APIC 发布亚硝胺风险评估报告模板 Revision 4（2026 年 1 月）
Template for report on Nitrosamine Risk Evaluation Update January 2026 – V4
APIC 发布亚硝胺风险评估报告模板第 4 版，修订日期为 2026 年 1 月，供原料药生产企业按 EMA 与美国 FDA 等指南评估并报告潜在亚硝胺风险。模板要求填写原料药、生产商与文件编号等信息，并按 EMA/409815/2020 的根源原因逐项给出是、否或不适用判断及理由，另附可用于填写亚硝化剂与易亚硝化物质的表格。
材料以 EMA 与 FDA 指南的亚硝胺根源为框架，给出逐项评估与报告填写要求的模板，可供原料药企业对照自查文件结构。
APIC 技術出版物：Template for report on Nitrosamine Risk Evaluation Update January 2026 – V4
官方目錄發布日：2026-03-02（原文 02/03/2026，DD/MM/YYYY）；文件版本或修訂日期另見正文。
本文為 APIC 技術資料，不是監管機關發布的法規。
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第 1 页
1
ACTIVE PHARMACEUTICAL INGREDIENTS COMMITTEE
REPORT ON THE RISK OF POTENTIAL
PRESENCE
OF NITROSAMINE IMPURITIES
Revision 4, January 2026
Revision 4 – January 2026
Copyright © 2022 Active Pharmaceutical Ingredients Committee (APIC)
第 2 页
REPORT ON THE RISK OF POTENTIAL PRESENCE
OF NITROSAMINE IMPURITIES
Document ID:
ACTIVE PHARMACEUTICAL INGREDIENT (API) (/or other (specify), e.g. in case risk assessment is requested for API
intermediates)
Name: …………………………………………………………………………………………………………………………............................................
Material code(s): ………………………………………………………………………………………………………………………………………………………..............
MANUFACTURER (refers to the manufacturing site)
Name: ……………………………………………………………………………………………………………………………………………………………………...
Address: ……………………………………………………………………………………………………………………………………………………………………..
(Optionally)
CEP/ASMF/DMF reference: ……………………………………………………………………………….................................................................
(Optionally, if manufacturer is different than DMF holder):
DMF holder
Name: ……………………………………………………………………………………………………………………………………………………………………...
Address: ……………………………………………………………………………………………………………………………………………………………………..
(Optionally indicate name / function) This report was completed by [person / central service]:
Name and position: …………………………………………………………………………………………………………………………………………………………….......
E-mail address: ………………………………………………………………………………………………………………………………………………………………………….
Postal address: …………………………………………………………………………………………………………………………………………..................................
Declaration:
The current manufacturing process of (API name) was assessed with respect to the risk of the potential presence of Nitrosamine
impurities in line with EMA guidelines (current versions of EMA/369136/2020, EMA/409815/2020) and similar related
regulations published by other Health Agencies.
Document ID: Page 1 of 11
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All information contained in this report is based on current knowledge and is true and sincere to our actual knowledge
considering available supplier information and likely chemical production processes where information from the supplier is not
available.
The information in this document may be updated as more information becomes available.
Date
(Optionally sign) Signature and Company stamp
Document ID: Page 2 of 11
第 4 页
Delete this page when issuing the letter.
Instructions when using this template:
1. Replace APIC logo by your company logo.
2. In the footer, replace CEFIC logo by “This document was prepared based on APIC
template”.
3. Remove the text referring to the internal instruction (blue), e.g. definition of
Nitrosatable/vulnerable substances (amine, hydrazine, hydrazide or hydrazone) in
Chapter 7.
4. In the section 3, the detail would depend on the customer (or Health Authorities) with
whom the report will be shared. The process description can be replaced by a workflow
with the relevant information for the evaluation or just to reference the filing applicable
section. A description of the process step where the risk evaluation was initiated, e.g.
from starting material or from intermediate, should be provided with a rationale for the
selection.
5. In the table in the section 5 (Table 2), fill one line per nitrosamine which has been
identified as being possibly generated during the API manufacturing process.
6. Before finalization of the report, please check the references of currently valid Health
Authorities' (HAs) guidelines. If an updated revision, without changes in identified root
causes is available, a revision of the Table 1 is not needed and only references in a foot
note of the page 4 should be updated. However, if additional (new) root cause is
identified in any future revision of the HAs guidelines, an update of the APIC template
should be endorsed.
7. If justification for risk evaluation of the root cause in the Table 1 is supported by any
other document/literature reference, please provide any additional
information/document or reference within this table, as appropriate.
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1 INTRODUCTION
This document reports the outcome of the risk evaluation on the above mentioned API based on
the requirements defined in the EMA/369136/2020 assessment report “Nitrosamine impurities in
human medicinal products”1, the EMA/409815/2020 “Questions and answers for marketing
authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC)
No 726/2004 referral on nitrosamine impurities in human medicinal products”2 , the US FDA
Guidance for Industry “Control of Nitrosamine Impurities in Human Drugs”3 and other related
regulations published by other Health Agencies, such as Health Canada.4
Such evaluation on the risk of presence of nitrosamine impurities in the APIs was performed using
quality risk management principles, as per current ICH Q9 guideline (ICH guideline Q9 on quality
risk management) and ICH M7 (Assessment and control of DNA reactive (mutagenic) impurities
in pharmaceuticals to limit potential carcinogenic risk). Manufacturing processes are being
reviewed to identify and, if found, to mitigate risk of presence of N-nitrosamine impurities during
manufacture and storage of the API.
2 SCOPE
The Risk Evaluation has evaluated the items as potential sources of nitrosamines or their
precursors in line with root causes described in the EMA/409815/2020 guideline2.
Please note that listed root causes (Table 1) follow the EMA/409815/2020 guideline.2 In
addition, the root causes, such as “Quenching Process as a Source of Nitrosamine
Contamination” and “Lack of Process Optimization and Control” as described in FDA Guidance
for Industry3 are addressed within the present EMA’s root causes. Namely, both are covered
within questions related to combination of nitrosating agent and nitrosatable substances or
compounds susceptible for degradation into nitrosatable substances, as well as questions related
to contamination of starting materials/intermediates/raw materials.
3 MANUFACTURING / PROCESS STEPS COVERED BY RISK EVALUATION
The risk evaluation covers all API manufacturing steps as presented below.
(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED. Include route of synthesis and
process description, if relevant. The process description can be replaced by a workflow with the
relevant information for the evaluation or just to reference the filing applicable section.)
1
European Medicines Agency (EMA): Assessment report, Procedure under Article 5(3) of Regulation EC (No) 726/2004, Nitrosamine impurities
in human medicinal products. EMA/369136/2020, 25 June 2020, Nitrosamines EMEA-H-A5(3)-1490 - Assessment Report.
2
European Medicines Agency (EMA): Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article
5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. EMA/409815/2020, Rev.23, 10 October
2025. Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No
726/2004 referral on nitrosamine impurities in human medicinal products and corresponding Appendices: Appendix 1 (EMA/42261/2025),
Appendix 2 (EMA/451665/2023) and Appendix 3 (EMA/120337/2024).
3
U.S. Food & Drug Administration, Control of Nitrosamine Impurities in Human Drugs, Revision 2, September 2024, Nitrosamine final guidance,
Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance for Industry, August 2023
Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance for Industry and
Updated Information | Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) – published on
website CDER Nitrosamine Impurity Acceptable Intake Limits | FDA
4
Health Canada: Guidance on nitrosamine impurities in medications, date adopted 1 August 2025, Guidance on nitrosamine impurities in
medications
Document ID: Page 4 of 11
第 6 页
In the footnote on page 4, please update accordingly applicable and current guideline version.
Please add also other guidelines, for other scopes and reported by other National Competent
Authorities, if applicable.
4 RISK EVALUATION METHODOLOGY
The risk evaluation for potential presence of nitrosamines has been conducted taking into account
quality risk management principles, as per current ICH Q9 guideline (ICH guideline Q9 on quality
risk management).
5 SUMMARY OF ITEMS REVIEWED FOR THE RISK EVALUATION
(includes justification and risk evaluation outcome)
(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED. For each of the following items,
indicate whether a risk for presence of nitrosamines has been identified or not. In each case
consider the item’s potential as a direct source of nitrosamines and/or source of nitrosamine
precursors, which could subsequently pose a risk of nitrosamine formation. Please consider
presence of nitrosating agents and nitrosatable substances for the risk evaluation results in
Chapter 7. Provide justification as to why the response is yes / no / na. For additional information
regarding presence of nitrosating agents and nitrosatable substances in the API, please refer to
Chapter 7.)
Note:
Please note that below Summary table (Table 1) is done based on CMDh/439/2022 (Template
for nitrosamine RE)5 for convenience of drug product manufacturer and to transparently
demonstrate that the risk evaluation has been performed based on the current version of the
EMA/409815/2020 document2 and all risk factors related to active substance are sufficiently
addressed in the risk evaluation itself.
By assessing the risk factors related to the manufacture of API, also the potential risks arising
in finished product formulation due to active substance are addressed and the MAH is supported
with relevant information to perform further comprehensive risk evaluation for medicinal
product.
Table 1: Summary of items reviewed for the risk evaluation, justification and risk outcome
Currently identified risk factors for presence of Risk for presence of nitrosamines identified?
nitrosamines (Q4 of EMA/409815/2020) (Yes / No / NA)
Risk factors related to the manufacture of the active substance:
1 Use of nitrite salts and esters (e.g. NaNO2, alkyl YES ☐ NO ☐ NA ☐
nitrites), or other nitrosating agents (e.g. nitroso Justification:
halides, nitrosonium salts, nitrogen oxides, nitro
alkanes, halogenated nitro alkanes, Fremy’s salt,
5
CMDh practical guidance for Marketing Authorisation Holders of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3)
Referral on Nitrosamines, CMDh/412/2019, Rev.21, July 2023 CMDh_412_2019_Rev.21_2023_07_clean_-_PG_to_MAHs_on_nitrosamines
and The template for nitrosamine risk evaluation, CMDh/439/2022, May 2022
CMDh_439_2022_Rev.0_03_2022_clean_-_Template_for_nitrosamine_risk_evaluation.docx
Document ID: Page 5 of 11
第 7 页
nitroso sulfonamides), in the presence of secondary
or tertiary amines within the same or different steps
of the manufacturing process. Sources for secondary
or tertiary amines can also be starting materials,
intermediates, reagents, solvents (e.g. DMF, DMAc
and NMP) and catalysts, which contain amine
functionality, amine impurities (e.g. quaternary
ammonium salts) or which are susceptible to
degradation to reveal amines.
2 Nitrite formation by oxidation of hydroxylamine or YES ☐ NO ☐ NA ☐
nitrite release from nitro-aromatic precursors (e.g. by Justification:
fluoro de-nitration), in the presence of secondary or
tertiary amines within the same or different steps of
the manufacturing process.
3 Use of disinfected water (chlorination, chloro- YES ☐ NO ☐ NA ☐
amination, ozonisation) in the presence secondary or Justification:
tertiary amines within the same or different steps of
the manufacturing process.
4 Oxidation of hydrazines, hydrazides and hydrazones YES ☐ NO ☐ NA ☐
by hypochlorite, air, oxygen, ozone and peroxides in Justification:
the manufacturing process or during storage.
5 Use of contaminated raw, recovered or recycled YES ☐ NO ☐ NA ☐
materials (e.g. solvents, reagents and catalysts) in the Justification:
API manufacturing process.
6 Use of contaminated starting materials and YES ☐ NO ☐ NA ☐
intermediates supplied by vendors who use processes Justification:
or raw materials which may contain residual
nitrosamines or nitrosating agents.
7 Carry-over of nitrosamines deliberately generated YES ☐ NO ☐ NA ☐
(e.g. as starting materials or intermediates) during the Justification:
manufacturing process.
Risk factors also related to the finished product:*
8 A particular risk of formation of nitrosamines should be noted for active substances that contain a nitrosatable
amine functional group. Several examples have been reported where the amine functionality was shown to be
vulnerable to nitrosation and formation of the corresponding N-nitroso impurity (i.e. NO-API). Secondary amines
appear particularly vulnerable to this reaction, although some cases with tertiary amines have also been observed.
8a Does the API, or one of its known impurities, have a YES ☐ NO ☐
nitrosatable nitrogen functionality? Justification: Please refer to the Chapter 7.
8b May nitrites be present in one of the used excipients? NA
9 Degradation processes of active substances, YES ☐ NO ☐ NA ☐
including those induced by inherent reactivity (e.g. Justification:
presence of nitro-alkyl, oxime, or other functionality)
or by the presence of an exogenous nitrosating agent.
10 Oxidation of hydrazine or other amine-containing YES ☐ NO ☐ NA ☐
functional groups present in active substances or Justification: Please refer to the root cause No. 4.
their impurities/degradants (e.g. from hydrazones
and hydrazides), either in active substance
manufacturing processes or during storage.
11 Use of certain packaging materials. YES ☐ NO ☐
Justification:
12 Reaction of amines leaching from quaternary YES ☐ NO ☐ NA ☐
ammonium anion exchange resins (e.g. used for Justification:
purification steps) with nitrosating agents present in
the liquid phase. In addition, disinfection procedures
such as e.g. chlorination, chloro-amination and
ozonisation can lead to significant N-nitrosamine
generation as by-products in case vulnerable amines
Document ID: Page 6 of 11
第 8 页
are present. Given the source of contamination, risk
is related to the concentration of the reactive agent(s)
and thus, to the volume of water in or used to dilute
a particular product. The same risks could be
associated with active substances or finished
products manufactured using water purified using
similar resins.
Risk factors related to GMP aspects:
13 Cross-contamination due to different processes being YES ☐ NO ☐ NA ☐
run successively on the same manufacturing line. Justification:
14 Carry-over of impurities between process steps due YES ☐ NO ☐ NA ☐
to operator-related errors or insufficiently detailed Justification:
batch records such as inadequate phase separations
during work-up procedures.
15 Use of contaminated recovered or recycled materials YES ☐ NO ☐ NA ☐
(e.g. solvents, reagents and catalysts) where the Justification:
recovery is outsourced to third parties who are not
aware of the content of the materials they are
processing. Recovery processes carried out in non-
dedicated equipment should also be considered.
Any other risk factor identified:
16
NA – not applicable
*Risk factors are assessed for API.
(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED.
In case no risk identified evaluating root causes, no further action is expected by API
manufacturer and risk outcome is concluded with no risk (section 6).
In case risk is identified evaluating root causes, list all N-nitrosamine impurities for which risk is
identified and complete the Table 2.
Indicate if mitigation measures/control strategy is in place. In case the risk is identified and
further mitigation/control strategy, including testing, is developed, maximum daily dose (MDD)
of active substance used for acceptable limit determination for N-nitrosamine impurities is
recommended to be included. Indicate also acceptable limit with a reference to the
corresponding nitrosamine guideline, e.g. CPCA categorization, ICH Q3A limit for
nitrosamines reported as non-mutagenic impurities or APIs indicated for advanced cancer
treatment.)
Table 2: List of all potentially present N-nitrosamine impurities identified in the API risk
evaluation
Possible N- Origin of possible Acceptable limit Mitigation Test results
nitrosamine N-nitrosamine / (Acceptable measures / available?
(Chem. Name / Root cause intake, MDD) Control strategy
Code Name and (specify
Chem. Structure) nitrosating agent
and nitrosatable
substance)
YES* ☐
NO ☐
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* Analytical test results
(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED. Include analytical results or
provide reference to the appropriate attachment.)
6 RISK OUTCOME
Based on the risk evaluation conducted and mitigation measures, the risk for presence of
nitrosamines is evaluated as:
☐ negligible (no risk identified)
☐ potentially present (risk identified)
(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED. Please select appropriate
conclusion based on the applicable option. Example text:
Option 1:
The risk evaluation indicates that there is no risk for N-nitrosamine impurities in API (name).
No further actions is needed.
Option 2
The risk evaluation indicates that there is a potential presence of N-nitrosamine impurity (name)
in API (name). However, according to the analytical testing results it is demonstrated that the
levels of N-nitrosamine impurity (name) are below 10% of acceptable limit. Therefore, there is
no risk for the presence of N-nitrosamine impurity in drug substance (API name) from the
manufacturer (API manufacturer name).
Option 3:
The risk evaluation indicates that there is a potential presence of N-nitrosamine impurity (name)
in API (name). According to the analytical testing results it is demonstrated that the levels of N-
nitrosamine impurity (name) are above 10% of acceptable limit. Therefore, N-nitrosamine
impurity is controlled in final API specification (API name) with limit of xy ppm (indicate the
value)).
7 ADDITIONAL INFORMATION TO SUPPORT THE RISK EVALUATION BY
THE DRUG PRODUCT MANUFACTURER / MARKETING AUTHORIZATION
HOLDER (MAH)
Based on the manufacturing process reviewed and on its related risk evaluation for potential
presence of nitrosamines, the API manufacturer declares that:
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7.1 For nitrosating agents:
- ☐ Nitrosating agents are not likely to be present in the final API.
- ☐ A risk for potential presence of the following nitrosating agents in the final API is
identified (Table 3).
Table 3: Nitrosating agents
Nitrosating agent Structure Potentially present in final API /
Levels in API, if applicable
Nitrite salts MNO2
Nitrate salts MNO3
Nitrous acid HNO2
Nitrous acidium ion H2O+-NO
Nitric acid (contains N2O4) HNO3
Alkyl nitrites R-ONO
Peroxynitrite ONOO(-)
Nitrosonium ion NO+
Nitro compounds R-NO2
Nitrous anhydride N2O3
Dinitrogen tetroxide N2O4
Nitrosyl halides Halide-NO
Nitrosyl thiocyanate ONSCN
Nitrosophenol Phenol-NO
Nitrosothiol SH-NO
Aqua regia HCl + HNO3
Nitryl chloride NO2Cl
Other (specify)
(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED. The term “nitrosating agent”
corresponds to (but not limited to): nitric acid, nitrite salts, organic nitrites, nitrosonium salts,
nitrogen oxides and nitro compounds).
Document ID: Page 9 of 11
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7.2 For Nitrosatable/vulnerable substances:
- ☐ Nitrosatable/vulnerable substances are not likely to be present in the final API.
- ☐ A risk for potential presence of the following nitrosatable/vulnerable substances
in the final API or as integral part of the API is identified (Table 4)
Table 4: Nitrosatable/vulnerable substances in API
Nitrosatable/vulnerable Structure By-products (Potentially) present
substance in final API / Levels in
API
Secondary amines R1-NH-R2 -
(cyclic and acyclic)
Tertiary amines (cyclic NHR1R2,
and acyclic) NHR1R3, or/and
NHR2R3
N,N-Dialkylamides R1CONR2R3 NHR2R3
N-Methyl-2- N-methyl-4-
pyrrolidinone aminobutyric acid
N-Chloroalkylamines R1R2N-Cl NHR1R2
N,N-Dialkylcarbamates R1O-CO-NR2R3 NHR2R3
Hydrazine derivatives NH2-NR1R2 NHR1R2
Other (specify)
(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED. Justification on
vulnerability or non-vulnerability of amine, hydrazine, hydrazide or hydrazone function
should be added here. Decision should be supported by literature data.)
(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED. The term
nitrosatable/vulnerable substances consider amines, hydrazines, hydrazides or hydrazones.
The term “nitrosatable /vulnerable amines” corresponds to an amine function that have
potential to react with nitrosating agents. According to EMA "nitrosatable" and "vulnerable"
are used interchangeably.
It corresponds to (but not limited to): Secondary amines (cyclic, acyclic), tertiary amines
(cyclic, acyclic), secondary/tertiary amine precursors, such as (but not limited to) quaternary
ammonium salts, N,N-dialkylamides (e.g. N-methyl-2-pyrrolidone, dimethylformamide,
dimethylacetamide), N-chloroalkylamines, and N,N-dialkyl carbamates that may be converted to
corresponding vulnerable amines.
(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED. The term “vulnerable hydrazine,
hydrazide or hydrazone” corresponds to a hydrazine, hydrazide or hydrazone function that can
lead to N-nitrosamine derivative by means of an oxidation step. This nitrosamine should as well
be able to lead to an alkylating diazonium salt as described in below scheme.)
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(INTERNAL INSTRUCTION ONLY. SHOULD BE DELETED.
The risk assessment does not concern nitroso compounds other than N-Nitrosamines. Currently,
the EMA and FDA Guidelines are applicable to N-Nitrosamines, compounds that have a carbon
atom on both sides of the amino nitrogen, where the carbon is not directly double bonded to a
heteroatom.
Nitrosated impurities of other compounds such as nitroso-ureas, nitroso-guanidines, nitroso-
amides, nitroso-carbamates, etc. could be under certain conditions theoretically possible. These
classes of compounds are unstable compared to N-nitrosamines and have a different
metabolism. These structures are not included in the scope of the EMA, FDA and other
countries nitrosamine guidelines, and therefore are outside the scope of the nitrosamine risk
assessment.
8 CHANGES IN MANUFACTURING PROCESS WITH POTENTIAL IMPACT ON
NITROSAMINE IMPURITY FORMATION
In case of changes in the manufacturing process, starting materials, suppliers etc. that may affect
this risk evaluation document, we will evaluate the impact, revise this document when necessary
and inform our customers in case of any changes in the outcome.
Document ID: Page 11 of 11
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