Industry clamors for clearer guidance on transition to ICH M4Q(R2)

The pharmaceutical industry has expressed a need for greater clarity regarding the timeline for converting quality information for new and existing drug and biologics dossiers to the common technical document (CTD) format described in the International Council for Harmonisation’s (ICH) M4Q(R2) guideline.

These were among the many concerns raised by the EU pharmaceutical industry in their feedback submitted in response to the European Medicines Agency’s (EMA) request for comment on the M4Q(R2) guideline. The guideline was published by ICH in May 2025. (RELATED: ICH releases guidelines on developing medicines for pregnant population and quality information in CTD, Regulatory Focus 28 May 2025)

The guideline harmonizes the format and content of pharmaceutical quality data in the CTD. The guideline covers submissions, variations, and drug master files (DMFs).

According to a concept paper published in November 2021, the M4Q(R1) guideline needed to be updated since it was adopted in 2002. The guideline was due for a revision to “improve registration and lifecycle management efficiency, leverage digital technologies, and accelerate patient and consumer access to pharmaceuticals.”

EMA received 23 comments on the guidance from European pharmaceutical groups, companies, and physicians on many different aspects of the guideline.

Concerns with transition period

A common theme running through many of the comments was the lack a transition period for companies migrating from the format specified in M4Q(R1) guideline to the M4Q(R2) guideline.

BioPhorum said that “there is concern around the transition period from ICH M4Q (R1) to M4Q (R2). Companies need clear guidance on how and by when to submit newly prepared NDA/BLA applications under M4Q (R2). Similarly, for sNDA/sBLA submissions, it is unclear how and when current approved NDA/BLA information (based on M4Q (R1)) should be converted to the M4Q (R2) format. These instructions are essential to ensure a smooth transition for both companies and regulators. Provide clear guidance or instruction on the transition period, including timelines and expectations for both initial and postapproval submissions under M4Q (R2).”

The Active Pharmaceutical Ingredients Committee (APIC) similarly weighed in. “We propose providing clear guidance for industry implementation, along with appropriate timelines for the transition from the old CTD to new CTD.”

The German Pharmaceutical Industry Association (Bundesverband der Pharmazeutischen or BPI) said that “a grace period or transition mechanism for existing products is not addressed. A long transition period and a clear roadmap are needed. This roadmap should comprise the handling of legacy product.”

Many suggestions to map changes to new guideline

At least five companies and pharmaceutical groups recommended that a final guideline illustrate the changes between the previous ICH M3(R1) document and the proposed new guideline.

Bausch and Lomb said that “Industry would benefit from clear, detailed mapping between the current ICH M4Q(R1) and proposed M4Q(R2) revisions, along with significant new data elements and structural requirements that manufacturers must address. High level data does not help identify and separate new information that would now be in scope and would need to be submitted. This would help manufacturers prepare IT system updates to accommodate granular data elements, QbD documentation and lifecycle management.”

APIC added that “the current drafted version of the guideline does not outline any expectations on how to best handle such cross referencing within the new structure. We also acknowledge that this topic is not addressed in R1, and handled more at regional levels. Nevertheless, we believe that some guidance could be beneficial. We suggest that this is considered for inclusion, potentially as part of the guideline or in the form of FAQs.”

BioNTech proposed that the revised document include an annex that maps each current section of M4Q(R1) to its corresponding location in M4Q(R2). The company noted that while sponsors and regulators are likely to develop these mappings independently, a unified table issued by the ICH would promote alignment and reduce effort across the industry.

BioPhorum said that “there is a significant format change between M4Q(R1) and M4Q(R2), but the lack of illustrative guidance, such as comparison maps or mock templates, makes it difficult for authors and reviewers to understand how to reorganize information and apply new concepts in the R2 format.”

The European Federation of Pharmaceutical Industries and Associations (EFPIA) said that “the transition from M4Q(R1) to M4Q(R2) introduces a modular and digital structure. Significant resource impact is anticipated due to required updates to GMD templates, SOPs, and authoring tools. Recommend including a transition roadmap for legacy products and a regional compatibility matrix to support global implementation.”

Concerns expressed with CTD 4.0 overlap

Concerns were also expressed with respect to how the new guideline will mesh with the upcoming CTD Version 4 and whether implementation of the eCTD 4.0 is considered in the timetable for implementing ICH M4Q(R2).

The Association of the European Self-Care Industry (AESGP) said that “If the implementation of eCTD 4.0 is identified as a prerequisite for implementation of ICH M4Q(R2), the very different uptake of eCTD 4.0 between regions should be considered in the overall timetable for implementation of ICH M4Q(R2).”

The group added that “full benefit of ICH M4Q(R2) will only emerge if the SPQS [Structured Product Quality Submissions] concept is realised. Otherwise, there is a high risk that dossiers have to be transferred twice: to the granularity of ICH M4Q(R2) first and to the technical format of SPQS later on. The implementation of this new structure for legacy products authorised under ICH M4Q(R1) will be very time consuming and need high efforts from industry and authorities without benefit regarding quality, safety and efficacy of the products.”

The SPQS concept refers to the submission of Chemistry, Manufacturing, and Controls (CMC) data from a traditional, narrative PDF document-based approach to a structured, machine-readable data format.

In the EU, eCTD submissions in Version 4 will become mandatory for all centrally authorized products in 2027. The FDA will require mandatory eCTD submissions in Version 4 by 2029. (RELATED: FDA, EMA officials encourage companies to pilot eCTD 4.0, Regulatory Focus 3 February 2026)

Medicines for Europe said that “since the implementation of ICH M4Q(R2) could also have an impact on eCTD 4.0 and may require technical adjustments, how will regulators ensure that the timelines for adoption are coordinated, so that industry does not face misalignment between dossier content requirements and electronic submission standards?”

More information on incorporating QbD

There were also concerns that the guideline does not provide sufficient detail on how manufacturers should implement Quality by Design (QBD) in their submissions. Certara said that “ICH Q8/quality by design principles at this time would be appreciated, as industry trend seems to indicate that momentum of 10-20 years ago has slowed down (especially for US generics), or at the minimum been inconsistent in terms of adoption/implementation (see references).”

Certara added that “Expectations around QTPP [Quality Target Product Profile] and CQAs [critical quality attributes] are unclear, but the new guideline seems to assume that all companies will have an extensive understanding and implementation of ICH Q8 already in place. This does not reflect real-world experience nor does it account for various issues and barriers surrounding implementation … we urge the working group to consider that the implementation and adoption of ICH Q8 has been staggered, inconsistent, and unclear, especially when region, application/product type, and business size are taken into account.”

Unclear expectations for investigational applications

Several companies raised concerns about the lack of clarity regarding investigational products.

Certara said that “the expectations for clinical, pre-approval applications (such as INDs or IMPDs) are not clear. How would the increasing GMP expectations (as development experience increases) be handled in terms of the new structure, especially in terms of expectations around material attributes, CQAs, etc.? We are concerned that interconnecting these principles would also make the new structure difficult to use for early development programs.”

EFPIA concurred. The group wrote that the “current text is geared toward late stage (i.e. enabling marketing authorization) and post approval products… The application of M4QR2 to early development stage submissions should be clarified in an explanation guidance or in the scope of the guideline.”

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Industry clamors for clearer guidance on transition to ICH M4Q(R2)

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