An integrated development approach forms the foundation of a robust and successful chemistry, manufacturing and controls (CMC) section for a new drug application. By aligning process development, analytical strategy, formulation and manufacturing from the outset, development teams ensure that scientific intent, product quality and regulatory expectations evolve together rather than in isolation. This integration reduces late-stage surprises, supports a coherent control strategy and creates a credible narrative that demonstrates product and process understanding to regulators.
Equally important is the application of balanced, managed pragmatism throughout development. Rather than pursuing technical perfection at every stage, teams make risk-based decisions appropriate to the phase of development, the available data and the intended clinical and commercial pathway. Fit-for-purpose methods, scalable processes and staged optimization focus resources where they matter most for patient safety and product performance.
This article focuses on Module 3 of the CMC dossier and its seven sections, specifically on drug substance (DS) development. It outlines a practical early-phase approach aligned with an integrated workflow. The sections include:
General information
Manufacture
Characterization
Control of DS
Reference standard or materials
Container closure system
Stability
Defining the DS
The General information section captures the fundamental description of the DS, including its name, chemical structure and key physicochemical properties such as solubility, polymorphic form, pKa and melting point. Early development and pre-clinical teams typically generate much of this information, which can be transcribed directly into the dossier.
At this stage, the dataset does not need to be exhaustive. The objective is to establish a clear scientific baseline that supports subsequent development decisions, rather than to fully characterize every molecular attribute.
Process development and manufacture
The Manufacture section contains most of the chemistry development program. It describes the manufacturing sites, the current synthetic route, a high-level process description, and the control of raw materials, starting materials, intermediates and in-process controls. It should also summarize any process development work undertaken to date.
Chemical and solid-state development should proceed in parallel with analytical investigations to ensure that teams understand process characteristics using process-typical materials. In early phases, development should remain pragmatic. Processes must be fit for purpose and compatible with the available equipment, typically sub-100 L jacketed vessels for Phase I manufacture, producing low-kilogram quantities of DS.
Chemistry will almost certainly evolve as process understanding increases. Raw materials, specifications, unit operations and even the synthetic route may change as the program progresses toward commercialization. Over-developing the process too early can therefore be counterproductive.
Batch data are inevitably limited at this stage. While teams may perform some one-factor-at-a-time experimentation, formal design of experiments (DoE) and failure mode and effects analysis (FMEA) are rarely justified due to time and cost constraints. Regulators recognize this reality, and early-phase submissions are not expected to define critical process parameters (CPPs) or critical quality attributes (CQAs) with the same level of confidence required at later stages.
Where appropriate, teams should favor a data-gathering approach over rigid fixed specifications. Reporting limits can provide flexibility while still supporting scientific oversight and informed decision-making, reducing the risk of unnecessary out-of-specification results during early development.
DS characterization
For GMP manufacture, teams should produce an API reference standard that is fit for its intended purpose, typically supported by HPLC assay and identification testing. Orthogonal techniques such as NMR, FTIR, mass spectrometry and polymorphic analysis should confirm structural consistency with the DS.
A full single-crystal structure determination represents the gold standard, particularly for stereochemically complex molecules, but may not always be feasible due to time constraints or material limitations.
This section also addresses impurities arising from the process, including organic impurities, potential mutagenic impurities, solvents and elemental impurities. For early-phase programs, in-silico screening for mutagenic impurities is not required; assessments based on structural alerts are generally accepted. Where mutagenic impurities cannot be avoided, introducing or generating them early in the process may support a purge-based control strategy rather than extensive analytical development.
Solvents and elemental impurities should be controlled in line with ICH Q3C and ICH Q3D, using option-based or dose-based approaches as appropriate.
Establishing control of the DS
The Control section defines the API specification, analytical procedures, batch analysis data and the justification of acceptance criteria. Although ICH impurity guidelines do not strictly apply to early development, teams commonly use them as a reference point in the absence of phase-specific alternatives.
Given the limited batch history, specifications should remain pragmatic. For example, an HPLC purity specification of not less than 97 percent is generally acceptable at Phase I, even when batch data consistently exceed 99 percent. As development progresses and process control improves, regulators may reasonably expect tighter specifications.
Non-genotoxic impurity limits pose a particular challenge in early phases due to limited understanding of fate and purge. Dose-based justification, rather than fixed percentage limits, can provide a scientifically defensible and developmentally appropriate approach. Importantly, tightening specifications over time demonstrates increasing process understanding and regulatory maturity.
GMP manufacture requires a validated, stability-indicating HPLC method. Where possible, using a single method that covers starting materials, intermediates, degradants and the API simplifies impurity tracking and supports lifecycle management.
Reference standards, materials, packaging and container closure systems
The Reference standards and materials section summarizes the specification and analytical results for the API reference standard, confirming its suitability for use in release and stability testing.
The immediate packaging for the DS should be clearly described. For early-phase material, typical packaging consists of double food-grade polyethylene bags placed in high-density polyethylene containers and secured with tamper-evident seals. Packaging materials should comply with relevant FDA and EU regulations. Stability studies should use packaging representative of the intended API container closure system.
Stability strategy and data generation
Stability studies should commence as soon as teams manufacture the first significant GMP batch using the intended process. Early stability data simplify the justification of storage conditions, shipping controls and downstream processing.
Teams should select stability conditions based on chemical development insights, solid-state behavior and forced degradation studies. Forced degradation not only informs stability risk but also demonstrates that analytical methods are stability-indicating. Where appropriate, standard long-term and accelerated conditions are usually sufficient.
Assessment of hygroscopicity prior to study initiation is recommended, as moisture uptake can disproportionately affect small-scale stability samples.
The resulting stability data justify storage conditions, shipping requirements and the proposed retest period for the API.
Building a credible early-phase CMC narrative
When developed within an integrated framework, early-phase pragmatism can strengthen the CMC section rather than undermine it. Thoughtful justification of decisions, clear linkage between data and controls, and a credible plan for lifecycle development together give regulators confidence that the program is scientifically sound and positioned for progression.
At the same time, early-phase CMC strategies are inherently provisional. Teams may need to revisit assumptions based on limited data as process understanding increases, making flexibility and clear documentation of change essential. A balanced approach does not seek to eliminate uncertainty, but to manage it transparently while supporting efficient clinical progression and future development.
Author information
Richard Chubb, R&D Director Richard Chubb joined Syngenta as a Research & Development Chemist in 2001 before moving to Onyx in 2002. He has gained expertise in process development and scale-up, alongside a strong understanding of GMP regulatory requirements, through roles as Development Chemist (2002–2007), Team Leader (2007–2023) and R&D Manager (2023–2025). As R&D Director, Richard has overall responsibility for development and manufacturing activities at Onyx, including non-GMP and GMP scale-up (Phase I–III and commercial).