Industry calls for synchronized implementation of ICH M4Q(R2)

The Pharmaceutical Research and Manufacturers of America (PhRMA) has stated that the ICH M4Q(R2) involves a significant restructuring of the quality section of the Common Technical Document (CTD), bringing major changes for both the industry and regulators. As such, ICH and regulatory authorities should promote global synchronization of the guideline’s implementation to reduce the need for maintaining dual dossier structures.

There were also calls for more clarification on the timeline for converting legacy products to the new CTD format.

The concerns were raised in response to the US Food and Drug Administration’s (FDA) request for comments on the draft M4Q(R2) guideline that was issued in January 2026. A total of seven comments were available at the time of writing.

The guideline harmonizes the format and content of pharmaceutical quality data in the CTD. The guideline covers submissions, variations, and drug master files (DMFs). ICH released the guideline in May 2025. (RELATED: ICH releases guidelines on developing medicines for pregnant population and quality information in CTD, Regulatory Focus 28 May 2025)

PhRMA's concerns reflect similar sentiments shared by their counterparts in Europe. (RELATED: Industry clamors for clearer guidance on transition to ICH M4Q(R2), Regulatory Focus 23 February 2026)

Overall, PhRMA expressed its support for the guideline. The group said it “supports the efforts of the FDA and ICH to revise the quality module of the Common Technical Document (CTD) to enhance clarity, reduce duplication, and support global harmonization of pharmaceutical submissions. This revision is a key opportunity to better accommodate additional product types that may not be adequately addressed in the current version, including combination products. In addition, PhRMA anticipates that the revision will result in more efficiency and usefulness in terms of regulatory submissions and their assessment.”

‘Significant restructuring’

PhRMA stated that the guideline entails a "significant restructuring of the CTD-Quality module," which will require substantial changes for companies and regulators. PhRMA emphasized the necessity of a “carefully crafted” plan to ensure successful implementation of the guideline across various countries and to promote international regulatory alignment.

The group “encourages that R2 implementation be synchronized across regulatory authorities globally, to the extent possible, to minimize the need to maintain a dual dossier structure and to decrease maintenance burden. While an implementation plan may not be able to mandate a defined implementation timeframe, it could enable ICH members to better coordinate and synchronize implementation activities and inform regional timelines and planning.”

PhRMA also encouraged FDA and ICH members and observers to be flexible regarding the timelines for transitioning legacy products to the M4Q(R2) format. The guideline is supposed to go into effect in June 2027 for all new products. It is less clear when this will apply to legacy products.

“FDA and ICH should also consider a coordinated approach regarding the application of M4Q(R2) to legacy products and for post-approval changes, as appropriate, and allow for flexibility. We recommend that R2 be applicable for new molecule submissions and their associated post-approval changes. While M4Q(R2) could be applied to some legacy products, it should be at the discretion of the applicant.”

In other areas, PhRMA said that it supports the addition of a section on core quality information (CQI) in section 2.3.3 and sees this as a “key benefit” to the M4Q revision. Yet the group said that “it should remain clear that this section will be the one section to contain all lifecycle relevant information and that other parts of the dossier should be supportive.

In other areas, PhRMA stated that there is a need for greater clarity regarding the placement of information in sections 2.3.3 (CQI) and 2.3.4 (Development Summary and Justification) for biological products. Specifically, it should be clearer how the information should be divided between these two sections.

Biopharmaceutical services provider Sartorius also asked for more clarification on the timeline for converting previously submitted drug master files (DMFs) and legacy products to the new CTD format.

The company wrote that “the need for this documentation emphasizes that all legacy files will have significant changes and it is not clear how those changes will be processed as well as updated.”

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