References in Nitrosamines Exchange

I would like to introduce you to references used in this community in this thread.


  1. 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

  2. FDA: Control of Nitrosamine Impurities in Human Drugs

  3. ANVISA: Guide on Controlling Nitrosamines in Active Pharmaceutical Ingredients and Medicines ver.2 English translated by google uploaded by @Naiffer_Host

  4. Health Canada: Guidance on nitrosamine impurities in medications


  6. Japan: Self-inspection on Risks of Contamination with Nitrosamines in Drugs

  7. M7(R2) ADDENDUM Draft

  8. CMDh: CMDh practical guidance for Marketing Authorisation Holders of nationally authorised products (incl. MRP/DCP) in relation to the Art. 5(3) Referral on Nitrosamine

Additional information;

  1. FDA: Updates on possible mitigation strategies to reduce the risk of nitrosamine drug substance-related impurities in drug products

  2. AAM/CHPA/PhRMA Questions for 4th FDA-Industry Meeting to Discuss Nitrosamine Impurities in Pharmaceuticals

  3. AAM white paper Nitrosamines An Industry Position Paper Based on Risk

  4. Nitrosamines as Impurities in Drugs—Health Risk Assessment and Mitigation Public Workshop

  5. APIC: Additional guidance on the assessment on the risk assessment for presence of N-nitrosamines in APIs

  6. EMA: Assessment report


Limits of nitrosamines;

  1. Permitted daily exposure limits for noteworthy N-nitrosamines June 2021

  2. Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N -Nitrosamine Impurities February 2022

  3. Review of the Threshold of Toxicological Concern (TTC) approach and development of new TTC decision tree March 2016

  4. Category approaches, Read-across, (Q)SAR November 2012

  5. Use of less-than-lifetime (LTL) durational limits for nitrosamines: Case study of N -Nitrosodiethylamine (NDEA) July 2021

  6. Less than lifetime limits for N -nitrosamine mutagenic impurities October 2021

Additional information:

  1. Setting limits for complex nitrosamines (record)

  2. PhARMA-Global Workshop on Nitrosamine Impurities, Slides 1 Semtember 2021 uploaded by @DAB

  3. PhARMA-Global Workshop on Nitrosamine Impurities, Slides 2 Semtember 2021 uploaded by @DAB

If you want to add your favorites, don’t hesitate to post, please.


Analytical procedures;

  1. Publications review on Nitrosamines (Analytical) 2022

  2. Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development January 2022

  3. Development of an analytical method for the determination and quantification of n-nitrosodimethylamine in olmesartan by HPLC-MS/MS August 2022

  4. Absolute Quantitation of N -Nitrosamines by Coulometric Mass Spectrometry without Using Standards April 2022

  5. The Specificity of the Release of Nitrite from N-Nitrosamines by Hydrobromic Acid May 1971


Checklists and workflow;

  1. swiss medic: Checklist for the risk assessment of N-nitrosamine contamination

  2. IPEC: Questionnaire for Excipient Nitrosamines Risk Evaluation ver.3

  3. EFPIA: Workflows for Quality risk management of nitrosamine risks in medicines


  5. A Checklist For Risk Assessment Of Nitrosamine Impurities In Oral Solid Dose Drugs

Additional information:

  1. Risk Assessment Best Practice - Development of a Cross Pharma Work-flow for
    DP Nitrosamine Risk Assessment


  1. Lhasa Carcinogenicity Database (LCDB)

  2. Original CPDB (provided by leadscope)

  3. Structurally complex and API-like nitrosamine data added to the Complex Nitrosamines Database

Additional information;

  1. 5 things you should know about the data in the Lhasa Carcinogenicity Database (LCDB)

  2. Nitrites in Excipients(Lhasa)

  3. A Nitrite Excipient Database: A useful Tool to Support N- Nitrosamine Risk Assessments for Drug Products April 2022


Risk assessment: Purge factor;

  1. New Semi-Automated Computer-Based System for Assessing the Purge of Mutagenic Impurities October 2019

  2. Controlling a Cohort: Use of Mirabilis-Based Purge Calculations to Understand Nitrosamine-Related Risk and Control Strategy Options June 2020

  3. Control of Mutagenic Impurities: Survey of Pharmaceutical Company Practices and a Proposed Framework for Industry Alignment March 2021

Additional information;

  1. Nitrosamine Reactivity: A Survey of Reactions and Purge Processes July 2021

  2. Prediction of N -Nitrosamine Partition Coefficients for Derisking Drug Substance Manufacturing Processes March 2021


@Yosukemino Fantastic summary… a great first step for anyone starting the journey of Nitrosamines.


Thank you for your kind message, @Naiffer_Host. I hope everyone enjoys this fantastic journey in this community.

Risk assessment: root causes;

  1. Avoiding N-nitrosodimethylamine formation in metformin pharmaceuticals by limiting dimethylamine and nitrite May 2022

  2. Potential for the Formation of N -Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water August 2020

  3. Inhibition of N -Nitrosamine Formation in Drug Products: A Model Study December 2021

  4. Pathways for N -Nitroso Compound Formation: Secondary Amines and Beyond July 2020

  5. Nitrocellulose blister material as a source of N -nitrosamine contamination of pharmaceutical drug products April 2022

  6. Evaluating Nitrosamines from Elastomers in Pharmaceutical Primary Packaging July 2021

  7. Reaction of Irbesartan with Nitrous Acid Produces Irbesartan Oxime Derivatives, rather than N -Nitrosoirbesartan March 2022

  8. Ranitidine—Investigations into the Root Cause for the Presence of N -Nitroso- N , N -dimethylamine in Ranitidine Hydrochloride Drug Substances and Associated Drug Products December 2020

  9. Investigating the root cause of N-nitrosodimethylamine formation in metformin pharmaceutical products Apr 2021


Review articles and features of nitrosamines;

  1. Tolerability of risk: A commentary on the nitrosamine contamination issue June 2021

  2. An Organic Chemist’s Guide to N -Nitrosamines: Their Structure, Reactivity, and Role as Contaminants January 2021

  3. Managing the Risk of Nitrosamine Impurities March 2021

  4. Defining the molecular properties of N -nitrosodimethylamine (NDMA) precursors using computational chemistry May 2017

  5. Mutagenic Impurities: Strategies for Identification and Control February 2022


Thankyou for summarising the information links together as a one point quick reference. Great idea, excellent initiative :ok_hand: :point_up_2:


New checklists and workflow;

  1. EFPIA workflows (ver 2.0)
  2. IPEC questionnaire (ver 4.0)
  3. APIC nitrosamine risk assessment template