ICH M4Q(R2): The Common Technical Document for the Registration of Pharmaceuticals for Human Use – Quality

The U.S. Food and Drug Administration announced the availability of a draft guidance for industry titled "M4Q(R2) The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality." Prepared under the International Council for Harmonisation (ICH), this draft establishes a globally harmonized framework for organizing and presenting quality data in registration applications for human medicines. It updates the CTD's quality section to enhance registration and lifecycle management efficiency, promote digitalization and knowledge management, and accommodate emerging technologies.

When a pharmaceutical product is submitted for marketing authorisation anywhere in the world, regulators are not just evaluating the clinical data — they are deeply assessing how the product is made, controlled, and maintained throughout its lifecycle. This is where the Common Technical Document (CTD), and more specifically the Quality module, plays a central role.

Why M4Q(R2) Matters

Since the original M4Q guideline was introduced, pharmaceutical development and manufacturing have evolved significantly. Products today are more complex, manufacturing processes are more advanced, and regulators increasingly expect applicants to demonstrate robust lifecycle management rather than provide static data snapshots.

M4Q(R2) was developed to address these changes. It encourages applicants to move beyond simply compiling data and instead present a clear quality story, explaining development decisions, control strategies, and how product quality will be maintained over time. The guidance also aligns closely with newer ICH guidelines such as Q8, Q9, Q10, and Q12, reinforcing a lifecycle-oriented approach to quality.

Overall Structure of the M4Q(R2) Quality Dossier

M4Q(R2) focuses on two key sections of the Common Technical Document: Module 2.3 (Quality Overall Summary) and Module 3 (Quality). Module 2.3 provides an integrated, high-level overview designed to support regulatory assessment, while Module 3 contains the detailed technical data that underpins the summaries and justifications.

Together, these modules allow regulators to understand not only what controls are in place, but why they were chosen and how they interact to ensure product quality.

Module 2.3: Presenting the Quality Story

The Quality Overall Summary begins with general product information, clearly identifying the drug substance, drug product, dosage form, strength, route of administration, and packaging configuration. This establishes the context for the quality discussion that follows.

A major emphasis of M4Q(R2) is the description of the overall development and control strategy. Applicants are expected to explain the Quality Target Product Profile and identify Critical Quality Attributes that are essential for safety and efficacy. The guidance encourages a clear explanation of how scientific knowledge, risk assessments, and prior experience informed formulation design, process development, and control selection.

Central to this section is the overall control strategy, which shows how raw material controls, manufacturing processes, in-process tests, specifications, and stability studies work together to assure consistent product quality across the lifecycle.

Core Quality Information and Development Rationale

M4Q(R2) introduces the concept of Core Quality Information, which represents information subject to lifecycle management and regulatory oversight. This information is structured in a consistent manner, covering description, manufacture, control, and storage aspects of the drug substance, excipients, and drug product.

Rather than repeating raw data, the guidance places strong emphasis on development rationale and justification. Applicants are expected to explain why specific specifications, processes, and controls were selected, how impurities are managed, and why particular container closure systems and stability conditions are appropriate. Special situations, such as products without isolated drug substances or those involving medical devices, are also addressed in this narrative approach.

Lifecycle Management Focus

Another key feature of M4Q(R2) is its strong alignment with product lifecycle management principles. The guidance supports the identification of Established Conditions, planning for post-approval changes, and the use of structured change management tools. This approach aims to provide regulatory predictability while maintaining a high level of quality assurance throughout a product’s commercial life.

An optional section also allows applicants to describe the quality benefit–risk balance, particularly where residual risks exist but are adequately controlled in the context of patient benefit.

Module 3: Supporting Technical Detail

While Module 2.3 tells the quality story, Module 3 serves as the technical foundation. It contains detailed information on manufacturing processes, analytical methods, validation studies, stability data, and facilities. This module supports regulatory conclusions without duplicating high-level summaries.

For complete regulatory details and official guidance, kindly refer to:

• M4Q(R2): The Common Technical Document for the Registration of Pharmaceuticals for Human Use – Quality (FDA)