Why CMC is the Most Underestimated Function in Drug Development

How chemistry, manufacturing and controls impacts regulatory approval, timelines and risk in drug development

Seventy-four percent of complete response letters (CRLs) issued by the FDA between 2020 and 2024 cited quality and manufacturing deficiencies, based on an independent industry analysis of more than 200 CRLs published in 2025. That figure should give pause to any organization that treats chemistry, manufacturing and controls as a downstream concern. 

CMC failures remain one of the most predictable and preventable causes of regulatory delay, yet the function is systematically underestimated across the pharmaceutical and biotech industry.

Clinical development continues to command the majority of attention and investment, yet CMC ultimately determines whether a promising molecule can actually be manufactured consistently, safely and at scale. For many organizations, it takes a regulatory setback to bring that reality into focus.

 

What CMC (Chemistry, Manufacturing and Controls) actually covers in drug development

CMC stands for chemistry, manufacturing and controls. Often described as the technical backbone of drug development, it covers the full body of technical and regulatory work required to develop, manufacture and test a drug product consistently and to the standard global regulators require.

CMC readiness is a prerequisite for clinical and commercial progression, because each component depends on the others to demonstrate that a product can be made safely and reliably. In practice, it is the function that determines whether a scientific concept can be translated into a reproducible and approvable product.

Chemistry

The drug substance itself. 

Its molecular structure, physical and chemical properties, production route, impurity profile and stability characteristics. Understanding the chemistry of a product is the foundation on which everything else is built. This includes defining critical quality attributes (CQAs), identifying potential impurities early, and establishing the analytical framework that supports later-stage development.

Manufacturing

How the drug is produced at scale. 

This spans process development, technology transfer, scale-up operations and GMP-compliant production. Manufacturing is where science meets commercial reality and where robustness, reproducibility and scalability must be proven, long before regulators assess commercial readiness.

Controls

The analytical and quality systems that prove compliance.

Controls ensure every batch meets specifications for identity, strength, purity and quality. They provide the evidence base underpinning regulatory submissions, comparability exercises, stability commitments and ongoing lifecycle management.

Together they form the technical backbone of every regulatory submission. Global agencies including the FDA, EMA and PMDA require comprehensive and increasingly rigorous CMC regulatory data at every stage, from first-in-human studies through to post-approval change management.

 

The cost of getting CMC wrong

CMC problems do not announce themselves early. They surface at the worst possible moments, during a Phase III validation campaign, ahead of a pre-approval inspection or buried in a complete response letter that arrives after years of development investment.

The organizations most exposed are not always those lacking scientific talent. A process development gap at Phase I is often recoverable. At Phase III, with process validation timelines locked and manufacturing sites under scrutiny, the same gap can add months to a programme and significant cost to an already stretched budget.

Inadequate pharmaceutical development, poor drug product controls, stability deficiencies and GMP-related findings are among the most consistently cited reasons for complete response letters across NDA and BLA submissions. These are not novel findings. In most cases, they trace back to the same root cause: CMC capability that was not in place when it was needed most.

 

How CMC requirements evolve across the drug development lifecycle

CMC requirements follow a predictable regulatory timeline, but the depth of data expected increases sharply at each stage. CMC is not a fixed function. Its requirements vary across the development lifecycle, and the expertise needed to support each stage develops in line with those demands.

Preclinical and IND-enabling

The focus is on characterizing the drug substance, developing initial formulations and building the analytical methods needed to support toxicology studies. The goal is generating enough CMC data to support an IND application and demonstrate the drug is safe for first-in-human studies.

Phase I and Phase II

Manufacturing processes must be GMP-compliant, batches consistent and traceable, and analytical methods validated to support data integrity. Formulation work continues in parallel, with a focus on identifying the optimal drug product for later-stage development. Regular agency engagement during this period is strongly encouraged to avoid late-stage surprises. At this stage, gaps most often emerge in analytical validation and process consistency, which can limit the reliability of data carried forward into later phases.

Phase III and pre-approval

By Phase III, the demands on CMC teams intensify significantly. Process validation must be complete, long-term stability studies finalised and the CMC sections of the marketing application ready for submission. The End of Phase II meeting is a critical checkpoint that sets the tone for everything that follows. Organizations that arrive at it without the right CMC capability already in place rarely have enough time to course correct. At this point, incomplete process validation or insufficient stability data can directly delay submission timelines or result in regulatory findings.

Post-approval: approval is not the finish line

Approval is not the finish line for CMC. Manufacturing site changes, process improvements, formulation adjustments and product lifecycle extensions all require ongoing regulatory management. It is one of the most consistently understaffed phases in the development lifecycle, and organizations that deprioritise it often find themselves unprepared when post-approval changes require regulatory re-engagement.

 

The functions within CMC and where the talent gaps are deepest

CMC is not one job. It is a collection of distinct specialisms, each with its own talent market.

Function	What they deliver	Where they sit in development
Process Development	Design and optimisation of drug substance and drug product manufacturing processes, including scale-up and technology transfer	Preclinical through to commercial launch
Analytical Development	Development and validation of methods to characterize the drug and confirm batch consistency	Every stage, from IND-enabling studies to post-approval
Formulation Development	Translation of drug substance into a stable, scalable and market-ready drug product	Early development through to commercial manufacture
Regulatory CMC	Submission strategy, technical dossier authoring and post-approval change control	IND through to lifecycle management
Manufacturing Science and Technology	Technology transfer, process validation and continuous improvement between development and commercial manufacturing	Late-stage development and commercial operations
GMP Quality and Compliance	Maintaining manufacturing standards, managing deviations and ensuring inspection readiness	Commercial manufacturing and post-approval

The talent shortage is not evenly distributed. Process development, regulatory CMC and MSAT consistently present the greatest hiring challenges, particularly at senior level and across biologics and advanced therapy programmes. These are profiles that require years of highly specific experience and are rarely found through conventional hiring channels.

 

The CMC talent market is under sustained pressure

The data makes the scale of the problem clear.

Together, this reflects a tightening talent market where demand for experienced CMC professionals continues to outpace accessible supply.

Experienced CMC professionals are not sitting in a talent pool waiting to be found. They are employed, well-compensated and deeply embedded in programmes that depend on them. The organizations that secure the best people are not always the ones with the biggest budgets. They are the ones that engage early, understand the market and have access to professionals who will never appear on a job board.

In CMC, by the time a need becomes urgent, the best candidates are already committed elsewhere.

 

What the strongest CMC teams have in common

Having placed CMC professionals across pharmaceutical, biotechnology and CDMO organizations for over a decade, certain patterns hold consistently.

The organizations with the strongest CMC teams invest early. CMC capability built at the preclinical stage pays dividends at every subsequent regulatory checkpoint. Organizations that wait until they need a hire urgently consistently pay more and wait longer.

They plan for their modality. The CMC workforce requirements for a small molecule program are fundamentally different from those for a biologics or advanced therapy programme. Generic workforce planning does not work in a function this specialized.

They access the passive market. Most experienced CMC professionals are not actively looking. The organizations that secure the best people are those that can reach professionals who are not visible through conventional channels.

They build flexibility into their hiring strategy. Contract and interim CMC specialists play a critical role across regulatory submissions, technology transfers, process validation campaigns and inspection preparation. Permanent capability combined with targeted contract support gives organizations the agility to respond to program demands without overextending headcount.

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Finding the right CMC expertise at the right stage

CMC capability is not something most organizations discover they lack at the preclinical stage. They discover it at Phase III, during a pre-approval inspection, or when a complete response letter arrives after years of development investment. By that point, closing the gap costs significantly more in time, budget and regulatory goodwill than building it earlier would have.

The organizations that reach approval without CMC-related delays treated CMC as a strategic function from the start, not a problem to solve when it became urgent. In a talent market this tight, that distinction rarely comes without a cost.

EPM Scientific has placed CMC professionals across pharmaceutical, biotechnology and CDMO organisations for over a decade, from IND-enabling process development through to post-approval regulatory management. Whether you need a single critical hire or are building out a full CMC function, our team is ready to help.

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