ICH M7 & Nitrosamines Impurities -Updates

With the announcement of ICH’s plan to revise M7, I would like to create a space dedicated to all ICH M7 updates related to posts, information, and news.

Please bookmark this post below to keep yourself informed




ICH announces forthcoming documents on nitrosamine impurities, RWDThe International Council for Harmonisation (ICH) announced plans to issue two new documents: an addendum to the M7 guideline on assessing carcinogenic risk that would establish daily acceptable intake limits (AIs) for nitrosamine impurities and a reflection paper on harmonizing real-world data (RWD) in analyzing drug efficacy.

These developments were announced on 12 June following a 5 June meeting in Fukuoka, Japan. ICH also noted that “significant milestones” had been reached on advancing other guidelines.

Plans are in the works to issue an addendum to the ICH M7(R2) guideline on “Assessment and Control of DNA Reactive (mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” to control the safety of nitrosamines through the development of a harmonized set of acceptable intakes (AIs).

The current ICH M7(R1) guideline labels nitrosamines as a “cohort of concern” but does not set daily intake limits for these compounds.

The ICH Assembly also endorsed an upcoming reflection paper, soon to be published, on harmonizing RWD to generate real-world evidence, with a focus on using this data to measure drug effectiveness. The paper will accommodate public comments received during a consultation held June-September 2023.

The ICH also noted “significant milestones” had been reached on advancing other guidelines, including the adoption of the ICH M12 guideline on “Drug Interaction Studies” and supporting M12 questions and answers (Q&As) and the release of a Step 2 ICH M14 guidance on the principles for planning, designing and analyzing pharmacoepidemiologic studies that use RWD for assessing the safety of medicines (RELATED: ICH adopts M12 guideline on drug interaction studies, releases draft M14 guidance on RWD, Regulatory Focus 28 May 2024).

Another milestone was the release of the ICH E2D(R1) draft guideline which harmonizes post-market safety reporting requirements as a Step 2 in February 2023 (RELATED: ICH consults on revised post-approval safety guideline that accounts for digital platforms, Regulatory Focus 16 February 2024).

In other new news, the ICH Management Committee approved the development of a new concept paper on general considerations for patient preference studies.

The ICH Assembly also approved the revision of Q4B(R1) Guideline on “Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions” which has not yet been published. “The revision reflects that responsibility for the maintenance of Q4B and its annexes is handed over to the Pharmacopoeial Discussion Group (PDG),” said an ICH announcement.

ICH further announced that “the new procedure takes account of the growth in ICH Regulatory Members in recent years and will give non-PDG pharmacopoeias the option to harmonise their method with the PDG method or to implement the PDG method in parallel of a local method.”

In other areas, a survey was released to understand the current level of implementation and adherence to ICH guidelines. The results of the survey, which has not yet been released, “demonstrate good progress made by Regulatory Authorities in implementing ICH Guidelines since the two previous surveys from 2019 and 2021.”

1 Like

Press release by ICH on the Fukuoka meeting.

The Assembly adopted a new topic for harmonisation at the Fukuoka meeting:

  • An Addendum to the Multidisciplinary Guideline M7 on “Assessment and Control of DNA Reactive (mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” to address safety assessment and establishment of appropriate controls for nitrosamine impurities through a staged approach, leveraging the Formal ICH Procedure, as well as to develop a harmonised set of acceptable intakes (AIs) leveraging the M7 Maintenance Procedure.



Good Morning, @trust_user_a @trust_user_b @trust_user_c @trust_user_d
The ICH Secretariat has launched the process to establish the following working group, to begin the drafting of its Concept Paper:

ICH M7 Sub-Group:Addendum to ICH M7 on Risk Assessment and Control of Nitrosamine Impurities

ICH Members and Standing Observers who are either required or interested in nominating expert(s) are invited to complete their nomination in M7 Sub-group - Founding Members, Regulatory Members and Standing Observers Nominations within the 6 Weeks deadline

  • Founding Regulatory Members may nominate up to 2 experts;
  • Other Members and Standing Observers may nominate up to 1 expert;
  • Industry as a group (i.e. Founding Industry Members, Industry Members, Industry Standing Observer and Industry Observers) may collectively nominate up to 3 experts per WG for industry as a group.

Expected issue to be resolved by the WG:

Development of an M7 Addendum that would include principles and examples to support hazard assessment of nitrosamines and consistent derivation of AIs. The below topics will be addressed in a staged approach, including:
Stage 1 (2 years or less to reach Steps 1 and 2)
• Principles for the design and use of in vitro assays (e.g., Ames test) to differentiate mutagenic and non-mutagenic nitrosamines
• Principles for defining AIs based on Structure Activity Relationships (SAR) (e.g., considering knowledge of structural features of the nitrosamine molecule)
• Application of less than lifetime (LTL) adjustments to AIs based on exposure, provided that sufficient scientific data is available.6
Stage 2 (Topics to initiate when appropriate data and scientific literature become available)
• Principles for the design and use of in vivo mutation studies as follow-up studies to in vitro studies and/or in derivation of AIs
• Framework for deriving AIs based on read across methods
Following the completion of the stage 2 topics, a harmonised set of AIs for nitrosamines will be developed by the sub-group following the M7 maintenance process. The M7 sub-group will review and agree on the AIs to be included for specific nitrosamines in the new Addendum based on the adequacy of public data.
When appropriate resources and expertise become available, the proposed working group could also address relevant quality principles such as the application of M7 to nitrosamines risk assessment and control, particularly the finished dosage form, such as through the development of training materials and examples

CPOutline_M7NitrosaminesAddendum_2024_0603_EndorsedbyAssembly_2024_0604.pdf (165.2 KB)


Thank you for sharing, @Naiffer_Host. The document clarified EWG’s works and schedule under ICH M7. As we thought, it will take time to be resolved.

indeed informative ! thanks for sharing.

Dear @Naiffer_Host, thank you very much for sharing the Concept paper. Where did you get this document from? I could not find it on the ICH website.