ANDAs for Certain Highly 
Purified Synthetic Peptide 
Drug Products That Refer to 
Listed Drugs of rDNA 
Origin 
 
Guidance for Industry 
 
 
   
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
 
May 2021  
Generics 
   
ANDAs for Certain Highly 
Purified Synthetic Peptide 
Drug Products That Refer to 
Listed Drugs of rDNA 
Origin 
 
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  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
 
 May 2021 
Generics 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 3 
III.  SCIENTIFIC CONSIDERATIONS FOR ANDAS FOR PROPOSED GENERIC 
SYNTHETIC PEPTIDES ................................................................................................ 5 
A.  Active Ingredient Sameness .......................................................................................................... 5 
B.  Impurities ....................................................................................................................................... 6 
IV.  SUBMISSION OF ANDAS FOR PROPOSED GENERIC SYNTHETIC  
  PEPTIDES ......................................................................................................................... 9 
V.  REQUESTING ASSISTANCE FROM FDA ..................................................................... 10 
APPENDIX 1  RECOMMENDED EVALUATION OF PEPTIDE-RELATED 
IMPURITIES TO DETERMINE WHETHER SUBMISSION OF AN ANDA FOR A 
SYNTHETIC PEPTIDE THAT REFERENCES A PEPTIDE OF rDNA ORIGIN IS 
APPROPRIATE .......................................................................................................................... 12 
  Contains Nonbinding Recommendations 
 
 
 
ANDAs for Certain Highly Purified Synthetic Peptide Drug 
Products That Refer to Listed Drugs of rDNA Origin 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the 
title page.   
 
 
I.  INTRODUCTION  
This guidance is intended to assist potential applicants in determining when an application for a 
synthetic peptide drug product (synthetic peptide) that refers to a previously approved peptide 
drug product of recombinant deoxyribonucleic acid (rDNA) origin (peptide of rDNA origin) 
should be submitted as an abbreviated new drug application (ANDA) under section 505(j) of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) rather than as a new drug application (NDA) 
under section 505(b) of the FD&C Act.2  Specifically, this guidance provides recommendations 
for evaluating whether an ANDA submission is appropriate for a synthetic peptide that 
references any of the following five previously approved peptide drug products of rDNA origin: 
glucagon, liraglutide, nesiritide, teriparatide, and teduglutide.3 
 
Given the current state of technology for peptide synthesis and characterization, FDA believes it 
is now possible for an ANDA applicant to demonstrate that the active ingredient in a proposed 
 
 
1 This guidance has been prepared by the Office of Generic Drugs (OGD) in the Center for Drug Evaluation and 
Research (CDER) at the Food and Drug Administration.  
2  This guidance does not address ANDAs for peptides of rDNA origin.  Based on the types of data permitted to be 
submitted in an ANDA (see section 505(j)(2)(A) of the FD&C Act) and current scientific considerations, FDA does 
not expect that an ANDA could include sufficient evidence (e.g., clinical investigations to assess potential 
immunogenicity) for approval of a proposed peptide of rDNA origin at this time.  An applicant seeking approval of 
a proposed peptide of rDNA origin may file a 505(b)(2) application or a stand-alone NDA submitted under section 
505(b)(1) of the FD&C Act. 
3 This guidance does not address all studies and information that should be submitted in support of an ANDA for a 
synthetic peptide.  Applicants should check on the availability of other guidances, including product-specific 
guidances, for such recommendations.  Guidances relating to generic drugs can be found at 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs.  Product-specific 
guidances for generic drug development can be found athttps://www.fda.gov/drugs/guidances-drugs/product-
specific-guidances-generic-drug-development.  Also, a potential applicant may request information on a specific 
element of generic drug development via controlled correspondence or, for complex products such as peptides, may 
submit a request for a Pre-ANDA meeting. 
  1 
 
 
  Contains Nonbinding Recommendations 
 
 
 
generic synthetic peptide drug product (proposed generic synthetic peptide) is the same as the 
active ingredient in a previously approved peptide of rDNA origin.  For a synthetic peptide that 
is intended to be a duplicate4 of a previously approved peptide of rDNA origin, a 
determination of whether an application for the synthetic peptide should be submitted as an 
ANDA depends largely on its impurity profile as compared to the impurity profile for the peptide 
of rDNA origin.  Differences in impurities, particularly peptide-related impurities, may affect the 
safety or effectiveness of a peptide drug product as compared to the RLD. 
 
Submission of an ANDA for a proposed generic synthetic peptide for which the reference listed 
drug (RLD) is a peptide of rDNA origin generally would be appropriate if, among other things, 
the applicant can: 1) show that, for each peptide-related impurity that is found in both the 
proposed generic synthetic peptide and the RLD, the level of such impurity in the proposed 
generic synthetic peptide is the same as or lower than that found in the RLD; 2) show that the 
proposed generic synthetic peptide does not contain any new specified peptide-related impurity 
that is more than 0.5 percent of the drug substance;5 3) characterize each new specified peptide-
related impurity; and 4) justify for each new specified peptide-related impurity that is no more 
than 0.5 percent of the drug substance why the presence of such impurity would not be expected 
to affect the safety or effectiveness of the proposed generic synthetic peptide as compared to that 
of the RLD.6  This information will enable FDA to evaluate the purity of the proposed generic 
synthetic peptide and to confirm that it and the RLD of rDNA origin can be expected to have the 
same safety profile (including with respect to the risk of immunogenicity due to peptide-related 
impurities) when administered to patients under the conditions specified in the labeling. 
 
The  contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract.  This document is 
intended only to provide clarity to the public regarding existing requirements under the law. 
FDA guidance documents, including this guidance, should be viewed only as recommendations, 
unless specific regulatory or statutory requirements are cited.  The use of the word should in 
Agency guidance means that something is suggested or recommended, but not required. 
  
 
 
 
4 The term duplicate generally refers to a drug product that has the same active ingredient(s), dosage form, 
strength, route of administration, and conditions of use as a listed drug.  See the proposed rule entitled Abbreviated 
New Drug Application Regulations (54 FR 28872 at 28877, July 10, 1989).  
5 A new specified peptide-related impurity refers to an impurity that is present in the proposed generic synthetic 
peptide, but not in the RLD. 
6 For definitions of specified and unspecified impurities, see guidances for industry ANDAs: Impurities in Drug 
Substances and ANDAs: Impurities in Drug Products, and the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidances Impurities in New Drug Substances (ICH 
Q3A(R2)) and Impurities in New Drug Products (ICH Q3B(R2)). The guidances referenced in this document are 
available athttps://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs .  We update 
guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs 
guidance Web page athttps://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs. 
  2 
 
 
  Contains Nonbinding Recommendations 
 
 
 
II.  BACKGROUND 
 
FDA considers any alpha amino acid polymer composed of 40 or fewer amino acids to be a 
peptide, not a protein.  Glucagon, liraglutide, nesiritide, teriparatide, and teduglutide are 
peptides.  A peptide is regulated as a drug under the FD&C Act unless the peptide otherwise 
meets the statutory definition of a biological product (e.g., a peptide vaccine) and is therefore 
regulated under the Public Health Service Act.7   
 
In order for FDA to approve an ANDA, an applicant must demonstrate, among other things, that 
the proposed generic drug8 has the same active ingredient(s), conditions of use, dosage form, 
route of administration, strength, and (with certain permissible differences) labeling as the RLD, 
and is bioequivalent to its RLD.9  Additionally, FDA must find that the methods used in, and the 
facilities and controls used for, the manufacture, processing, and packing of the generic drug are 
adequate to assure and preserve its identity, strength, quality, and purity.10  FDA approval of an 
ANDA reflects an Agency determination that the proposed generic drug is therapeutically 
equivalent to its RLD.11 
 
In the past, analytical methods have not always been capable of adequately characterizing 
peptide products for submission in an ANDA.  However, given the current state of technology 
for peptide synthesis and characterization (e.g., advances in high resolution mass spectrometry, 
liquid chromatography, high-resolution multi-dimensional NMR), FDA now believes it is 
possible for an ANDA applicant to demonstrate that the active ingredient in a proposed generic 
 
 
7 For more information about terminology and regulatory authorities applied to amino acid polymers, see FDAs 
final rule, Definition of the Term Biological Product (85 FR 10057, February 21, 2020).  This final rule amends 
FDAs regulation that defines biological product to incorporate changes made by the Biologics Price Competition 
and Innovation Act of 2009 (BPCI Act) and the Further Consolidated Appropriations Act, 2020, and provides 
FDAs interpretation of the statutory term protein.  FDA interprets the statutory definition of biological product 
in section 351 of the Public Health Service Act such that any alpha amino acid polymer composed of 40 or fewer 
amino acids (i.e., a peptide) is outside the scope of the term protein. 
8 Throughout this guidance we use the term generic drug to refer to a new drug product described in an ANDA 
submitted under section 505(j) of the FD&C Act. 
9 See section 505(j)(2)(A) of the FD&C Act.  An applicant may submit a petition seeking permission to submit an 
ANDA for a change in route of administration, dosage form, strength, or one active ingredient in a fixed 
combination drug product. See 21 CFR 314.93.  
10 Section 505(j)(4) of the FD&C Act. 
11 Therapeutic equivalents are approved drug products that are pharmaceutical equivalents for which bioequivalence 
has been demonstrated, and that can be expected to have the same clinical effect and safety profile when 
administered to patients under the conditions specified in the labeling (21 CFR 314.3(b)).  Pharmaceutical 
equivalents are drug products in identical dosage forms and route(s) of administr(ation that contain identical 
amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the 
case of modified-release dosage forms that require a reservoir or overage or such forms as prefilled syringes where 
residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing 
period; do not necessarily contain the same inactive ingredients; and meet the identical compendial or other 
applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content 
uniformity, disintegration times, and/or dissolution rate. Id. 
  3 
 
 
  Contains Nonbinding Recommendations 
 
 
 
synthetic peptide is the same as the active ingredient in the RLD that is of rDNA origin, and 
demonstrate that such products are pharmaceutical equivalents.  
 
All ANDAs must contain a description of the composition, manufacture, and specifications of 
the drug substance and the drug product.12  An ANDA applicant is required to submit a full 
description of the drug substance including its physical and chemical characteristics and stability; 
the method of synthesis (or isolation) and purification of the drug substance; and the 
specifications necessary to ensure the identity, strength, quality, and purity of the drug substance 
and the bioavailability of the drug products made from the substance.13  To ensure purity, 
applicants should propose and justify appropriate limits on the impurities in their drug substances 
and drug product.14 
 
In reviewing an ANDA, FDA considers the types and amounts of impurities present in a 
proposed generic drug in comparison to its RLD.15  While certain differences in impurity profiles 
between a proposed generic drug and the RLD may be permissible, FDA evaluates whether a 
generic drug contains impurities at levels greater than those found in the RLD and whether the 
impurities, including new impurities, are otherwise justified to help ensure, among other things, 
that the generic drug does not pose a greater safety risk than the RLD. 
 
Whether a peptide is produced by a recombinant or synthetic process, impurities may result from 
the insertion, deletion, or modification of amino acid sequences or residues.  These impurities 
can be controlled in the synthetic process. At low levels, consistent with batch-to-batch 
variability, they generally pose minimal pharmacological or toxicological risks that would affect 
safety or effectiveness.  However, 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. Because of these concerns about the potential for 
immunogenicity for glucagon, liraglutide, nesiritide, teriparatide, and teduglutide, 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 
differences in impurities between the proposed product and the previously approved product.   
 
The recommendations for submission of an ANDA for the peptides covered by this guidance are 
designed primarily to help ensure that there is adequate information to assess the impurity profile 
 
 
12 21 CFR 314.94(a)(9) and 314.50(d)(1). 
13 21 CFR 314.94(a)(9)(i) and 314.50(d)(1)(i). 
14 FDA may refuse to receive an ANDA that is incomplete because it does not on its face contain information 
required under section 505(j) of the FD&C Act or 21 CFR 314.94, which includes a demonstration of the purity of 
the drug substance and drug product and information on the impurities and residues (21 CFR 314.101(d)(3) and 
314.94(a)(9) (requiring an ANDA to contain the information required under 314.50(d)(1)).  See also the guidance 
for industry ANDA Submissions  Refuse to Receive for Lack of Proper Justification of Impurity Limits. 
15 See, e.g., the guidances for industry: ANDAs: Impurities in Drug Substances and ANDAs: Impurities in Drug 
Products.  
  4 
 
 
  Contains Nonbinding Recommendations 
 
 
 
of the proposed generic product as compared to the RLD of rDNA origin, particularly with 
respect to the risk of immunogenicity due to peptide-related impurities. 
 
III.  SCIENTIFIC CONSIDERATIONS FOR ANDAS FOR PROPOSED GENERIC 
SYNTHETIC PEPTIDES 
 
A.  Active Ingredient Sameness 
 
A crucial factor in determining whether an ANDA meets the statutory requirements for approval 
is whether the active ingredient in the proposed generic drug is the same as that of the RLD.16    
The sameness of active ingredient in a proposed generic synthetic peptide can be established 
through physicochemical characterization, and biological evaluation such as comparative clinical 
pharmacokinetic (PK) and/or pharmacodynamic (PD) studies.  Although compendial standards 
may be available for some peptides covered by this guidance, comparative testing of the 
proposed generic synthetic peptide and RLD product is recommended, as applicable.17 ANDA 
applicants are encouraged to apply orthogonal analytical methods to characterize the following 
properties and other properties, as appropriate:  
 
  Primary sequence and physicochemical properties 
  Secondary structure 
  Oligomer/aggregation states 
  Biological activities (by in vitro or animal studies18) 
 
Where data demonstrate that the proposed synthetic peptides active ingredient is the same as 
the active ingredient in the RLD, whether an application should be submitted as an ANDA or as 
an application submitted pursuant to section 505(b)(2) of the FD&C Act may depend on the 
proposed products impurity profile, because differences in impurities may affect, among other 
things, the potential for immunogenicity.19   
 
 
 
16 Section 505(j)(2)(A)(ii)(I) of the FD&C Act.  Active ingredient is defined at 21 CFR 314.3(b). 
17 Because some properties, such as secondary structure, oligomer/aggregation states, and biological activity, may be 
affected by the formulation of the drug product, an applicant should compare and assess the formulation of the 
proposed generic and the RLD. 
18 FDA supports the principles of the 3Rs, to reduce, refine, and replace animal use in testing when feasible.  We 
encourage sponsors to consult with the Office of Generic Drugs (OGD) (see section V below) if it they wish to use a 
non-animal testing method they believe is suitable, adequate, validated, and feasible.  OGD will consider if such an 
alternative method could be assessed for equivalency to an animal test method.   
19 If an applicant has questions about submission of an application through the 505(b)(2) pathway, the applicant 
should contact the appropriate Office of New Drugs review division for assistance.  For more information on 
contacting the appropriate Office of New Drugs review division for a possible 505(b)(2) application, see FDAs 
Enhanced Communication web page athttps://www.fda.gov/industry/prescription-drug-user-fee-
amendments/enhanced-communication. 
 
  5 
 
 
  Contains Nonbinding Recommendations 
 
 
 
B.  Impurities 
 
In reviewing an ANDA, FDA considers the types and amounts of impurities present in a 
proposed generic drug in comparison to its RLD.20  In general, a proposed generic synthetic 
peptide should not contain impurities at levels greater than those found in the RLD.  Any 
impurities, including new impurities, should be justified to help ensure, among other things, that 
the generic drug does not pose a greater safety risk, including with respect to immunogenicity, 
than the RLD.   
 
Regardless of whether a peptide drug product is produced by a recombinant or synthetic process, 
it may contain impurities resulting from degradation during product storage or from the method 
of producing the peptide.  In general, impurities that result from degradation during storage of 
the product, rather than from how the peptide is produced, would be expected to be the same 
where the RLD and proposed generic synthetic peptide have the same active ingredient, 
generally the same inactive ingredients21, and the same labeled storage conditions.  FDA intends 
to generally consider the sameness of active ingredient, inactive ingredients, storage conditions, 
and impurities that result from degradation in its evaluation of an ANDA for a peptide drug 
product in the same manner it does for ANDAs for non-peptide drug products. 
 
Impurities may also occur as a result of the specific process used to produce the peptide.  The 
impurities produced by rDNA technology can be divided into three categories: 
 
  Peptide-related impurities  
  Host cell-related impurities 
  Other (non-peptide-related) impurities 
 
Peptide-related impurities include amino acid sequences related to, but different from, that of the 
active ingredient, as a result of insertion, deletion, or other modifications (e.g., oxidation or 
glycosylation) to the amino acid sequence, and residues of the peptide.  Host cell-related 
impurities include host cell DNA and host cell proteins.  Other impurities include residual 
 
 
20 See, e.g., the guidances for industry ANDAs: Impurities in Drug Substances and ANDAs: Impurities in Drug 
Products.  
21 At present, approved drug products for the five peptides covered by this guidance are all intended for parenteral 
use.  A parenteral drug product generally must contain the same inactive ingredients in the same concentration as the 
reference listed product, although an applicant may seek approval of a drug product that differs from the RLD in 
preservative, buffer, or antioxidant provided that the applicant identifies and characterizes the differences and 
provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug 
product.  See 21 CFR 314.94(a)(9)(iii); see also guidance for industry ANDA SubmissionsRefuse-to-Receive 
Standards.  
  6 
 
 
  Contains Nonbinding Recommendations 
 
 
 
solvents, reagents, and metals.22  Peptide-related impurities and other (non-host cell-related) 
impurities may result from the production of a peptide by both recombinant and synthetic 
processes. Host cell-related impurities, however, occur only in rDNA-origin peptide drug 
products.  
 
Differences between the peptide-related impurities in a proposed generic synthetic peptide and 
those in an RLD of rDNA origin could produce different impurity profiles, which could 
adversely affect the safety or effectiveness of a proposed generic synthetic peptide product, if 
uncontrolled.  The peptide-related impurity profiles for approved peptides of rDNA origin have 
been well characterized for the peptides covered by this guidance.  Therefore, it may be feasible 
to compare the peptide-related impurity profile of the RLD to the peptide-related impurity profile 
of the proposed generic synthetic peptide.  To enable such comparison, applicants should 
complete the following two actions: 
 
1.  Verify that for each peptide-related impurity found both in the proposed generic synthetic 
peptide and in the RLD, the level of this peptide-related impurity in the proposed generic 
synthetic peptide is not more than the level found in the RLD. Applicants may 
accomplish this verification by, for example, adjusting the synthetic route or purification 
strategies. 
 
2.  Identify and reduce or mitigate risks related to peptide-related impurities. Because of (1) 
the peptide-related impurities that could be present in the peptides covered by this 
guidance and (2) advances in analytical chemistry, synthetic peptide manufacturing and 
purification technology, and biological assays,23 it would generally be appropriate for 
applicants to submit an ANDA for one of the peptides covered by this guidance if, among 
other things, for any new peptide-related impurity, the level for the proposed generic 
synthetic peptide is no more than 0.5 percent of the drug substance. A new peptide-
related impurity level higher than 0.5 percent of the drug substance could raise concerns 
about the potential risk of immunogenicity; as a result, it may not be possible to 
adequately address the larger variance through the ANDA process (e.g., if the risk of 
immunogenicity requires a clinical investigation). 
 
Accordingly, FDA believes that submitting an ANDA for one of the peptides covered by this 
guidance would be generally appropriate if, among other things, for any new specified peptide-
 
 
22 The ICH guidance Q3C Impurities: Residual Solvents recommends acceptable amounts for residual solvents in 
pharmaceuticals for the safety of the patient.  The ICH guidance Q3D Elemental Impurities presents a process to 
assess and control elemental impurities in the drug product using the principles of risk management described in 
ICH Q9.  This process provides a platform for developing a risk-based control strategy to limit elemental impurities 
in the drug product.  
23 Because peptide-related and other impurities come from the starting materials, reagents, solvents, and the process 
used, an ANDA applicant should be able to determine what impurities might occur and could take steps (e.g., by 
following FDA and ICH guidances) to ensure that the impurity profile of a proposed synthetic peptide is acceptable. 
  7 
 
 
  Contains Nonbinding Recommendations 
 
 
 
related impurity, the level for the proposed generic synthetic peptide is no more than 0.5 percent 
of the drug substance.   
 
A new specified peptide-related impurity level of no more than 0.5 percent of the drug substance 
for purposes of evaluating the appropriateness of submission as an ANDA is consistent with the 
small amount of unspecified peptide-related impurities observed in finished peptide drug 
products due to batch-to-batch variability, which occurs regardless of whether the peptide is 
produced by a recombinant or synthetic process.  This flexibility is, however, subject to 
subsequent scientific review upon the submission of an ANDA and FDA may ask the ANDA 
applicant to further reduce the level of a specified peptide-related impurity depending on the 
risks associated with a particular impurity as well as with the proposed drug product.    
 
For each new specified peptide-related impurity, the ANDA applicant should characterize the 
impurity.  Further, the ANDA applicant should provide justification for why the presence of such 
impurity would not be expected to affect the safety of the proposed generic synthetic peptide or 
its effectiveness as compared to that of the RLD, including with respect to the risk of 
immunogenicity related to peptide-related impurities.  This justification should take into 
consideration, among other things, the identity and amount of an impurity, the impuritys impact 
on the physicochemical and biological properties of the peptide, and the potential risks specific 
to the peptide.24  The justification should include data showing that any differences in impurities 
between the proposed generic synthetic peptide and the RLD do not modify each of the 
following: the physicochemical properties, biological activity, or immunogenicity risk of the 
product.  Such data should demonstrate for each new impurity that the impurity does not contain 
sequences that have an increased affinity for major histocompatibility complex (MHC), known 
as T-cell epitopes.  Further, the data should demonstrate that the proposed generic synthetic 
peptide does not increase the aggregation propensity or the nature of the aggregates formed, 
especially under stress conditions, and does not contain impurities or contaminants that produce 
a greater or distinct stimulation of innate immune activity as compared to the RLD. Prospective 
ANDA applicants should contact the Office of Generic Drugs (OGD) if they have specific 
questions regarding what information should be provided.25 Based on the information provided, 
FDA may recommend that additional non-clinical immunogenicity evaluations be completed for 
the proposed generic synthetic peptide. 
 
 
 
 
 
 
 
24 For example, where a peptide drug has a sequence identical to part of a human endogenous protein, and some 
function(s) of the protein is non-redundant, an immunogenic response that leads to antibodies directed against the 
endogenous protein could have far reaching consequences. 
25 See section V of this guidance for information about requesting assistance from OGD. 
  8 
 
 
  Contains Nonbinding Recommendations 
 
 
 
IV.  SUBMISSION OF ANDAS FOR PROPOSED GENERIC SYNTHETIC PEPTIDES 
    
The submission of an ANDA for a synthetic glucagon, liraglutide, nesiritide, teriparatide, or 
teduglutide drug product that references an approved peptide of rDNA origin would be generally 
appropriate if the statutory and regulatory requirements for an ANDA are met and, with respect 
to active ingredient sameness and peptide-related impurities:26   
 
  The proposed generic synthetic peptide is characterized to show the sameness of the 
active ingredient to that of the RLD with respect to the following properties: 
 
  Primary sequence and physicochemical properties, 
  Secondary structure, 
  Oligomer/aggregation states, and  
  Biological activity/function (by in vitro or animal studies); 
  
  For each peptide-related impurity that is found in both the proposed generic synthetic 
peptide and the RLD, the level of such impurity in the proposed product is the same as or 
lower than that found in the RLD;  
 
  The proposed generic synthetic peptide does not contain any new specified peptide-
related impurity (i.e., an impurity that is not also present in the RLD) that is more than 
the recommended threshold for a new peptide-related impurity (i.e., 0.5 percent of the 
drug substance);27 and 
 
  For any new specified peptide-related impurity that is no more than 0.5 percent of the 
drug substance, the applicant has characterized the impurity (e.g., the amino acid 
sequence and structure) and provided a justification for why, for each such impurity, the 
presence of such impurity would not be expected to affect the safety of the proposed 
generic synthetic peptide or its effectiveness as compared to that of the RLD, including 
with respect to the risk of immunogenicity. 
 
 
 
26 Determinations as to whether FDA will receive for substantive review or approve an ANDA will be made 
subsequent to submission. Applicants are encouraged to review the following guidances for industry for more 
information: ANDA Submissions  Content and Format of Abbreviated New Drug Applications, ANDA Submissions 
 Refuse-to-Receive Standards, ANDA Submissions  Refuse-to-Receive for Lack of Justification of Impurity Limits,  
and Immunogenicity Assessment for Therapeutic Protein Products (which notes that [a]lthough this guidance 
focuses on therapeutic protein products, the scientific principles may also apply to ... peptides). 
27 If the proposed synthetic peptide product contains a new specified peptide-related impurity that is more than 
0.5%, the applicant should consider following the procedures outlined in section V of this guidance for contacting 
the OGD to discuss a suitable pathway. 
  9 
 
 
  Contains Nonbinding Recommendations 
 
 
 
For such applications, FDA recommends that applicants apply sensitive and high resolution 
analytical procedures (e.g., UHPLC-HRMS)28 to detect and characterize peptide-related 
impurities in a proposed generic synthetic peptide in comparison to the RLD.  In general, for the 
peptides covered by this guidance, applicants should identify29 each peptide-related impurity that 
is 0.10 percent of the drug substance or greater.30  Depending on the potential immunogenicity 
risk of a particular product, applicants may be asked to also identify peptide-related impurities 
present at levels below this threshold.   
 
Also for each new specified impurity, the applicant should provide justification, including data, 
to show that any differences in impurity profiles between the proposed generic synthetic peptide 
and the RLD do not modify each of the following: the physicochemical properties, biological 
activity, or immunogenicity risk of the product.31  For example, such data should demonstrate 
that each new impurity does not contain sequences that have an increased affinity for MHC, 
known as T-cell epitopes, and that the proposed generic synthetic peptide does not alter the 
innate immune activity.  
 
FDA may recommend conducting additional comparative studies that can be submitted under 
section 505(j) of the FD&C Act (e.g., in vitro, in vivo animal, clinical PK/PD equivalence), as 
appropriate, to assess whether a proposed generic synthetic peptide meets relevant approval 
standards, including that the methods used in, and 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. 
 
If it is necessary to conduct clinical studies to independently establish the safety or effectiveness 
of a proposed synthetic peptide, submission of an application under section 505(b) of the FD&C 
Act would be necessary.  Once an application for a synthetic peptide product has been approved 
under section 505(c) of the FD&C Act, subsequent applications for that synthetic peptide product 
may be submitted as ANDAs.  
 
V.  REQUESTING ASSISTANCE FROM FDA 
 
An applicant developing a proposed generic synthetic peptide for one of the peptides covered by 
this guidance may contact OGD to confirm whether the application may be submitted as an 
 
 
28 See, e.g., Zeng K, et al., Liquid Chromatography-High Resolution Mass Spectrometry for Peptide Drug Quality 
Control, AAPS J, 17(3), 643-51 (2015). 
29 For each peptide-related impurity that is 0.10%-0.5% of the drug substance, identify means characterize the 
structure of the peptide-related impurity. 
30 Identification of impurities that are 0.10% to 0.5% of the drug substance for proposed generic synthetic peptides 
supports FDAs assessment of the risk of immunogenicity. 
31 Appendix 1 illustrates FDAs recommendations for evaluating peptide-related impurities to determine whether 
submission of an ANDA for a synthetic peptide that references a peptide of rDNA origin is appropriate. 
  10 
 
 
  Contains Nonbinding Recommendations 
 
 
 
ANDA.  An applicant may submit a controlled correspondence32 to or request a pre-ANDA 
meeting with OGD.  Controlled correspondence is appropriate if an applicant has a specific and 
targeted inquiry about the generic drug development process.  The pre-ANDA meeting is 
appropriate for a prospective applicant seeking a dialogue with the Agency on a particular matter 
outside the scope of controlled correspondence.  Requests for pre-ANDA meetings should be 
sent electronically through the CDER Direct NextGen Collaboration Portal.33 
   
 
 
32 See the guidance for industry Controlled Correspondence Related to Generic Drug Development for information 
on the types of inquiries accepted as controlled correspondence and submission of controlled correspondence to 
OGD. 
33 The CDER Direct NextGen Collaboration Portal may be accessed at 
https://edm.fda.gov/EDMIDPLogin/welcome?response_type=code&client_id=0oa1as7rb2poiYTch297&scope=ope
nid%20profile&state=1802935594_1580919665259&redirect_uri=https%3A%2F%2Fedm.fda.gov%2Foidcclient%
2Fedmrp. 
  11 
 
 
  Contains Nonbinding Recommendations 
 
 
 
APPENDIX 1  RECOMMENDED EVALUATION OF PEPTIDE-RELATED 
IMPURITIES TO DETERMINE WHETHER SUBMISSION OF AN ANDA FOR A 
SYNTHETIC PEPTIDE THAT REFERENCES A PEPTIDE OF rDNA ORIGIN IS 
APPROPRIATE 
 
 
 
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