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Designing High Quality CMC Regulatory Submissions – A Systematic Approach  

Product quality is paramount to the development of safe and effective therapeutics. This is an intuitively simple and well-understood concept; however, in the increasingly complex world of biopharmaceutical development, the design and control of product quality is far from simple.

Fortunately, the U.S. Food and Drug Administration (FDA) and other global regulatory bodies have long recognized this challenge. More than fifteen years ago, the FDA issued a final report on “Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach”, setting the stage for Quality by Design (QbD). The primary message was that quality should be built into the final product by defining target product attributes early in development and designing the corresponding manufacturing processes and controls based on science- and risk-based principles.

The industry’s adoption and implementation of QbD principles have been a slow process, but the benefits of this approach were apparent early on.  By enhancing prospective planning and designing with the end in mind, product development can proceed in a more efficient and informed process thereby reducing waste and increasing quality output.

While product development scientists and quality professionals are often accustomed to writing about QbD principles within the Chemistry, Manufacturing and Controls (CMC) components of marketing applications (e.g. NDA/BLA, MAA), the preparation of such documentation often fails to invoke the central tenet of building quality into the preparation process itself. This is particularly true for expedited programs (e.g. Breakthrough Designation, Accelerated Approval, etc.) where CMC activities are rate-limiting to registration and the corresponding NDA/BLA preparation processes are held to extremely short timelines. By applying some basic QbD principles to the preparation of CMC components for marketing applications (e.g. prospective risk-assessments, beginning with the end in mind), sponsors can significantly de-risk the process and develop high-quality submission packages for even the most aggressive timelines.

Building quality into your submissions

In electronic common technical document (eCTD) format, Module 3 is the primary home of product quality (i.e. CMC) information. While this content may take slightly different forms across global applications, the preparation process generally remains the same. Conceptually, it can be helpful to envision Module 3 development like the construction of a new house. In both scenarios, there are primary components and steps within the process that are essential to ensure quality in the end result(s). These components (e.g. the foundation, the framework, and the floorplan) and associated steps are further described below.

Source Documentation – The Foundation:

Every CMC submission begins with source documentation – the underlying protocols, raw data, and reports that encompass the information related to the development, manufacture and characterization of your active pharmaceutical ingredient (API) and final drug product. Major gaps and/or weaknesses in source documentation can compromise the integrity of the entire submission. In order to de-risk the authoring process and to streamline data-integrity reviews, sponsors should compile a comprehensive list of all source documentation that will support the preparation of Module 3. It is important to build this list prior to 1st draft generation to identify gaps as early as possible. If you’ve acquired your product from a former sponsor and/or Contract Manufacturing Organizations (CMO) are part of the supply chain, this exercise becomes even more critical as documentation gaps can lead to major timeline delays when coordinating with third parties.

Key Messaging – The Framework:

The Office of Pharmaceutical Quality (OPQ) at the FDA typically begins (and concludes) their review of Module 3 (for marketing applications) with a product-specific risk assessment based on the information provided in the dossier. Therefore, NDAs and BLAs should guide the reviewer through potential product-related quality-risks to the patient and clearly demonstrate the ability of the proposed control strategy to mitigate any of these identified risks.

Building the risk-based framework of your dossier should always begin with a key messaging exercise as informed by product modality (e.g. small-molecule vs. monoclonal antibody), route of administration and therapeutic indication. Each modality has unique quality requirements, and the risk-based messaging should be adapted accordingly.

Use this exercise to identify safety/efficacy concerns that could result from potential failure modes within the process/product and key elements of the design that provide consistent control over specific risks. For example, process-related impurities and degradation products are key safety concerns that regulators assess during a review of applications for small-molecule drug candidates. Sponsors should develop robust messaging relevant to the formation, fate, and purge of impurities and the corresponding control strategies applied via the manufacturing process(es) and through end-product testing. The nature of each impurity should be clearly discussed within the context of patient safety and the approach to impurity control may be justified accordingly. Impurities that are known metabolites or those that have demonstrated safety qualification via nonclinical (or clinical) tested may be controlled to higher levels than impurities with limited data and unknown toxicity. In all cases, a holistic evaluation of all available data and information should be performed to support the presentation of clear and concise science-based justifications thereby allowing regulators to adequately assess safety risk.

By framing key messages early in the process (e.g. prior to 1st draft authoring), you can build a consensus around submission content and eliminate delays and/or major rework in downstream document preparation. In addition, this approach facilitates the development of Module 3 content that is highly focused on key process- and product-related control strategies as it pertains to the assurance of patient safety.

Interconnectedness – The Floorplan:

All too often, homes that appear well-constructed on the exterior are found to be poorly designed on the inside. As our homes should be easily navigable with proper flow and interconnectedness so too should our regulatory dossiers. It is important to note that Module 3 is highly granular, comprised of more than fifty individual components. With a variety of primary authors contributing to specific portions of Module 3 (e.g. process chemistry, formulation science, analytical, etc.), it is not uncommon to find a disjointed presentation of interrelated topics. For example, if a sponsor implements a new potency method late in development (e.g. following initiation of the pivotal trial), the timing, rationale, and implications of method optimization should be discussed in all relevant modules, not isolated to analytical modules only.

Careful consideration of the interconnectedness of Module 3 can significantly improve assessment time for FDA reviewers and reduce the likelihood of information requests resulting from unclear (or inconsistent) messaging.

Thinking long-term – Build it to last:

With “Pharmaceutical cGMPs for the 21st Century” came the concept(s) of product lifecycle management (LCM) which promotes a long-range view (i.e. discovery through patent expiry) during the development process. LCM principles should also be applied to the preparation of (CMC/Quality) aspects of marketing applications in order to minimize the post-approval regulatory burden. Rarely are the manufacturing processes, analytical tools and/or drug product presentations intended to remain unchanged following initial product approval. Process optimization, scale-up and the inclusion of new manufacturing sites are common post-approval changes and the CMC dossier(s) should be built with the future evolution of the product and process in mind. One common – and easy to fix – LCM pitfall is the inclusion of many appended documents (often from CMOs) within Module 3, e.g. analytical test methods. Site-specific test methods are living documents that frequently undergo revision. Including these documents in your package will mean that all revisions – big and small – will need to be tracked and reported to the filing. By integrating key content into the body of Module 3 and minimizing the need to append test methods, reports and other supporting documents the lifecycle management of the dossier will become much less burdensome.

Expanded product lifecycle management initiatives have been working their way through the International Council of Harmonization (ICH) and FDA for several years now. ICH Q12, “Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management”, has reached Step 5 of the ICH process and a new quality assessment tool, “Knowledge-aided Assessment and Structural Application” (KASA) is in late stage development. The concepts introduced and implemented via ICH Q12 and KASA have the potential to fundamentally change the way in which sponsors compile, prepare and manage the content that goes into marketing applications. These future changes only highlight the need for quality in planning and executing the development of Module 3.


Product development teams can spend many years and countless resources bringing novel therapies from the first clinical batch through process validation and commercial launch. Therefore, sponsors should take careful consideration to plan and build robust regulatory dossiers that effectively communicate all the critical thinking and strategic design comprising each CMC program. Building quality into your dossier by borrowing some basic QbD principles can de-risk major aspects of the NDA/BLA preparation process and facilitate the construction of a dossier that is built to last.