Phase-Appropriate CMC Strategies for Complex Small Molecules: Integrating Drug Substance and Drug Product to Avoid Late-Stage Surprises

The development of new chemical entities (complex small molecules) presents increasing technical, regulatory, and operational challenges across both Drug Substance (DS) and Drug Product (DP) domains. When Chemistry, Manufacturing, and Controls (CMC) activities are not aligned with the evolving needs of each development phase, and when DS and DP decisions are made in isolation, the late-stage surprises often emerge. These can include scale-up failures, solid-state changes, formulation instability, regulatory delays, and costly redevelopment.

This white paper outlines how phase-appropriate, integrated DS–DP CMC strategies enable sponsors and CRDMOs such as Aragen to proactively manage these risks. By calibrating the depth and rigor of both DS and DP CMC activities to each development stage and by maintaining a strong scientific “DS–DP line of sight”, the programs can progress predictably from early development through clinical supply and toward late stages of development. When applied effectively, this approach minimizes late-stage issues, protects timelines, strengthens partnerships, and positions CMC as a strategic enabler rather than a reactive function.

The pharmaceutical industry is increasingly focused on developing NCEs with novel mechanisms of action, improved selectivity, and applications in precision medicine. While these molecules offer significant therapeutic promise, they also introduce heightened complexity across the CMC landscape. Challenges span synthetic chemistry, impurity control, and solid-state behaviour on the DS side, as well as formulation design, biopharmaceutical performance, manufacturability, and stability on the DP side.

As programs advance from preclinical development into clinical and later stages, these challenges often intensify. Decisions made early, such as solid form selection, particle attributes, impurity limits, or formulation strategy, can have far-reaching consequences during scale-up, validation, and regulatory review. Clinical development and manufacturing stage failures frequently arise when DS and DP CMC activities evolve independently or when early-phase decisions are not revisited with downstream requirements in mind. Phase-appropriate CMC strategies address this risk by aligning both DS and DP activities with the specific objectives, risk profile, and regulatory expectations of each development phase. When implemented in an integrated manner, they provide a structured roadmap that supports efficient progression from discovery to clinic while reducing technical and regulatory uncertainty.

CMC encompasses the activities required to consistently produce a pharmaceutical product that meets predefined quality attributes relevant to safety and efficacy. For small molecules, CMC spans DS development (chemical synthesis, solid-state control, impurity management) and DP development (formulation design, process development, and product performance control).

A phase-appropriate approach calibrates the depth, precision, and investment in both DS and DP activities according to development stage:

Early development (preclinical to early Phase I)

• DS focus: Synthetic feasibility, route scouting, preliminary impurity and genotoxic risk assessment, early solid form selection, and initial stability understanding to support tox and first-in-human supply.
• DP focus: Pre-formulation and material science to understand solubility, dissolution behavior, particle attributes, excipient compatibility, and early biopharmaceutic risk. Simple, fit-for-purpose formulations are selected to enable rapid clinical entry.

Mid-stage development (Phase I–II)

• DS focus: Improved process robustness, reproducibility at increasing scale, expanded impurity characterization, polymorph and solid-state control, and deeper understanding of critical process parameters.
• DP focus: Refinement of formulation strategy, development of scalable DP processes, phase-appropriate dissolution and performance specifications, and enhanced stability programs to support extended clinical studies.

Late-stage development (Phase III and beyond)

• DS focus: Fully validated processes, comprehensive impurity and solid-state control strategies, long-term stability, and reliable manufacturing.
• DP focus: Final formulation and process validation, robust control of critical quality attributes (CQAs), lifecycle stability programs, and packaging strategies aligned with global regulatory expectations.

This integrated, staged approach avoids unnecessary over-engineering early while ensuring that both DS and DP CMC activities are sufficiently mature and aligned to meet early to late-stage regulatory demands.

Surprises are unanticipated issues that emerge during pivotal clinical phases, scale-up, validation, or regulatory review. For complex small molecules, these issues often arise at the DS–DP interface, where early assumptions are stressed by scale, time, and regulatory scrutiny. Common sources include:

DS-related risks

• Emergence or amplification of impurities during scale-up or long-term stability
• Polymorphic or solid-state changes triggered by processing or storage
• Incomplete understanding of critical process parameters leading to batch variability

DP-related risks

• Formulation instability due to API–excipient interactions
• Dissolution or bioavailability failures as clinical exposure expectations evolve
• Scale-dependent process challenges (e.g., blending, granulation, filling)
• Changes in particle attributes impacting content uniformity or performance

Analytical and regulatory risks

• Insufficient analytical sensitivity to detect relevant impurities, solid forms, or degradation products
• Early CMC decisions misaligned with evolving regulatory expectations for DS or DP

Beyond technical remediation, these surprises increase cost, extend timelines, and may erode sponsor confidence—particularly when DS and DP development are managed in silos rather than as an integrated continuum.

Avoiding surprises requires a proactive, science-driven approach that integrates DS and DP decision-making across development stages. These include to identify chemical, solid-state, biopharmaceutical, and formulation risks during lead selection and preclinical development. This also include to combine predictive tools, experimental screening, and expert review to prioritize risks that could impact both DS manufacturability and DP performance. Some of the key facets are as following:

• Robust DS and DP process development
  Apply Quality by Design (QbD) principles to define CQAs and critical process parameters across both DS and DP. Synthetic routes and formulations should be optimized not only for early material generation but also for robustness, scalability, and downstream compatibility.
• Comprehensive analytical development
  Develop stability-indicating analytical methods that support both DS and DP needs, including impurity profiling, solid-state characterization, dissolution testing, and forced degradation studies. Integrated analytical strategies enable faster feedback and informed decision-making.
• Controlled scale-up and tech transfer
  Execute staged scale-up for both DS and DP, generating representative pilot batches to confirm process performance, impurity profiles, formulation robustness, and CQA trends before committing to validation or pivotal supply.
• Regulatory alignment and documentation
  Maintain phase-appropriate documentation of DS and DP development decisions, risk assessments, and change rationales. Early and ongoing regulatory engagement ensures alignment on expectations and reduces the risk of late-stage information requests.
• Effective CRDMO collaboration
  Establish transparent, technically driven partnerships where DS and DP teams collaborate closely with sponsors, enabling seamless knowledge transfer and joint problem-solving rather than reactive remediation.

CRDMOs play a central role in operationalizing integrated, phase-appropriate CMC strategies for complex small molecules. Their value lies not only in execution but in connecting DS and DP science across the lifecycle. At Aragen, integrated DS–DP CMC capabilities provide a continuous, co-located workflow that strengthens scientific line of sight from early material science through clinical DP supply.

Clinical development and manufacturing surprises remain among the most costly and disruptive risks in the development of NCEs. A phase-appropriate, integrated DS–DP CMC strategy provides a rigorous framework to anticipate and mitigate these risks by ensuring that chemistry, formulation, manufacturing, and controls evolve together in a structured, science-driven manner. By working with CRDMO partners like Aragen, who are capable of aligning DS and DP CMC across the lifecycle, clients can move from reactive problem-solving to predictable execution—accelerating development timelines, strengthening regulatory confidence, and enabling reliable clinical supplies.