Big Changes Coming for INDs, BLAs, & NDAs (Module 3 and Module 2.3)
First Major Revisions to the Common Technical Document (CTD) CMC Section Guidance in 25 Years
“Module 2.3 now serves as the primary basis for regulatory review.”
-ICH
Big changes lie ahead for the ICH Common Technical Document (CTD) Quality Module 3 and Module 2.3. After 25 years, the Guidance covering the content and organization of information for these CTD sections is being extensively revised to align with other major changes to FDA and ICH guidelines.
The revised document, called “M4Q(R2) The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality”, was published in draft form on FDA’s website on May 14, 2025, accessible here: FDA M4Q(R2) Draft Guidance (PDF).
The public comment period for the draft Guidance opened on January 21, 2026. Anyone interested can submit comments online to FDA regarding the draft M4Q(R2) through March 23, 2026, here: Submit Comments Online.
The revised Guidance will still require substantial discussion before finalization and acceptance by the ICH assembly, meaning it probably won’t officially come into effect until 2027. Nonetheless, it’s worth looking at the main issues that the revised CTD Guidance addresses:
Expanding the scope of the M4Q(R1) guideline. This M4Q(R2) guideline applies to all pharmaceutical drug substances and products (both chemical and biological) that require a marketing authorization.
Establishing the role of M4Q(R2) as the main source of the structure and location of regulatory quality information.
Organizing product and manufacturing information in a suitable format for easy access, analysis, and knowledge management.
Incorporating concepts and data expectations presented in ICH Quality guidelines and aligning with currently recognized international standards and guidelines.
Better capturing the pharmaceutical development and the proposed overall control strategy, which should be the backbone of the revised M4Q structure. This should address key elements of the proposed pharmaceutical product, including the Quality Target Product Profile (QTPP), manufacturing process, and overall control strategy.
Enhancing Quality Module 2 to facilitate the efficiency and effectiveness of regulatory submissions and assessments.
It’s important not to underestimate just how substantial the proposed changes for the CTD guidance are. According to ICH supportive materials, “…, Module 2.3 now serves as the primary basis for regulatory review.” Under M4Q(R2), Module 2.3 no longer simply summarizes critical information from Module 3; instead, information across the two modules will be “complementary, not duplicative.” Module 2.3.3 will cover information considered critical to ensuring product quality, Module 2.3.4 will present development summary and justification information, and Module 3 will house all supportive information for those Module 2.3 sections.
Moreover, Module 3 will be radically restructured to subsections based on drug substances (DS), substance intermediates (SI), starting materials (SM), raw materials (RM), excipients (EX), reference standards (RS), impurities (IM), drug products (DP), product intermediates (PI), medical devices (MD), packaged medicinal products (for multiconstituent products if applicable) (PM), pharmaceutical products after transformation (if applicable) (PH), analytical procedures, (AP), and facilities (FA).
Part of the intent behind these proposed changes is to support streamlining the submission process by allowing sponsors to focus on critical information while reducing direct incorporation of less relevant information. The proposed changes will also eliminate unnecessary repetition of information between Module 3 and Module 2.3 [I think we should drop the rest of this sentence] by fundamentally reorganizing where information critical to ensuring product quality is presented.
Although the ICH (and FDA) will provide a transition period before M4Q(R2) becomes effective, it will be valuable for industry professionals to get a head start on assessing how the proposed CTD changes relate to regulatory compliance and Health Authority expectations as well as what that will mean for submission lifecycle project management. That assessment can be used as yardstick to help determine the scope of regulatory / CMC changes needed to be ready for when M4Q(R2) takes effect.
Check back to CMC Regulatory Services’ News & Views blog in the future for new articles analyzing these proposed changes in more depth and assessing their impact on how IND, NDA, and BLA submissions should be written once the CTD Guidance is finalized.
