A new chapter for CTD: Implications for the Industry

As the CTD structure faces its most significant update in over two decades, Diapharm takes a closer look at what this regulatory milestone could mean for the future of pharmaceutical submissions  — and why industry leaders should be paying attention.

In 12^th of September 2002 the switch from NTA Vol. 2B (ed. 1998) to CTD (Common Technical Document) was adopted by the regulatory members of the ICH assembly. The CTD content is presented in ICH M4Q(R1), the granularity of the CTD is described in ICH M4 Organisation of the Common Technical Document for the registration of pharmaceuticals for human use. 

Now, more than 20 years later a significant update of the CTD structure is in preparation. Currently the updated draft guideline is undergoing step 3 (regulatory consultation and discussion) of the procedure.

What are the drivers of the update for ICH M4Q(R1)?

The drivers of the update are to:

• facilitate increased/improved convergence and harmonisation of the quality part of the dossier as the current ICH M4Q(R1) was not fully implemented in some ICH regions.
• to align ICH M4Q with ICH Q8 to Q14 which in the present format of the eCTD structure are not adequately reflected.
• provide more guidance on the location of information on complex products (e.g. biotechnological products, multi-component products, combination products).
• take into consideration the advance in digital tools, data management and standardization, and analytics to enhance regulatory submissions and assessment. (ICH M4Q(R2) per se will not address the IT topics. Details are provided in ICH M8 eCTD.) 

What will be changed?

The updated version of ICH M4Q literally represents a “reverse thrust” in the importance of the dossier sections of dossier Module 2.3. Quality Overview and Module 3 Quality. 

Up to now the preparation of the Module 2.3 Quality Overview was a “copy-paste-exercise” to transfer relevant information from Module 3 to Module 2.3, whereas Module 3 included the major information. With the update of ICH M4Q the significance of Module 2.3 will more resemble the significance of Module 2.4/2.6 and Module 2.5/2.7 for preclinical and clinical data and Module 3 will provide supportive documentation.

Module 2.3 will consist of:

• 2.3.1. General information
• 2.3.2. Overall Development and overall control strategy
• 2.3.3. Core Quality information on drug substance and related topics as well as drug product and related topics (including medical devices if applicable)
• 2.3.4. Development Summary and Justification regarding drug substance and related topics as well as drug product and related topics.
• 2.3.5. Product Life Cycle Management Document
• 2.3.6. Product Quality Benefit Risk (optional)

and Module 3 will consist of:

• 3.1. Table of contens of Module 3
• 3.2. Body of data
• Abbreviations
• Glossary
• References

A presentation of the ICH Assembly on the updated ICH M4Q characterises the new Module 2 and Module 3 as depicted in the picture below. 

What are the implications for the MAHs?

The modification of both, Module 2 und Module 3 will require a major rearrangement of dossier sections. Significant differences to the current Module 2.3 and Module 3 are:  

• Modules 2 and Module 3 are complementary to each other
• Two different categorisation and header logics are applied
  • Quality information which is material related is aligned with the roles of these materials (e.g. materials related to drug substance like raw materials, starting materials, intermediates and packaging as well as materials related to drug product like excipients, intermediates and packaging of the drug product).
  • Information not directly liked to materials are presented in overarching sections (e.g. analytical procedures irrespective of the application for materials related to drug substance or drug product and information of manufacturing facilities.)
• More recent development and control concepts are considered such as:
  • The Quality Target Product Profile (QTPP)
  • The control strategy for the development of the product starting with the introduction of starting/source material down to the finished product (ICH Q6A/B; Q8, Q9, Q10, Q11)
  • Science and risk-based justification of changes made during development of drug substance and product and their manufacture (e.g. choice of starting material, excipients, manufacturing process etc.)
• Topics that have previously only been addressed indirectly or not at all are given a platform, e.g.
  • Intermediates, starting/source materials, raw materials
  • Extractables and leachables, adventitious agents
  • Medical devices
  • Multiconstituent products and products after transformation
  • Analytical procedure development (ICH Q14)
  • Life Cycle Management (ICH Q12)

What are the implications for manufacturers of medical devices?

The update of the ICH M4Q will not only concern pharmaceutical manufacturers but also manufacturers of medical devices if their product incorporates a medical substance that has an action ancillary to that of the device. 

According to Regulation (EU) 2017/745 on medical devices (MDR) Chapter 5.2 Procedures in the case of devices incorporating a medicinal substance it is required that “the quality, safety and usefulness of the substance shall be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC).”  The requirements of Annex I are reflected in ICH M4Q and therefore, will be updated accordingly. 

Which will be the timeline for implementation?

According to the work plan the step 3 sign-off and step 4 adoption of the final guideline is envisaged for June 2027. 

The actual implementation of the current ICH M4Q(R1) Guideline in the member states of the ICH Assembly varied. However, the requirements were implemented very promptly in the founding states of the ICH Assembly (USA, EU/Europe and Japan between 2001 and 2003).

New submissions:

It can be assumed that upon adoption of the updated guideline (ICH M4Q(R2) the new requirements will have to be implemented quickly within the EU for new submissions. Therefore, the changed structure and the more detailed information requirements should already be considered during product development.

Existing products:

Existing products are subject to a different set of circumstances. Here, it can be assumed that there will be a transition period during which variations to the existing dossier can be submitted in the new format without a complete update of the remainder of the dossier to the new format. 

Since the harmonisation of marketing authorisation dossiers is of great interest to MAHs (reduced time/costs), the establishment of a baseline is particularly desirable for very active products (products with frequent change notifications). 

Outlook

Diapharm will carefully track developments and consider their implications for manufacturers of medicinal products, medicinal products with an integral medical device constituent part and medical device manufacturers including an ancillary medicinal product. 

We are happy to guide you through the transformation process with your new registrations and the life cycle management of your existing products.