently,  FDA generally  considers  appropriate  for submission in an ANDA  
130   certain highly purified synthetic peptides that reference  a previously approved synthetic peptide  
131   drug product or  a  peptide of rDNA origin.27   The sameness of the active ingredient of a proposed 
132   generic synthetic peptide drug product (proposed generic synthetic peptide) can generally  be 
133   established through physicochemical characterization and biological evaluation.28   Although 
134   compendial standards may be available  for some peptides  for which an ANDA may be  
135   appropriate, it is recommended that applicants also perform comparative testing of the proposed 
136   generic synthetic peptide  to the RLD.29   For  example, FDA  recommends that ANDA applicants  
137   apply orthogonal analytical methods to characterize  the following properties:   
138    
139      Primary sequence and physicochemical properties  
140      Secondary structure  
141      Oligomer/aggregation states  
142      Biological activities (by in vitro or animal studies)30  
 
24  Polymorph Guidance at 6 (noting that over the years FDA has approved a number of ANDAs in which the active  
ingredient in the generic drug product had a different polymorphic  form  from the RLD (e.g., warfarin sodium,  
famotidine, and ranitidine), and that FDA also has approved some ANDAs in which the active ingredient in the  
generic drug product differed in solvate or  hydrate forms from the RLD (e.g., terazosin hydrochloride, ampicillin,  
and cefadroxil)).  
 
25  See the guidance for industry ANDAs for  Certain Highly Purified Synthetic Peptide Drug Products That Refer to 
Listed Drugs of rDNA Origin  (May 2021)  (Peptides Guidance).  
 
26  See, e.g., 21 CFR 600.3(h)(6) (defining protein)  and  85 FR 10057 (Feb.  21,  2020) (discussing FDAs  
interpretation  of the term  protein).  
 
27  See generally  Peptides Guidance.   
 
28  Id. Irrespective of establishing the sameness of the active ingredient, in some circumstances, peptide-related  
impurities may create the potential for differences in immunogenicity or may  otherwise affect the safety or  
effectiveness of a peptide drug product.  Id. at 3. Thus, the  type of application that should be submitted for a  
proposed synthetic peptide that refers to a peptide of rDNA origin depends largely on the type of data that would be  
necessary to evaluate the difference in impurities between  the proposed product and the previously approved 
product.  Id.  
 
29  See generally Peptides Guidance.  
 
 
5  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
143    
144   2.   Complex Mixtures   
145    
146   For  an  active ingredient  in a  complex mixture, FDA evaluates  all relevant data  in the ANDA  and 
147   other relevant scientific information  to determine whether  an active ingredient  of  a complex  
148   mixture  has been  adequately characterized for the purposes of  assessing  active ingredient  
149   sameness.  FDA recommends orthogonal  methods to characterize  components of the complex 
150   mixture and will consider the  totality of evidence  submitted to characterize the complex mixture.  
151    
152   In  the past, FDA has identified several different categories  of complex mixtures, for  example: (1) 
153   naturally derived mixtures  with  multiple  components  (e.g., fish oil, conjugated estrogens);  (2) 
154   synthetic  polymers  (e.g., sevelamer, colesevelam);  and (3) synthetic or semi-synthetic mixtures  
155   (e.g., pentosan polysulfate,  low-molecular weight  heparins).  In most instances, complex 
156   mixtures are treated as  a single active ingredient  because it is not possible to distinguish each and  
157   every  specific  constituent  component in the complex mixture  that is intended to furnish 
158   pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or  
159   prevention of disease, or  to affect the structure or  any function of the body of man or other  
160   animals.31   For  certain complex mixtures, however,  it may be  possible to identify each and every  
161   constituent  component in the mixture that is intended to furnish pharmacological activity or other  
162   direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the  
163   structure or  any function of the body of man or other animals.   For such complex mixtures, if 
164   there is more than one such constituent  component identified in the complex mixture, FDA 
165   generally  will  treat  each constituent  component  as  a separate active ingredient.   At the same 
166   time, FDA will generally not consider such mixtures to be fixed-combination drug products, 
167   since fixed-combination drug products  contain  separate active ingredients  that have been 
168   intentionally  combined together.32     
169    
170   To  support an active ingredient sameness determination for complex mixtures, we  recommend 
171   that ANDA applicants characterize constituent components  of the active ingredient in multiple  
172   batches of  both the proposed generic drug product  (test product)  and reference product  under  
173   similar conditions.  In addition,  to the extent a complex mixture contains  well-characterized  
 
30  Id.   We support  the  priniciple  of principles of the 3Rs, to reduce, refine, and replace animal use in testing when 
feasible. We encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is  
suitable, adequate,  validated, and feasible. We will consider if such an alternative method could be assessed for  
equivalency to an animal test method.  
 
31  For example,  Conjugated Estrogens  is treated as a single active ingredient. Conjugated Estrogens  active 
pharmaceutical ingredient  is obtained from a  natural source  and contains a mixture  of many steroidal  and 
nonsteroidal  components derived from pregnant mares urine.  Although it is not possible to distinguish each and 
every specific constituent component in the complex mixture that is intended to furnish pharmacological activity (or  
other direct effect in the diagnosis, cure, mitigation, treatment, or  prevention of disease,  or to affect the structure or  
any function of the  body of man or  other animals), the Conjugated Estrogens USP monograph defines  10  
representative individual steroidal components and the acceptable criteria in the labeled content of Conjugated 
Estrogens, which can be used  to support a demonstration of  active ingredient sameness. See  Draft Guidance on 
Conjugated Estrogens  (December 2014), available at:  https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm.   
When final, this guidance will represent FDAs current thinking on this topic.  
 
32  See 21 CFR 300.50.   
6  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
174   components,  the applicant  generally  should propose ranges  for each molecule in common based  
175   on the comparative testing, and provide a justification and/or rationale for acceptability of  any 
176   component differences  between  the test  product  and the reference product (i.e., the presence or 
177   absence of any component in the test  product compared to the  reference product).  
178    
179   C.   Characterization of  the Active Ingredient in the Drug Product   
180    
181   Typically, the chemical form of the active ingredient in the  RLD  is the same as the chemical  
182   form introduced at the start of drug product  manufacture.  However, in certain circumstances,  the 
183   active ingredient may undergo a change in chemical form during drug product manufacture such 
184   that the active ingredient is converted to a different chemical form through an intentional or  
185   obvious change  such that  the  converted  chemical form is present  as the active ingredient  in the  
186   RLD  drug product.  In such cases, it is the converted chemical form of the active ingredient,  as  
187   present in the finished dosage  form of the RLD, that  generally  should be used for comparison 
188   when demonstrating active ingredient sameness.33   
189    
190   When developing a  generic drug product, a prospective ANDA applicant  generally  should look 
191   to the  approved RLD labeling (e.g., the DOSAGE FORMS AND STRENGTHS,  
192   DESCRIPTION, CLINICAL PHARMACOLOGY,  and HOW SUPPLIED sections  of the  
193   labeling) to gain an understanding of the chemical form of the active ingredient in the  approved  
194   drug product.  However,  FDA is aware of certain  cases in which there may be ambiguity as to  
195   the chemical form of an  RLDs active ingredient compared to what is described in that RLDs  
196   labeling,34  which may, as  a scientific matter,  result in  additional investigations by and 
197   information from  the prospective ANDA applicant  (e.g., comparative testing and scientific  
198   rationale) to determine the chemical form of the  active ingredient.    
199    
200   The following  is a non-exhaustive  list of  examples  of active ingredient  characterization  for 
201   certain  drug products.  These  examples,  and our recommendations,  assume  there is no ambiguity 
202   in the RLD labeling as to  the chemical form of the  active ingredient, as  described above.   
203    
204   Examples:  
205    
 
33  If the chemical form (or forms) of the active ingredient do not appear in the drug product formulation in a  
consistent or known manner, then the  demonstration of active ingredient sameness may not be assisted by the  
general recommendations provided in this guidance, and a prospective ANDA applicant may contact the Office of  
Generic Drugs during drug product development.  See  section  III.D.  
 
34  See, e.g., Letter  from J. Woodcock to R.A. Dormer, RE: Vascepa (icosapent ethyl) Capsules (NDA 202057)  
Exclusivity Determination (May 31,  2016), at  2 (noting that  Lovazas labeling lists omega-3-acid ethyl esters as 
the active ingredient, which could suggest that Lovasas active ingredient is its omega-3-acid ethyl ester  
component but FDA defined the drugs active ingredient  as the entire [fish oil]  mixture  at the time of approval,  
which included ethyl esters of  eicosapentaenoic acid and  docosahexaenoic acid, among several other minor  
compounds)  (letter is part of the administrative and correspondence document record found at:  
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202057Orig1s000AdminCorresedt3.pdf); see also Letter  
from  Patrizia Cavazzoni  to Areta Kupchyk, Docket No. FDA-2016-P-1163 (May 26, 2021) (concluding that the  
active ingredient in Velphoro is ferric oxyhydroxide, not sucroferric  oxyhydroxide, as indicated on the approved  
drug product labeling)  (https://downloads.regulations.gov/FDA-2016-P-1163-0097/attachment_1.pdf).  
7  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
206      The portions of a molecule that cause a drug to be an ester or salt are considered to be 
207   part of the active ingredient.35   Therefore, the  salt or ester form  of the active 
208   ingredient in the proposed generic drug product  must  be the same as  that in the RLD  
209   it references.36   If the RLD labeling states that there are two or more salt or ester  
210   forms in the drug product  that  are known to be present in consistent and reproducible  
211   proportions,  then  the ANDA generally should contain the same salt or ester forms  in 
212   the same proportions  as  described in  the RLD  labeling.37  
213    
214      In general, a complex,  clathrate, or  chelate will be considered part of the active 
215   ingredient  only if  the complex, clathrate, or chelate  is intended to furnish 
216   pharmacological activity or other direct effect in the  diagnosis, cure, mitigation, 
217   treatment,  or prevention of disease  associated with the approved use of the drug 
218   product.38   
219    
220      In general, the active ingredient for  solid oral  dosage forms (e.g., orally 
o
221   disintegrating tablets)  will not  be considered to include a  complex-forming 
222   excipient so long as that  excipient  is not intended to furnish pharmacological  
223   activity or other direct effect in the  diagnosis, cure, mitigation, treatment,  or 
224   prevention of disease  associated with the approved use of the drug product.   
225   For example,  a weak complex formed with the active ingredient  solely to  
226   reduce  or slow  contact  of the active ingredient  with the tongue by a few  
227   seconds  to  mask an unpleasant taste  (taste-masking)   would generally not be  
228   considered part of the  active ingredient. This includes  ionic  polymers  (e.g.,  
229   polystyrene sulfonate) that form a complex  with the active ingredient.   Often  
230   these polymers  are employed  for the  purpose of taste-masking,  such as in 
231   risperidone orally disintegrating tablets, or  to modulate oral drug release.  
232   These polymers may  bind to the active ingredient  via an ionic interaction  
233   which is  poorly defined  (e.g., non-stoichiometric)  and  thus do  not constitute  a 
234   new  active ingredient salt form.  As  such,  these ionic  polymers  would 
235   generally not be  considered part of  the active ingredient.  
236    
237      In general,  carbohydrates (e.g., starch) used to form complexes with the active 
o
238   ingredient  in order to stabilize the active ingredient and facilitate  bulk 
239   processing of the  active ingredient  and  enable the manufacture  of the  drug 
240   product, would not  be considered  part of  the active ingredient.   In some cases,  
 
 
35  See, e.g.,  314.3  (defining pharmaceutical equivalents  as drug products in identical dosage forms and route(s)  
of administration that contain  identical amounts of the identical active drug ingredient, i.e., the same salt or ester of  
the same therapeutic moiety . . . ).  
 
36  See section 505(j)(2)(A)(ii) of the  FD&C Act.  
 
37  See generally id.  
 
38  A prospective applicant seeking assistance in developing a  product that may include a complex, clathrate, or  
chelate is encouraged to contact the Agency during  product development  via  the methods described in section III.D.  
of this guidance.  
8  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
241   carbohydrate complexes  are formed such that the entire complex is necessary  
242   to function in the intended therapeutic manner (e.g., ferumoxytol). In these  
243   instances, the complexed carbohydrate would be  considered to be part of the  
244   active ingredient.   
245    
246      In general,  clathrate forms do not constitute new chemical forms  that are 
o
247   considered in determining active ingredient sameness  because they are not  
248   intended to furnish pharmacological activity or other direct  effect in the  
249   diagnosis, cure, mitigation, treatment,  or prevention of disease  associated  with  
250   the approved use of the drug product.39   For example, although ethinyl  
251   estradiol (in drospirenone/ethinyl estradiol tablets) is stabilized by the  -
252   cyclodextrin as  a clathrate, this is not  considered a different  active ingredient  
253   from its non-clathrate form that appears in oral dosage forms.  
254    
255      In general,  the active ingredient in gadolinium  products  is considered to be  the 
o
256   entire complexed molecule of gadolinium. Gadolinium  products  used in 
257   medical  imaging require  that the intact gadolinium  complex does not  
258   dissociate to liberate free gadolinium ion, which is extremely toxic, and are  
259   designed to be tenacious complexes with minute liberation of free gadolinium  
260   ion.  In addition, the  entire complex impacts tissue distribution and thereby 
261   impacts its ability  to furnish its direct effect as an imaging agent  for diagnostic  
262   purposes.  
263    
264   D.   Additional Recommendations   
265    
266   Prospective ANDA  applicants  are encouraged  to  review product-specific guidances for generic 
267   drug development, which may include  recommendations on how to demonstrate active  
268   ingredient sameness.40   In those guidances, FDA may recommend specific testing for an  
269   applicant to demonstrate  active ingredient  sameness.  For example, FDA has  recommended  
270   pharmacodynamic data to support a demonstration of  active ingredient sameness, and also  may, 
271   in certain situations, recommend pharmacokinetic studies to adequately characterize an active 
272   ingredient.   
273    
 
39  For example, in a formulation of cetirizine hydrochloride chewable tablets, the active ingredient was formulated  
as a cyclodextrin clathrate to  mask the bitter taste of the cetirizine hydrochloride.   See Walsh, J. et al,  Playing hide  
and seek with poorly tasting  paediatric medicines: Do not forget the excipients,  Advanced Drug Delivery Reviews, 
Vol. 73, June  30,  2014, pp. 1433, available at:  
https://www.sciencedirect.com/science/article/pii/S0169409X14000349.  For this product,  cetirizine hydrochloride  
was regarded as  the chemical form of the active ingredient with  -cyclodextrin (Betadex)  constituting an inactive  
ingredient in the formulation.   See FDA Clinical Pharmacology Biopharmaceutics Review(s) and Printed Draft  
Labeling for Zyrtec Chewable Tablets  (NDA 021621),  dated March 16, 2004, available at:  
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.   
 
40  See, for example, the draft  product-specific guidance  for industry on enoxaparin sodium injection (October 2011),  
which includes equivalence of in vivo pharmacodynamic profile as one of the five  recommended criteria  for  
demonstrating active ingredient sameness of the test and reference products. When final, this guidance will represent  
FDAs current thinking on this topic. Product-specific guidances are available at:  
https://www.fda.gov/drugs/guidances-drugs/product-specific-guidances-generic-drug-development.  
9  Contains Nonbinding Recommendations  
Draft   Not for Implementation  
274   As scientific understanding and technology evolve, FDA  will continue to assist in and support  
275   the adequate characterization of an active ingredient so that prospective ANDA applicants may 
276   adequately demonstrate sameness.   In addition, prospective ANDA applicants may submit 
277   controlled correspondence41  to or request a pre-ANDA meeting42  with the Office of Generic 
278   Drugs  to discuss their proposed methods for demonstrating sameness.    
 
41  Controlled correspondence is  appropriate if an applicant  has a specific and targeted inquiry about the generic drug 
development process.   See the guidance for industry  Controlled Correspondence Related to Generic Drug 
Development  (December 2020) for information on the types  of inquiries accepted as controlled correspondence and 
on how to submit controlled correspondence to the Office  of Generic Drugs.      
 
42  A pre-ANDA meeting is appropriate for a prospective applicant seeking a dialogue with the Agency on a  
particular matter that would fall outside the scope of controlled correspondence.   See the  guidance for industry   
Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA  (October  2022) for 
information on the enhanced pathway for  discussions between FDA and a prospective applicant preparing to submit  
an ANDA for a complex product as defined in the guidance.   
10