Control of Nitrosamine 
Impurities in Human Drugs 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
February 2021 
Pharmaceutical Quality/ Manufacturing Standards/ 
Current Good Manufacturing Practice (CGMP) 
 
Revision 1 
   
  Control of Nitrosamine 
Impurities in Human Drugs 
 
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) 
 
 
February 2021 
Pharmaceutical Quality/ Manufacturing Standards/ 
Current Good Manufacturing Practice (CGMP) 
 
Revision 1  Preface 
 
FDA is implementing  this guidance without prior public  comment because the Agency has 
determined that prior public  participation  is not feasible or appropriate (see Section 
701(h)(1)(C)(i) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR 
10.115(g)(2) and (g)(3)). FDA made this determination  because of the importance of providing 
timely information  to manufacturers regarding risk assessments, testing, and other appropriate 
actions they should take to reduce and mitigate nitrosamine impurities  in active pharmaceutical 
ingredients (APIs)1 and drug products. This guidance document is being implemented 
immediately,  but it remains subject to comment in accordance with the Agencys good guidance 
practices. 
 
Comments may be submitted at any time for Agency consideration. Submit  written comments to 
the Dockets Management Staff (HFA-305), Food and Drug Administration,  5630 Fishers Lane, 
Rm. 1061, Rockville,  MD 20852. Submit  electronic comments to https://www.regulations.gov.  All 
comments should be identified  with the docket number FDA-2020-D-1530 and complete title of 
the guidance in the request. 
                                              
1 The term API used throughout this guidance should be interpreted to mean drug substance, the active ingredient in 
a drug product. See 21 CFR 210.3(b)(7) (defining active ingredient) and 314.3 (defining drug substance).  Contains Nonbinding Recommendations 
 
  TABLE OF CONTENTS   
 
I.  INTRODUCTION ...................................................................................................... 1 
II.  BACKGROUND ........................................................................................................ 2 
A.  Nitrosamine Impurities ................................................................................................. 3 
B.  General Root Causes for the Presence of Nitrosamine Impurities in APIs.......................... 5 
C.  Nitrosamine Impurities in Drug Products From Sources Other Than API Contamination.. 9 
III.  RECOMMENDATIONS............................................................................................ 9 
A.  Acceptable Intake Limits ..............................................................................................10 
B.   Recommendations to API Manufacturers ......................................................................12 
C.   Recommendations to Drug Product Manufacturers ........................................................14 
IV.   MAINTAINING THE DRUG SUPPLY................................................................... 15 
V.   REPORTING CHANGES TO FDA......................................................................... 16 
A.  Recommended Timeline for Risk Assessment, Confirmatory Testing, and Submission of 
Required Changes........................................................................................................16 
APPENDIX A. ADDITIONAL RESOURCES ...................................................................... 1 
APPENDIX B. FDA DETERMINATION OF THE ACCEPTABLE INTAKE.................... 1 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
Control of Nitrosamine  Impurities  in Human  Drugs 
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 recommends steps manufacturers of APIs and drug products should take to detect 
and prevent unacceptable levels of nitrosamine2 impurities  in pharmaceutical products.3 The 
guidance also describes conditions  that may introduce nitrosamine impurities.  The recent 
unexpected finding  of nitrosamine  impurities,  which are probable human carcinogens, in drugs 
such as angiotensin  II receptor blockers (ARBs),4 ranitidine,5  nizatidine,6  and metformin,7 has 
made clear the need for a risk assessment strategy for potential nitrosamines  in any pharmaceutical 
product at risk for their presence. This document revises the guidance of the same title issued in 
September 2020. This revision extends the time period for preparing initial  risk assessments to 
March 31, 2021 (i.e., within 7 months of publication  of the original  guidance). 
 
                                              
1 This guidance has been prepared by the Office of Pharmaceutical Quality (OPQ) in the Center for Drug Evaluation 
and Research (CDER) at the Food and Drug Administration. You may submit comments on this guidance at any 
time. Submit comments to Docket No. FDA-2020-D-1530 (available at https:/regulations.gov/docket/FDA-2020-D-
1530) (see the instructions for submitting comments in the docket). 
2 The term nitrosamine as used in this guidance means N-nitrosamine. 
3 New drug application (NDA) and abbreviated new drug application (ANDA) holders or sponsors, drug master file 
(DMF) holders, and owners of marketed products that are not the subject of approved NDAs or ANDAs (such as 
compounded products or products marketed under an over-the-counter (OTC) drug monograph) who are not also the 
manufacturer of the drug products and APIs should work with their contract manufacturers to take the steps 
recommended in this guidance. This applies to drug products currently available on the U.S. market as well as those 
with pending applications. 
4 The first nitrosamine detected in ARBs was N-nitrosodimethylamine (NDMA), which is a genotoxic and 
carcinogenic agent in animals and is classified as probably carcinogenic to humans (Class 2A carcinogen) by the 
World Health Organizations (WHOs) International Agency for Research on Cancer (IARC). Other nitrosamines, 
including N-nitrosodiethylamine (NDEA) and N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), have also been 
detected in various ARB products.  
5 https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-
ranitidine 
6 See footnote 5. 
7 https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-metformin 
 
  1  Contains Nonbinding Recommendations 
 
The discovery of nitrosamines  in some types of drug products led FDA and other international 
regulators to conduct a detailed analysis of these impurities  in affected APIs and drug products.8,9 
Based on the Agencys current understanding,  this guidance discusses potential root causes of 
nitrosamine  formation and advises API and drug product manufacturers that they should (1) 
conduct risk assessments of their approved or marketed products and products with pending 
applications,  and (2) take appropriate actions to reduce or prevent the presence of nitrosamines  in 
APIs and drug products. 
 
Although nitrosamine  impurities  have been found in only some drug products, and batches of those 
products have been recalled when there were unacceptable levels10 of these impurities,  nitrosamine 
impurities  might exist in other APIs and drug products due to use of vulnerable processes and 
materials that may produce nitrosamine impurities. Therefore, the recommendations  made in this 
guidance apply to all chemically  synthesized APIs. They also apply to drug products containing 
chemically  synthesized APIs and to drug products at risk due to other factors described in this 
guidance (see sections II.B and C), and not just to the drug products that have been identified  in 
FDA announcements. 
 
In general, FDAs guidance documents 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 cited.  The use of the 
word should in Agency guidances means that something is suggested or recommended, but not 
required. 
 
II.  BACKGROUND 
 
FDA has been investigating  the presence of nitrosamine  impurities  in certain drug products. Since 
2018, several drug products including  ARBs, ranitidine,  nizatidine,  and metformin have been 
found to contain unacceptable levels of nitrosamines. 
 
In June 2018, FDA was informed of the presence of an impurity  identified  as N-
nitrosodimethylamine  (NDMA) in the ARB valsartan.11 Through investigation,  the Agency 
determined that numerous lots of valsartan and a few other ARB drug products from different 
manufacturers contained unacceptable levels of nitrosamines. The drug product manufacturers 
                                              
8 Other regulators with which FDA has been collaborating include the European Medicines Agency (EMA), 
European Directorate for the Quality of Medicines and Healthcare (EDQM), Health Canada (HC), Therapeutic 
Goods Administration (TGA, Australia), Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical 
Devices Agency (PMDA/MHLW, Japan), Health Sciences Authority, Singapore (HSA, Singapore), and Swissmedic 
(Switzerland). 
9 FDAs validated laboratory methods used in assaying nitrosamine impurities in various drugs as well as the 
analytical results for various drugs and batches are available at https://www.fda.gov/news-events/press-
announcements/fda-statement-fdas-ongoing-investigation-valsartan-impurities-and-recalls-and-update-fdas-current, 
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-
ranitidine, and https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-
metformin. 
10 See Table 1 in section III.A. of this guidance. 
11 https://www.fda.gov/news-events/press-announcements/fda-statement-fdas-ongoing-investigation-valsartan-
impurities-and-recalls-and-update-fdas-current 
 
  2  Contains Nonbinding Recommendations 
 
voluntarily  recalled the affected batches of these drug products,12 which led to a drug shortage in 
some of the affected products.13 In addition,  FDA evaluated processes that use common amines in 
API synthesis and learned that common synthetic pathways could also introduce other types of 
nitrosamine  impurities  besides NDMA. 
 
In September 2019, FDA learned that some common heartburn products (ranitidine,  commonly 
known as Zantac, and nizatidine,  commonly  known as Axid) contained unacceptable levels of 
NDMA.14 FDA recommended that manufacturers voluntarily  recall ranitidine  and nizatidine 
products with NDMA levels above what the Agency considers acceptable.15,16 Recently, 
preliminary  findings  from FDA stability  testing raised concerns that NDMA levels in some 
ranitidine  products stored at room temperature can increase with time to unacceptable levels. 
FDAs preliminary  results using accelerated stability  testing demonstrated that elevated levels of 
NDMA were measured in all products after 2 weeks. FDAs testing suggests that NDMA levels 
increase with storage time. On April 1, 2020, FDA requested that all ranitidine  products be 
withdrawn from the U.S. market. 
 
In December 2019, FDA became aware that some metformin diabetes medicines in other countries 
were reported to have NDMA. In light of this information,  FDA acquired samples of metformin to 
test for NDMA. By February 2020, the Agency had identified  NDMA in some samples but did not 
find levels exceeding the acceptable intake limit.  In May 2020, further FDA testing revealed that 
certain lots of metformin extended-release formulation  contained NDMA above the Agencys 
recommended acceptable intake limit.  Based on that testing, FDA requested that identified 
applicants voluntarily  recall these lots of the extended-release metformin. FDA continues to 
investigate possible NDMA impurities  in metformin and other drug products and will advise 
companies on appropriate action. 
 
Because the nitrosamine impurity  issue extends beyond the U.S. drug supply, FDA and other 
regulatory authorities have partnered to share information,  coordinate inspection efforts, 
communicate effective analytical methods to detect and identify various nitrosamines,  and to 
develop rapid solutions  to ensure the safety and quality  of the drug supply. 
 
A.  Nitrosamine Impurities  
 
The term nitrosamine describes a class of compounds having the chemical structure of a nitroso 
group bonded to an amine (R1N(-R2)-N=O), as shown in Figure 1. The compounds can form by a 
                                              
12 For a list of recalled products, see FDAs Recalls, Market Withdrawals, & Safety Alerts web page at 
https://www.fda.gov/node/360167. 
13 See FDAs public web page on drug shortages at https://www.fda.gov/drugs/drug-safety-and-availability/drug-
shortages and FDAs list of recalled ARB products at https://www.fda.gov/drugs/drug-safety-and-
availability/search-list-recalled-angiotensin-ii-receptor-blockers-arbs-including-valsartan-losartan-and. 
14 https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-
ranitidine 
15 https://www.fda.gov/news-events/press-announcements/statement-new-testing-results-including-low-levels-
impurities-ranitidine-drugs 
16 https://www.fda.gov/news-events/press-announcements/fda-statement-fdas-ongoing-investigation-valsartan-
impurities-and-recalls-and-update-fdas-current 
  3  Contains Nonbinding Recommendations 
 
nitrosating  reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid 
(nitrite salts under acidic conditions). 
 
Figure 1. Representative Reaction to Form Nitrosamines  
 
H
R R
1 HNO2 -HX 1
N H R1 N N O X N N O
N O
R R
2 2
R
2  
 
FDA has identified  seven nitrosamine impurities  that theoretically  could be present in drug 
products: NDMA, N-nitrosodiethylamine  (NDEA), N-nitroso-N-methyl-4-aminobutanoic  acid 
(NMBA), N-nitrosoisopropylethyl  amine (NIPEA), N-nitrosodiisopropylamine  (NDIPA), N-
nitrosodibutylamine  (NDBA), and N-nitrosomethylphenylamine  (NMPA) (Figure 2). Five of them 
(NDMA, NDEA, NMBA, NIPEA, and NMPA) have actually been detected in drug substances or 
drug products. 
 
Figure 2. Chemical Structures of Seven Potential Nitrosamine Impurities in APIs and Drug 
Products 
 
N N N N N
N O
O O
N-Nitrosodimethylamine N-Nitrosodiethylamine N-Nitrosomethylphenylamine 
(NDMA) (NDEA) (NMPA)  
 
N N N N
O O
N-Nitrosodiisopropylamine N-Nitrosoisopropylethylamine
(NDIPA) (NIPEA)  
 
O
OH
N N
N
O
N
O
N-Nitrosodibutylamine N-Nitroso-N-methyl-4-aminobutyric Acid 
(NDBA) (NMBA)  
  4  Contains Nonbinding Recommendations 
 
Nitrosamine compounds are potent genotoxic agents in several animal species and some are 
classified as probable or possible17 human carcinogens by the International  Agency for Research 
on Cancer (IARC).18 They are referred to as cohort of concern compounds in the ICH 
guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities 
in Pharmaceuticals To Limit Potential Carcinogenic Risk (March 2018).19 The guidance 
recommends control of any known mutagenic carcinogen, such as nitroso-compounds,  at or 
below a level such that there would be a negligible  human cancer risk associated with the 
exposure to potentially  mutagenic impurities.  Following  the discovery of nitrosamine 
contaminants in ARBs, FDA published  interim acceptable limits  for these impurities.20  FDA 
recommended that manufacturers take action to quantify nitrosamine levels in their drugs and to 
reduce or remove these impurities  when above the interim limit;  FDA has used the interim limits 
to guide immediate  decision-making  for additional  evaluation and product recalls21 while 
balancing the risks of potential  long-term carcinogen exposure with disruption  to clinical 
management of patients. 
 
B.  General Root Causes for the Presence of Nitrosamine Impurities in APIs 
 
Recent information  gathered by FDA suggests several general root causes of the presence of 
nitrosamine  impurities  in APIs: 
 
1.  General Conditions That Lead to Nitrosamine Formation  
 
Formation of nitrosamines  is possible in the presence of secondary, tertiary, or quaternary amines22 
and nitrite salts23 under acidic reaction conditions.  Under these conditions,  nitrite salts may form 
nitrous acid, which can react with an amine to form a nitrosamine  (see Figure 1). There is a greater 
risk of nitrosamine  formation if nitrous acid is used to quench residual azide (a reagent commonly 
used in tetrazole ring formation or introduction  of azide functional group into a molecule) in the 
presence of precursor amines. 
 
Nitrites used as reagents in one step can carry over into subsequent steps, despite purification 
operations, and react with amines to generate nitrosamine impurities.  Therefore, whenever nitrite 
salts are present, carryover into subsequent steps cannot be ruled out. In general, processes that use 
nitrites in the presence of secondary, tertiary, or quaternary amines are at risk of generating 
nitrosamine  impurities. 
 
                                              
17 NDBA is classified as possibly carcinogenic (2B) by IARC. 
18 https://monographs.iarc.fr/list-of-classifications 
19 The Agency updates guidances periodically. For the most recent version of a guidance, check the FDA guidance 
web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
20 See the 2/28/2019 announcement at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-
press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan. 
21 https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-
ranitidine 
22 Secondary and tertiary amines may be present as impurities or degradants of quaternary ammonium salts. 
23 Secondary, tertiary, and quaternary amines and nitrite also can be called nitrosamine precursors. 
 
  5  Contains Nonbinding Recommendations 
 
2.  Sources of Secondary, Tertiary, and Quaternary Amines That Can Form 
Nitrosamines 
 
Amines may be present in a manufacturing process for a variety of reasons. The API (or API 
degradants), intermediates,  or starting materials may contain secondary or tertiary amine functional 
groups. Tertiary and quaternary amines may also be added intentionally  as reagents or catalysts. 
All of these types of amines can react with nitrous acid or other nitrosating  agents to form 
nitrosamines.24,25,26 
 
Amide solvents, which are susceptible to degradation under certain reaction conditions,  are another 
source of secondary amines. For example, under high reaction temperatures for an extended 
reaction period, N,N-dimethylformamide  can degrade into dimethylamine,  which can react with 
nitrous acid to form NDMA (see Figure 3). N-methylpyrrolidone,  N,N-dimethylacetamide,  and 
N,N-diethylacetamide  also have similar degradation pathways to form secondary amines that can 
react with nitrous acid to form nitrosamine impurities.  Secondary amines could also be present as 
impurities  in amide solvents. For example, dimethylamine,  which can react with nitrous acid to 
form NDMA, may exist as an impurity  in N,N-dimethylformamide. 
 
Figure 3. Formation of NDMA From N,N-Dimethylformamide 
 
O
C N H+
NH + NaNO2 N N
H
Sodium Nitrite
O
Dimethylformamide Dimethylamine N-Nitrosodimethylamine 
Tertiary and quaternary amines used as reagents in the synthesis of APIs may contain other amine 
impurities.  Tertiary amines, such as triethylamine,  have been shown to contain low levels of other 
secondary amines (such as dipropylamine  and isopropylethylamine).  Secondary and tertiary 
amines may be present as impurities  or degradants formed by dealkylation  of quaternary amines. 
For example, a common phase-transfer catalyst, tetrabutylammonium  bromide,  may contain 
tributyl-  and dibutylamine  impurities.  The amine impurity  level that may lead to nitrosamine 
contamination  of the API is process dependent and should be determined by each API 
manufacturer. 
 
This list of the aforementioned sources is not exhaustive, as amine reagents can be used to mediate 
a wide range of synthetic transformations. Manufacturers should evaluate other reagents containing 
amine functional  groups for potential risk of nitrosamine formation. 
 
                                              
24 Smith, PAS and RN Loeppky, 1967, Nitrosative cleavage of tertiary amines, J Am Chem Soc, 89(5): 11471157 
25 Fiddler, W, JW Pensabene, RC Doerr, and AE Wasserman, 1972, Formation of N-nitrosodimethylamine from 
naturally occurring quaternary ammonium compounds and tertiary amines, Nature, 236: 307 
26 Gillatt, PN, RJ Hart, CL Walters, and PI Reed, 1984, Susceptibilities of drugs to nitrosation under standardized 
chemical conditions, Food Chem Toxicol, 22(4): 269274 
  6  Contains Nonbinding Recommendations 
 
3.  Contamination in Vendor-Sourced Raw Materials 
 
Nitrosamine impurities  can be introduced when vendor-sourced materials, including  starting 
materials and raw materials, are contaminated. The Agency has observed the following 
contaminations  due to this root cause: 
 
  Nitrosamine contamination  has occurred when fresh solvents (ortho-xylene, toluene, and 
methylene chloride) were contaminated during shipment from vendors (e.g., during transfer 
between storage vessels). 
 
  Sodium nitrite is a known impurity  in some starting materials (such as sodium azide) and 
may be present and react with amines under acidic conditions  to form nitrosamines. 
Nitrate-containing  raw materials, such as potassium nitrate, may contain nitrite impurities. 
The amount of nitrite impurity  that can be tolerated is process dependent and should be 
determined by each API manufacturer. 
 
  Secondary or tertiary amines have been reported as impurities  in some raw materials (see 
details in section II.B.2 in this guidance) and in fresh solvents such as toluene. 
 
  Starting materials or outsourced intermediates may be at risk through cross-contamination 
if they are manufactured at sites where nitrosamine  impurities  are produced in other 
processes. 
 
Awareness of the supply chain of raw materials is an important factor in preventing 
contamination.  For example, API producers may not be aware of nitrosamine  contamination  in 
raw or starting materials they have sourced from vendors; a producer whose manufacturing 
process is not normally  susceptible to nitrosamine  formation may not realize that vendor-sourced 
material may have had impurities  introduced during production  or transport. 
 
4.  Recovered Solvents, Catalysts, and Reagents as Sources of Contamination 
 
Recovered materials such as solvents, reagents, and catalysts may pose a risk of nitrosamine 
impurities  due to the presence of residual amines (such as trimethylamine  or 
diisopropylethylamine).  If the recovery process involves  a quenching step (i.e., nitrous acid used to 
decompose residual azide), nitrosamines could form during solvent recovery. These nitrosamines 
may be entrained if they have boiling  points or solubility  properties27 similar  to the recovered 
materials, depending  on how recovery and subsequent purification  takes place (e.g., aqueous 
washes or distillation).  This further increases the risk of contamination  in material recovery. For 
these reasons, some drug products using APIs manufactured by certain low risk processes28 were 
found to be contaminated. The Agency has observed the following  contaminations  due to this root 
cause: 
 
                                              
27 NDMA and NDEA have boiling points of 151153C and 175177C, respectively 
(https://pubchem.ncbi.nlm.nih.gov). Both are miscible with water and soluble in organic solvents. 
28 Low risk processes are those deemed not normally susceptible to nitrosamine formation. 
  7  Contains Nonbinding Recommendations 
 
  A manufacturing site may produce the same API by more than one synthetic process that 
uses common solvents. If any of those synthetic processes produces nitrosamines  or 
contains precursor amines, the solvents sent for recovery are at risk. The use of recovered 
solvents that are comingled  from different processes or across manufacturing  lines without 
control and monitoring  can introduce nitrosamine  impurities.  If a recovered solvent is 
contaminated in this way and then used to manufacture an API, the API will be 
contaminated even if the synthetic route is not normally  susceptible to nitrosamine 
formation.  
 
  Recovery of raw materials (e.g., solvents, reagents, and catalysts) is often outsourced to 
third-party contractors. Process outsourcing can pose a risk if the third-party recovery 
facility does not receive enough specific information  on the contents of the materials they 
are processing and relies solely on routine recovery processes. 
 
  Raw materials can be contaminated if adequate cleaning of equipment between customers, 
or between different materials, is not carried out or is not validated as capable of removing 
each impurity  of concern. It was reported that ortho-xylene and toluene were contaminated 
during recovery due to inadequate cleaning and to use of shared storage equipment between 
different customers. Inadequate and unvalidated cleaning procedures can also lead to cross-
contamination  if precautions to avoid nitrosamine contamination  are not in place before 
materials from different customers are combined for recovery. For example, the catalyst tri-
N-butyltin  chloride (used as a source of tri-N-butyltin  azide) was contaminated at a third-
party contractor facility due to the combination  of this catalyst from different customers. 
 
5.  Quenching Process as a Source of Nitrosamine Contamination 
 
There is a risk of nitrosamine  formation when a quenching  step is performed directly in the main 
reaction mixture (i.e., when nitrous acid is added to the reaction mixture to decompose residual 
azide). This allows nitrous acid to come into direct contact with residual amines in the raw 
materials used in the manufacturing  process. The nitrosamine  impurities  could be carried to the 
subsequent steps if there are not adequate removal or purification  operations in place, or if the 
operations are not optimized  for removing specific impurities  of concern. This can contaminate the 
entire downstream process once they are introduced. Even if the quenching process is conducted 
outside of the main reaction mixture (see section II.B.4 in this guidance), there is a risk if 
contaminated recovered materials are introduced into the main process. 
 
6.  Lack of Process Optimization and Control 
 
Another potential source of formation of nitrosamine  impurities  is lack of optimization  of the 
manufacturing process for APIs when reaction conditions  such as temperature, pH, or the sequence 
of adding reagents, intermediates,  or solvents are inappropriate  or poorly controlled. FDA has seen 
instances in which reaction conditions  varied widely between batches and even between different 
processing equipment in the same facility for the same API.  
 
The multiple  root causes of nitrosamine contamination  listed above can occur within  the same API 
process. Therefore, multiple  strategies may be necessary to identify  all potential  sources of 
  8  Contains Nonbinding Recommendations 
 
contamination.  Typical routine tests (e.g., HPLC) for API purity, identity,  and known impurities 
are unlikely  to detect the presence of nitrosamine  impurities.  Further, each failure mode could 
result in different nitrosamines in different amounts across batches from the same process and the 
same API producer, with contamination  detected in some batches but not all. 
 
C.  Nitrosamine Impurities in Drug Products From Sources Other Than API 
Contamination 
 
Nitrites are common nitrosating impurities  that have been reported in many excipients at ppm 
levels. Nitrite impurities  are found in a range of commonly  used excipients, which may lead to 
nitrosamine  impurities  forming in drug products during the drug product manufacturing process 
and shelf-life storage period. The supplier qualification  program29 should take into account that 
nitrite impurities  vary across excipient lots and may vary by supplier. Drug product manufacturers 
should also be aware that nitrite and nitrosamine  impurities  may be present in potable water. 
 
Some drug products may undergo degradation pathways that form nitrosamine  impurities;  this 
could potentially  occur during drug product storage. 
 
III.  RECOMMENDATIONS 
 
Because nitrosamines are probable or possible human carcinogens, FDA recommends that 
manufacturers consider the potential causes of nitrosamine formation described in this guidance as 
well as any other pathways observed and evaluate the risk for nitrosamine contamination  or 
formation in their APIs and drug products. Manufacturers should prioritize  evaluation of APIs and 
drug products based on factors such as maximum  daily dose, duration of treatment, therapeutic 
indication,  and number of patients treated.30 As new information  becomes available and FDAs 
understanding  of nitrosamines in drugs evolves, the Agency may recommend that certain drug 
products become higher priorities  for risk assessment. 
Manufacturers should refer to the ICH guidance for industry Q9 Quality Risk Management (June 
2006) for details related to quality risk identification,  analysis, and management. Manufacturers of 
APIs and drug products should take appropriate measures to prevent unacceptable levels of 
nitrosamine  impurities  in their products. 
 
                                              
29 In accordance with the ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009), the 
manufacturers pharmaceutical quality system extends to control of the quality of purchased materials. The supplier 
qualification program is a manufacturers system (e.g., audits, material evaluations, qualification) for selecting 
material suppliers who can provide materials using a defined and approved supply chain. 
30 For example, a drug product with a maximum daily dose (MDD) of 2000 mg with the same detected level of the 
same type of nitrosamine would pose a greater risk than a drug product with a maximum daily dose of 200 mg. A 
drug product intended for only short-term use (e.g., a 7-day course of an antibiotic) poses less risk than a drug 
product intended for chronic use. 
 
  9  Contains Nonbinding Recommendations 
 
A.  Acceptable Intake Limits 
 
FDA recommends the following  acceptable intake (AI)31 limits  for the nitrosamine impurities 
NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA (Table 1). We further recommend that 
manufacturers use these AIs when determining  limits  for nitrosamine impurities  in APIs and drug 
products.32  
 
Table 1. AI Limits for NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA in Drug 
Products 
 
Nitrosamine  AI Limit (ng/day)1,2 
NDMA  96 
NDEA  26.5 
NMBA  96 
NMPA  26.5 
NIPEA  26.5 
NDIPA  26.5 
1 The AI limit is a daily exposure to a compound such as NDMA, NDEA, NMBA,NMPA, NIPEA, or NDIPA that 
approximates a 1:100,000 cancer risk after 70 years of exposure. Appendix B includes a description of the AI derivation for 
NDMA, which is an example of how FDA applied ICH M7(R1) to set a limit. 
2 The conversion of AI limit into ppm varies by product and is calculated based on a drugs maximum daily dose (MDD) as 
reflected in the drug label (ppm = AI (ng)/MDD (mg)). 
 
These limits are applicable only if a drug product contains a single nitrosamine.  If more than one 
of the nitrosamine  impurities  identified  in Table 1 is detected and the total quantity of 
nitrosamine  impurities  exceeds 26.5 ng/day (the AI for the most potent nitrosamines) based on 
the maximum  daily dose (MDD), the manufacturer should contact the Agency for evaluation. 
For drug products with an MDD of less than 880 mg/day, a recommended limit  for total 
nitrosamines of 0.03 ppm is not more than 26.5 ng/day and is considered acceptable. For drug 
products with an MDD above 880 mg/day, the limit  for total nitrosamines should be adjusted so 
as not to exceed the recommended limit  of 26.5 ng/day.33 
 
If nitrosamines without published  AI limits  are found in drug products, manufacturers should use 
the approach outlined  in ICH M7(R1) to determine the risk associated with the nitrosamine  and 
contact the Agency about the acceptability of any proposed limit.34 
 
Generally,  sensitive methods with limits  of quantitation  (LOQ) in the parts-per-billion  (ppb) range 
are needed to meet the low AIs recommended for nitrosamines. Manufacturers of APIs and drug 
                                              
31 The term acceptable intake (AI) is used in ICH M7(R1) to indicate the threshold of toxicological concern (TTC) 
considered for the impurity to be associated with negligible risk of carcinogenicity or other toxic effects. FDA 
announcements regarding limits for nitrosamines used the term acceptable daily intake (ADI). For the purposes of 
this guidance, the term AI is used rather than ADI. 
32 API manufacturers should control nitrosamine impurities to ensure that the drug products in which the APIs are 
used will meet the recommended AI limits. 
33 Manufacturers should contact CDER-OPQ-Inquiries@fda.hhs.gov if multiple nitrosamine impurities are detected 
in an API or drug product in which the total nitrosamine level exceeds 26.5 ng/day based on MDD. Inquiries 
submitted to this mailbox will be routed to the appropriate FDA office. 
34 See footnote 33 for contact information. 
 
  10  Contains Nonbinding Recommendations 
 
products should use methods with LOQs at or below 0.03 ppm.35 Manufacturers should establish 
methods for which the LOQ and limit  of detection (LOD) are as low as reasonably practical for 
products for which the maximum  daily dose is high (e.g., greater than 1 g). If more than one 
nitrosamine  listed in Table 1 is detected, then the analytical method should be validated for LOQs 
below 0.03 ppm to accurately quantify a total nitrosamine  level of not more than 26.5 ng/day. For 
example, if the MDD is 1200 mg, the LOQ should be below 0.02 ppm. FDAs public webpage 
includes validated analytical  test methods recommended for detecting nitrosamine  impurities  in 
several different APIs and products.36,37 
 
API and drug product manufacturers should take the following  steps to mitigate nitrosamine 
impurities  in their products: 
 
1.  Assess the risk of nitrosamine  impurities  in APIs, marketed products, and 
products under approved and pending applications.  Risk assessments should be 
conducted in a timely manner based on the prioritization  of drugs.38 
Manufacturers do not need to submit risk assessment documents to the Agency, 
but they should retain these documents so that they are available if requested. 
 
2.  Conduct confirmatory testing39 when there is any risk for the presence of 
nitrosamine  impurities.  Due to nitrosamines physiochemical  properties (low 
molecular weights, some volatility  and high toxicity),  the analytical methods for 
nitrosamines need to have specificity,  excellent chromatographic separation, and 
highly  sensitive detection capability. 
 
3.  Report changes implemented  to prevent or reduce nitrosamine impurities  in APIs 
and drug products to FDA. This includes submission  of any drug master file (DMF) 
amendments in accordance with 21 CFR 314.420(c) and changes to approved 
applications  as required under 21 CFR 314.70 and 314.97 and pending applications 
under 21 CFR 314.60 and 314.96. 
 
                                              
35 The LOQ may be considered the reporting threshold for nitrosamine impurities (i.e., the limit above which an 
impurity should be reported in the certificate of analysis). 
36 FDA-recommended analytical methods for detecting nitrosamine impurities can be found at 
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-
ranitidine, at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-
metformin, and in the 12/12/2018 update at https://www.fda.gov/Drugs/DrugSafety/ucm613916.htm. 
37 Manufacturers or laboratories are encouraged to make validated test methods publicly available (e.g., by posting 
on the method developers website) to facilitate faster testing of other similar products. FDA also accepts requests to 
post privately developed methods at FDAs website if FDAs review of the method protocol finds it is scientifically 
sound, and if the method owner provides written authorization for posting by FDA. The manufacturers or 
laboratories should send their test methods to CDER-OPQ-Inquiries@fda.hhs.gov. 
38 In accordance with quality management principles, manufacturers should consider manufacturing changes and 
shifts over the product lifecycle that may impact the potential for nitrosamine impurities, including new sources of 
raw materials or excipients. Risks should be reassessed periodically (see ICH Q9). 
39 Testing using appropriately validated methods may be conducted by the API manufacturer or by a qualified 
laboratory. 
 
  11  Contains Nonbinding Recommendations 
 
B.   Recommendations to API Manufacturers 
 
While nitrosamines  are not expected to form during the manufacture of the vast majority  of APIs, 
all manufacturers of chemically synthesized APIs should take appropriate actions to mitigate the 
risk of nitrosamine  contamination  for APIs where there is a potential for nitrosamine  impurities. 
 
API manufacturers should review their API manufacturing processes and perform risk assessments 
to identify the potential for nitrosamine  impurities.  If a risk of nitrosamine impurities  is identified, 
confirmatory testing of batches should be conducted using sensitive and appropriately validated 
methods. If the risk assessment determines that there is no potential for nitrosamine  impurities, 
there is no need to take further action. If a nitrosamine  impurity  is detected, API manufacturers 
should investigate the root cause. They should implement  changes in the manufacturing process to 
reduce or prevent nitrosamine impurities.40 
 
1.  Mitigating the Presence of Nitrosamine Impurities in APIs 
 
FDA recommends that API manufacturers take the following  actions:  
  
  API manufacturers should optimize  the design of the manufacturing process for APIs 
during route of synthesis (ROS) development  to minimize  or prevent the formation of 
nitrosamine  impurities.  API manufacturers should refer to the recommendations in ICH 
M7(R1) and the ICH guidances for industry Q7 Good Manufacturing Practice Guidance 
for Active Pharmaceutical Ingredients (September 2016) and Q11 Development and 
Manufacture of Drug Substances (November 2012) in this respect. The following  factors 
should be considered during process development: 
 
  Avoiding reaction conditions  that may produce nitrosamines whenever possible; 
o
when not possible,  demonstrating that the process is adequately controlled and is 
capable of consistently reducing nitrosamine  impurities  through appropriate and 
robust fate and purge studies. 
 
  Using bases other than secondary, tertiary, or quaternary amines (when possible) if 
o
ROS conditions  may form nitrosamines. 
 
  Using caution when the ROS involves the use of amide solvents (e.g., N,N-
o
dimethylformamide,  N,N-dimethylacetamide,  and N-methylpyrrolidone). 
 
  Replacing nitrites with other quenching agents for azide decomposition  processes. 
o
 
  Optimizing  and consistently  controlling  the sequences of reactions, processes, and 
o
reaction conditions  (such as pH, temperature, and reaction time). 
 
  Designing a manufacturing process that facilitates the purge of nitrosamine 
o
impurities  in the subsequent processing steps. 
                                              
40 See section V in this guidance for reporting changes to approved applications and DMFs. 
  12  Contains Nonbinding Recommendations 
 
  API manufacturers should consider removing quenching steps (when there is a risk of 
nitrosamine  formation, e.g., using nitrous acid to decompose residual azide) from the main 
reaction mixture to reduce the risk of nitrosamine  formation. The API, or an intermediate 
formed through a reaction using an azide salt, can be separated from the mother liquor into 
the organic phase. The aqueous waste phase separated from the organic phase should then 
be quenched with nitrous acid without contacting the API, its intermediate,  or solvents 
intended for recovery. 
 
  API manufacturers should audit their supply chains and monitor  them for any at-risk raw 
materials, starting materials, and intermediates.41 API manufacturers should maintain 
records including  the name of the raw material manufacturer and its supplier,42  roles of the 
actual manufacturers of such materials, and any repackers and distributors  who handle the 
materials before API manufacture. When appropriate, API manufacturers should establish 
controls and consider additional  specifications for at-risk materials to prevent nitrosamine 
contamination. 
 
  To avoid cross-contamination  when recovered materials such as solvents, reagents, and 
catalysts are used in the manufacturing process, recovered material should be used only in 
the same step or in an earlier step (if there is sufficient purification)  of the same process 
from which it was collected. The recovered materials should meet appropriate standards 
before reuse. If the recovery of materials is outsourced to third-party contractors, the API 
manufacturer should audit the contractors validation  of cleaning procedures. API 
manufacturers should follow recommendations  in ICH Q7 for ensuring that cross-
contamination  with nitrosamine  or nitrosamine precursors can be prevented. API 
manufacturers should also verify with their suppliers whether the purchased materials used 
in their processes are recovered. 
 
  API manufacturers should be aware that potable water used in API manufacture may 
contain low levels of nitrite and even nitrosamines  from environmental  contamination.43 
The existence of nitrites in processing water may lead to nitrosamine  contamination  in API 
manufacture. Therefore, to avoid unacceptable levels of nitrosamine impurities  in APIs, 
API manufacturers should analyze nitrite and nitrosamine levels in water and use water that 
has been purified to remove unacceptable impurities. 
 
If a nitrosamine  is introduced to the API through exogenous sources44 that can be avoided, 
manufacturers should eliminate  the source of contamination. 
 
  API batches may be reprocessed or reworked to control the level of nitrosamine  impurities 
as provided in ICH Q7 for amending and controlling  such operations. If a batch is found to 
                                              
41 For a description of at-risk materials, see section II.B in this guidance. 
42 ICH Q7 
43 See the latest version of the WHOs Guidelines for Drinking-Water Quality at 
https://www.who.int/water_sanitation_health/water-quality/guidelines/en/. 
44 Exogenous sources, for the purposes of this guidance, refer to materials such as solvents and raw materials used in 
synthesis or processing that may introduce contamination. 
  13  Contains Nonbinding Recommendations 
 
contain nitrosamine and is reprocessed or reworked in any way, these operations should be 
conducted under oversight of the quality unit. 
 
2.  Control of Nitrosamine Impurities in APIs 
 
If a nitrosamine  impurity  is detected above the LOQ, the API manufacturer should develop a 
strategy to ensure that the nitrosamine level remains within the AI limit.  Manufacturers should 
develop an appropriate control strategy, which should include specification  limits,  to ensure that 
the nitrosamine  level reliably remains well below the AI limit  in the API. Given existing 
uncertainties regarding nitrosamine impurities  and their presence in drugs, for APIs with an 
impurity  detected above the LOQ or at-risk APIs, testing of each batch on release should be 
conducted. Alternate approaches (e.g., upstream test of an intermediate) should be supported by 
sufficient process understanding  and evidence of adequate statistical control and should be 
submitted to FDA in a supplement prior to implementation.45 
 
Any API batch found to contain levels of nitrosamine impurities  above the recommended AI 
should not be released by the API manufacturer for distribution  unless, with prior FDA agreement, 
the API is needed to prevent or mitigate a shortage of a drug.  
 
C.   Recommendations to Drug Product Manufacturers 
 
Drug product manufacturers should conduct risk assessments to determine the potential  for 
nitrosamine  impurities  in drug products. A risk assessment should involve  collaboration  with the 
API manufacturer to aid in the identification  of the API ROS or other process conditions  of the 
APIs manufacture that put the drug product at risk for nitrosamine impurities.  The risk assessment 
should also include evaluation of any pathway (including  degradation) that may introduce 
nitrosamines during drug product manufacture or storage. If the risk assessment determines that 
there is no potential for nitrosamine impurities,  there is no need to take further action. 
 
If a risk of nitrosamines in a drug product is identified,  confirmatory testing of batches should be 
conducted using sensitive and appropriately  validated methods.46 If a nitrosamine impurity  is 
detected, manufacturers should investigate the root cause and implement  changes in the 
manufacturing process to mitigate or reduce nitrosamine  impurities.47 
 
1.  Control of Nitrosamine Impurities in Drug Products 
 
Drug product manufacturers must test representative samples of all incoming  components, 
including  lots of at-risk API, prior to use, as required under 21 CFR 211.84.48 To meet the CGMP 
                                              
45All changes in specifications from those in the approved application must be submitted in a prior approval 
supplement unless otherwise exempted by regulation or guidance (see 21 CFR 314.70(b)(2)) and the guidance for 
industry Changes to an Approved NDA or ANDA (April 2004)). 
46 Testing using appropriately validated methods may be conducted by the API manufacturer or by a qualified 
laboratory. 
47 See section V in this guidance for reporting changes to approved applications and DMFs. 
48 At-risk APIs include APIs with secondary, tertiary, and quaternary amine functional groups. They also include 
any API with an ROS using at-risk materials (see section II.B in this guidance). 
  14  Contains Nonbinding Recommendations 
 
regulations in 21 CFR 211 subpart E and be consistent with the ICH guidance for industry Q10 
Pharmaceutical Quality System (April 2009), drug product manufacturers should continue testing 
API lots until  they have verified that the API supplier can consistently manufacture API without 
unacceptable levels of nitrosamine.  
 
Drug product manufacturers, when designing  their control strategy, should evaluate whether 
nitrites could be present during manufacturing  processes where at-risk APIs are used. They should 
also evaluate whether nitrosamines could form in a finished drug product over the drug products 
shelf life. If a nitrosamine is introduced to the drug product through exogenous sources that can be 
avoided, manufacturers should eliminate  the source of contamination.   
 
If a nitrosamine  impurity  is detected above the LOQ, the manufacturer should develop a strategy to 
ensure that the nitrosamine  level remains within the AI limit. The control strategy should include 
specification limits  for the identified  nitrosamine. Such a control strategy is also recommended 
when the introduction  of nitrosamine is inherent due to the API structure, the API ROS, or the 
manufacturing process of the API or drug product. Given existing  uncertainties regarding 
nitrosamine  impurities  and their presence in drugs, testing of each batch on release should be 
conducted. Alternate approaches should be supported by sufficient process understanding  and 
evidence of adequate statistical control and should be submitted to FDA in a supplement prior to 
implementation.49 
 
If drug product batches with unacceptable levels of nitrosamine impurities  are already in 
distribution,  drug product manufacturers should contact FDA so the Agency can determine the 
regulatory action for the specific drug products. Any drug product batch found to contain levels 
of nitrosamine  impurities  at or above the recommended AI should not be released by the drug 
product manufacturer for distribution.  Manufacturers should contact the Agency if a recall is 
initiated.50 Under section 501 of the Food, Drug, and Cosmetic Act (FD&C Act),51 a drug that is 
not manufactured, processed, packed, or held in conformity with CGMP to ensure that the drug 
meets certain quality  and purity standards is considered adulterated. FDA may exercise 
regulatory discretion when warranted to prevent or mitigate a shortage of a drug. 
 
IV.   MAINTAINING THE DRUG SUPPLY 
 
If any manufacturing changes or recalls are likely  to lead to a disruption  in the drug supply, 
manufacturers should immediately  contact CDERs Drug Shortage Staff at 
drugshortages@fda.hhs.gov;  FDA can work with manufacturers to mitigate the risk of nitrosamine 
impurities  in APIs and drug products while avoiding  interruptions  in the drug supply. Contacting 
the Drug Shortage Staff can assist manufacturers in meeting any obligations  to report 
discontinuances  or interruptions  in their drug manufacture under section 506C of the FD&C Act 
and implementing  regulations  under 21 CFR 314.81(b)(3)(iii).  It also allows FDA to consider, as 
                                              
49All changes in specifications from those in the approved application must be submitted in a prior approval 
supplement unless otherwise exempted by regulation or guidance (see 21 CFR 314.70(b)(2)(i)) and the guidance for 
industry Changes to an Approved NDA or ANDA (April 2004)). 
50 Manufacturers can contact the recall coordinator assigned to the product type and location. Contact information 
for recall coordinators is available at https://www.fda.gov/safety/industry-guidance-recalls/ora-recall-coordinators. 
51 See 21 U.S.C. 351. 
  15  Contains Nonbinding Recommendations 
 
soon as possible,  what actions, if any, may be needed to avoid shortages and protect the health of 
patients who depend on the affected products. 
 
V.   REPORTING CHANGES TO FDA 
 
Drug manufacturers must report changes implemented  to prevent or reduce nitrosamine 
impurities  in accordance with FDA regulations  (21 CFR 314.60, 314.70, 314.96, and 314.97). 
 
If an API DMF holder makes process changes in the ROS as a result of the risk assessment and 
confirmatory testing, the DMF holder must submit amendments and inform each drug product 
manufacturer that references the DMF (including  pending and approved applications),  in 
accordance with 21 CFR 314.420(c). If the API is manufactured by the applicant and not covered 
by a DMF, the manufacturer must report such ROS changes in the application  in accordance with 
21 CFR 314.70 and 21 CFR 314.97. If a batch of API is found to contain a nitrosamine and is 
reprocessed or reworked in any way, these operations should be reported in the DMF or 
application  (as applicable). 
 
Although each DMF may contain only a single synthetic route, if a change in synthetic process is 
needed to avoid nitrosamine contamination  and it is not possible to immediately  stop using the 
original  manufacturing  process, the API manufacturer should submit both processes in the DMF 
and provide an estimate for the earliest feasible timeframe for the removal of the original 
process. The different synthetic processes should be identified  by separate codes to designate 
batches manufactured through each process. If the original  process cannot be discontinued  within 
a reasonable timeframe, the new or revised process should be submitted in a separate DMF. 
 
If changes to the drug product are needed to prevent nitrosamine formation,  application  holders 
must submit a supplement to notify FDA of any changes to conditions  established in the 
approved applications  beyond the variations already provided for in their applications,  as 
required by 21 CFR 314.70 and 314.97. Holders of pending applications  must update their 
applications  through submission  of an amendment according to 21 CFR 314.60 and 314.96. 
Section V of this guidance includes additional  information  on reporting changes in APIs and 
drug products. 
 
A.  Recommended Timeline for Risk Assessment, Confirmatory Testing, and 
Submission of Required Changes  
 
FDA recommends different implementation  timelines  depending on the regulatory status of the 
drug product.52  
 
                                              
52 New drug application (NDA) and abbreviated new drug application (ANDA) holders or sponsors, drug master file 
(DMF) holders, and owners of marketed products that are not the subject of approved NDAs or ANDAs (such as 
compounded products or products marketed under an over-the-counter (OTC) drug monograph) who are not also the 
manufacturer of the drug products and APIs should work with their contract manufacturers to take the steps 
recommended in this guidance. This applies to drug products currently available on the U.S. market as well as those 
with pending applications. 
  16  Contains Nonbinding Recommendations 
 
1.  Approved or Marketed Drug Products 
 
To ensure the safety of the U.S. drug supply, manufacturers should conclude a risk assessment of 
approved or marketed products within 7 months of publication  of the original  guidance, with a 
recommended completion  date of on or before March 31, 2021. Confirmatory testing should start 
as soon as the risk of nitrosamine  is identified  from the risk assessment and should begin 
immediately  for products considered at high risk. To ensure the safety of the U.S. drug supply, 
confirmatory testing of drug products and submission  of required changes in drug applications 
should be concluded within 3 years of publication  of the original  guidance, with a recommended 
completion  date of on or before October 1, 2023. FDA acknowledges that the implementation 
timeline  includes investigating  the root cause of the contamination  or formation,  identifying 
changes that will eliminate  the root cause (e.g., change in manufacturing process, change in 
supplier),  and confirming  that any proposed changes will minimize  the risk of nitrosamine 
contamination  or formation without otherwise adversely affecting product quality. The timelines 
also include activities conducted by API manufacturers (i.e., risk assessment and testing) to 
support the drug products in which they are used. FDA may request an expedited risk 
assessment, confirmatory testing, or other regulatory action based on information  available to the 
Agency. 
 
2.  Pending Applications 
 
a.  Pre-Submission  Stage 
 
FDA recommends that applicants conduct a risk assessment for nitrosamine  impurities  in APIs 
and proposed drug products and conduct confirmatory testing as needed prior to submission  of 
an original  application.  However, the risk assessment and submission of confirmatory testing, if 
needed, and changes to the DMF or application  may be submitted in an amendment if they are 
not available at the time of the original  submission filing.  Such an amendment should be 
submitted as quickly  as possible after the original  submission  filing  to minimize  any potential 
adverse impact on the application  assessment timeline.53 
 
b.  Applications  Pending With the Agency 
 
Applicants with pending applications  should conduct the risk assessment expeditiously  and 
inform FDA if confirmatory testing finds nitrosamine levels above the AI limit.54  If a 
nitrosamine  impurity  is detected above the LOQ but is within the AI limit,  the applicant should 
amend the application  as appropriate. The Agency will work with the applicant to resolve issues 
during the review cycle or immediately  after approval, and before distribution,  if determined to 
be necessary by the Agency.55 
 
                                              
53 For NDA submissions, manufacturers should discuss the need for an amendment with the Agency at the pre-NDA 
stage.  
54 For NDAs, the applicant should contact the specific products review division. For ANDAs, the applicant should 
contact the project manager specified for the ANDA.  
55 In certain cases, FDA may consult with CDERs Drug Shortage Staff to ensure adequate supply on the U.S. 
market. 
  17  Contains Nonbinding Recommendations 
 
FDA generally will adhere to review goals established as part of the Prescription Drug User Fee 
Act reauthorization  for years 20182022 (PDUFA VI) and the Generic Drug User Fee 
Amendments Reauthorization  of 2017 (GDUFA II). 
   
  18  Contains Nonbinding Recommendations 
 
1  APPENDIX A. ADDITIONAL RESOURCES 
2   
3  The recommendations on reporting changes in APIs and drug products in this guidance are in 
4  accordance with the FDAs current regulations  and guidances. The following  guidances1 are 
5  generally relevant to API and drug product impurities,  including  reporting changes of controls 
6  for impurities  and application  submission  information:2 
7    Guidance for industry SUPAC-IR: Immediate-Release Solid Oral Dosage Forms: Scale-Up 
8  and Post-Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution 
9  Testing, and In Vivo Bioequivalence Documentation (November 1995) 
10    Guidance for industry SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up and 
11  Post-Approval Changes: Chemistry, Manufacturing and Controls; In Vitro Release Testing 
12  and In Vivo Bioequivalence Documentation (May 1997) 
13    Guidance for industry SUPAC-MR: Modified Release Solid Oral Dosage Forms Scale -Up 
14  and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution 
15  Testing and In Vivo Bioequivalence Documentation (October 1997) 
16    Guidance for industry Changes to an Approved NDA or ANDA (April 2004)  
17    ICH guidance for industry Q9 Quality Risk Management (June 2006) 
18    ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009) 
19    ICH guidance for industry Q11 Development and Manufacture of Drug Substances 
20  (November 2012) 
21    Guidance for industry CMC Postapproval Manufacturing Changes To Be Documented in 
22  Annual Reports (March 2014) 
23    ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active 
24  Pharmaceutical Ingredients (September 2016) 
25    ICH guidance for industry M7(R1) Assessment and Control of DNA Reactive (Mutagenic) 
26  Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk (March 2018) 
27    Draft guidance for industry Postapproval Changes to Drug Substances (September 2018)3 
28     
                                              
1 The Agency updates guidances periodically. For the most recent version of a guidance, check the FDA guidance 
web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
2 This guidance is not intended to cover all of the current good manufacturing practice (CGMP) requirements that 
are relevant. The DMF and drug product reporting provisions are the main focus in this section of the guidance. 
3 When final, this guidance will represent FDAs current thinking on this topic. 
  1  Contains Nonbinding Recommendations 
 
29  APPENDIX B. FDA DETERMINATION OF ACCEPTABLE INTAKE LIMITS 
30   
31  Identification  of the acceptable intake (AI) values listed in section III of this guidance follows 
32  the procedures recommended in the ICH guidance for industry M7(R1) Assessment and Control 
33  of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic 
34  Risk (March 2018).1 A compound-specific  AI can be calculated based on rodent carcinogenicity 
35  potency data such as TD  values (doses giving  a 50% tumor incidence equivalent to a cancer 
50
36  risk probability  level of 1:2) identified  in the public literature. Linear extrapolation  to a 
37  probability  of 1 in 100,000  (i.e., the accepted lifetime risk level used) is achieved by simply 
38  dividing  the TD  by 50,000. The AI (in mg/kg/day units) can then be converted to mg/day by 
50
39  multiplying  by the human body weight (50 kg is the assumed body weight identified  in the 
40  referenced guidance). Linear extrapolation from a TD  value is considered appropriate to derive 
50
41  an AI for M7 Class 1 impurities  (known mutagenic carcinogens) with no established threshold 
42  mechanism. In many cases, the carcinogenicity  data are available from the Carcinogenicity 
43  Potency Database (CPDB). When the CPDB contains a pre-calculated TD  value for a selected 
50
44  chemical, this value may be used to calculate the AI. Where carcinogenicity  study data for an 
45  impurity  are of lesser quality as described in ICH M7, a surrogate compound with 
46  carcinogenicity  data may be used to derive an acceptable intake but should be scientifically 
47  justified.   
48   
49  A summary of the AI derivation  for NDMA is provided as an example. NDMA was identified  as 
50  a mutagenic carcinogen in several species and is listed as a probable human carcinogen by the 
51  Environmental  Protection Agencys (EPAs) Integrated Risk Information  System (IRIS) 
52  program. TD50 values for NDMA are 0.0959 mg/kg/day (rat, based on Peto et al.2) and 0.189 
53  mg/kg/day (mouse) according to the CPDB.3 For the AI calculation,  the lower (more 
54  conservative) value of the rat is used. The resulting  AI associated with a 1 in 100,000  cancer risk 
55  over 70 years of exposure is calculated by dividing  the TD50 by 50,000 and then multiplying  by 
56  50 to account for a patient with a 50-kg body weight, resulting  in 0.0000959  mg/day NDMA, or 
57  approximately  96 ng/day NDMA. 
58   
59  Hence, a daily lifelong  intake of 96 ng/day NDMA corresponds to a theoretical cancer risk of  
60  10-5 and therefore represents an AI when present as an impurity. 
61   
                                              
1 The Agency updates guidances periodically. For the most recent version of a guidance, check the FDA guidance 
web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
2 Peto, R, R Gray, P Brantom and P Grasso, 1991, Dose and time relationships for tumor induction in the liver and 
esophagus of 4080 inbred rats by chronic ingestion of N-nitrosodiethylamine or N-nitrosodimethylamine, Cancer 
Research, 51: 64526469 
3 Carcinogenicity Potency Database entry for N-nitrosodimethylamine (CAS 62-75-9) (NDMA) accessed at 
https://www.nlm.nih.gov/databases/download/cpdb.html 
  1