Why CMC is the most underestimated risk in drug development
In early-stage biotech, the conversation tends to be dominated by the science. Target validation, proof of concept, mechanism of action, preclinical signals. These are the areas where founders, CSOs and investors spend most of their attention, and understandably so. The science is what justifies the next round of funding and the next development decision.
What often receives less attention is a more quiet risk that runs alongside the science from the very first months of a programme: Chemistry, Manufacturing and Controls (CMC). It rarely appears on a slide deck at seed or Series A. It is rarely the subject of the first board discussion. And yet, when programmes stall, are delayed, lose investor confidence or fail to enter the clinic on time, CMC is increasingly the reason.
The evidence on this has become difficult to ignore. According to publicly available analyses of FDA activity, over 33% of clinical holds in 2024 stemmed from CMC deficiencies, and the figure has continued to rise in 2025. One industry survey indicated that more than 40% of unsuccessful IND filings were related to CMC issues, particularly among smaller companies. At the marketing application stage, the picture is even more striking: an estimated 74% of Complete Response Letters issued between 2020 and 2024 cited quality or manufacturing deficiencies.
These numbers describe a pattern that is recognisable to anyone who has worked inside a development programme. CMC is rarely the reason a molecule is selected, but it is often the reason a programme slows down.
Why CMC gets underestimated
There are structural reasons why CMC is consistently underweighted in early-stage biotech.
The first is timing. Early development is organised around scientific milestones: lead identification, candidate selection, proof of concept, IND-enabling toxicology. CMC activities run in parallel with these milestones, but their deliverables become visible later, often only when a sponsor prepares for a regulatory submission or a GMP campaign. By the time the CMC pathway comes into focus, several irreversible decisions have usually already been made.
The second is perception. CMC is frequently framed as an operational or regulatory task rather than a strategic one. In this framing, it can reasonably be handled later, when the molecule is further along. This view underestimates how much early technical decisions shape later options. The expression system selected at research stage, the analytical methods used to characterise early batches, the formulation platform chosen for the first preclinical studies: each of these decisions narrows the set of options available for clinical development and eventual commercialisation.
The third is internal capability. Many early-stage biotechs are built around a strong scientific founding team, with limited senior CMC leadership in place at the time the most consequential decisions are being made. This is not a failing; it reflects how early-stage companies are funded and staffed. It does, however, mean that CMC decisions are often made without the benefit of experience across multiple development programmes.
The combination of these three factors creates a recurring pattern. CMC is not ignored, but it is not actively shaped. It evolves by default, as a series of practical responses to scientific decisions rather than as a deliberate strategy. By the time the consequences become visible, the cost of correcting them has significantly increased.
What CMC failure actually looks like
In practice, the CMC risk does not usually materialise as a single catastrophic event. It materialises as a sequence of delays, rework and forced compromises that accumulate across the programme. A few patterns recur across modalities and company sizes.
Impurity mismatches between toxicology and clinical batches
One of the most consistent sources of delay at IND or CTA stage is an impurity profile in clinical material that does not match the profile of material used in toxicology studies. When a new impurity appears in clinical lots that was not qualified in toxicology, the regulator is left without a defensible safety bridge. The programme then faces a choice between additional toxicology work, reformulation, or changes to the process, each of which consumes time and capital.
This issue is rarely caused by a single bad decision. It is usually the result of an analytical package that was not yet sensitive enough to detect the impurity at toxicology stage, combined with process changes introduced during scale-up.
Analytical methods that are not fit for purpose
Analytical methods developed at research stage are often adequate for internal decision-making but insufficient to support regulatory filings. Specificity, sensitivity, stability-indicating properties and the ability to detect process-related impurities all need to be demonstrated to a defined standard. When methods are transferred to a CDMO or a specialist laboratory without a clear qualification plan, gaps often appear late, sometimes during the preparation of the IND or IMPD itself.
For biologics and advanced therapies, potency assays are a particularly sensitive area. Regulatory expectations around potency have tightened, and surrogate methods alone are increasingly difficult to defend beyond early clinical phases. FDA guidance for cell and gene therapy products explicitly recommends initiating potency assay development during preclinical and early clinical investigations, precisely because these assays take time to mature.
Formulation that is not ready for the clinical plan
Another common delay source is a formulation that cannot support the intended clinical study. Stability profiles that do not cover the study duration, viscosity issues at therapeutic concentrations, container-closure incompatibilities, or drug product shelf life shorter than the trial window each have the same effect: the clinical plan cannot proceed as designed.
These issues are rarely identified before they become urgent. They emerge when the first GMP batch is released and the stability data starts to accumulate, which is often long after the clinical plan has been agreed with investors.
Comparability gaps after a manufacturing change
Almost every programme undergoes at least one significant manufacturing change between first GMP batch and pivotal trials. A site change, a scale change, a raw material change, a CDMO change. Without a structured comparability strategy, these changes create gaps that are difficult to close retrospectively. For biologics, where minor process changes can affect product structure or function, these gaps can trigger additional characterisation work, regulatory questions, or in some cases a bridging clinical study.
CDMO selection that does not match the development trajectory
The CDMO landscape is broad and uneven. Capabilities, documentation maturity, regulatory track record, slot availability and the ability to support future phases vary significantly from one partner to another. When CDMO selection is driven primarily by availability or cost, without a structured evaluation of fit with the development trajectory, the programme frequently faces a second transfer later, with all the technical and regulatory consequences that a transfer implies.
Why the cost of CMC delays is higher than it looks
The direct consequences of CMC issues, added months on the critical path, additional studies, batch reworks, are already significant. The indirect consequences are often larger.
A six-month delay at IND or CTA stage does not only add six months of operational burn. It adds additional direct costs linked to contract amendments, CDMO re-scheduling and regulatory interactions. It delays the data readout that typically drives the next financing round, which shifts the entire cash runway of the company. And it affects the perception of the programme in the eyes of investors and potential partners.
Listed biotech companies have experienced share price reductions of 10 to 20% on the announcement of CMC-related delays. Private companies face a quieter but equally consequential version of the same effect: existing conversations with future investors slow down, valuations are revisited, and the optionality of the company is reduced.
CMC is also, in absolute terms, a material share of total development spend. Process development and manufacturing activities represent close to 20% of overall drug development costs, and considerably more for cell and gene therapies. Managing this share well is not only a matter of regulatory risk; it is a direct driver of capital efficiency.
What changes when CMC is treated as a strategic function
The alternative to the default approach is not to over-invest in CMC at early stage. It is to treat CMC as a deliberate strategy, shaped alongside the scientific programme, with explicit decisions rather than default ones.
In practice, this usually means a few things.
Defining the product early. A Target Product Profile (TPP), followed by a Quality Target Product Profile (QTPP), creates the reference against which later CMC decisions are made. Without this reference, each decision is made in isolation. With it, the coherence of the development plan becomes visible, and the trade-offs between Safety, Efficacy and Manufacturability can be made explicit.
Mapping the CMC pathway to the clinical plan. The clinical plan defines the material requirements, the shelf-life requirements, the analytical release requirements and the regulatory timelines. A CMC strategy that is not mapped to the clinical plan tends to drift. A CMC strategy that is mapped to it surfaces bottlenecks early, when they can still be addressed.
Running structured risk assessments. Risk assessment is sometimes treated as a documentation exercise. In functioning programmes, it is a live tool. Each identified risk is linked to a mitigation action, a responsible owner, a decision point, and a defined impact on schedule and cost. This turns risk management from a snapshot into an operating discipline.
Selecting CDMOs with the full trajectory in mind. CDMO selection should consider not only current needs but also the next two to three phases of development. Technical capability, documentation maturity, deviation management practices, slot availability and regulatory track record all matter. An experienced external view on the CDMO landscape often shortens this evaluation significantly.
Building analytical methods that can travel. Analytical methods that are developed with transfer, qualification and eventual validation in mind generate less rework later. This is particularly important for biologics and advanced therapies, where analytical maturity defines the feasible CMC timeline.
Coordinating execution across stakeholders. Most CMC issues at IND or IMPD stage are not purely technical; they are coordination failures across multiple stakeholders operating on different timelines. Active coordination, with a single point of accountability on the sponsor side, reduces this risk substantially.
None of these activities requires a large internal organisation. They do require senior CMC judgement, applied early, and the ability to translate that judgement into an executable plan.
The underlying shift
The broader shift in the industry is that CMC is no longer a late-stage concern. Regulatory expectations are tightening across modalities, investors are increasingly looking at CMC readiness during due diligence, and the operational complexity of working with a distributed network of CDMOs, CROs and specialist laboratories continues to grow. Programmes that treat CMC as something to address after the science is validated are operating on an outdated model.
The programmes that move fastest and most predictably are not those that spend the most on CMC, but those that make CMC decisions with the same rigour they apply to their scientific decisions. They define the product early, they anticipate the regulatory and manufacturing requirements ahead, they select partners deliberately, and they treat coordination as a core capability rather than an afterthought.
For biotech leaders operating under the pressure of timelines, capital constraints and investor expectations, this shift is not a matter of perfectionism. It is a matter of reducing the most consequential and most underestimated risk in their programme.
If your programme is approaching IND, CTA or a key development milestone, 3Biotech helps biotech sponsors identify CMC risks before they affect timelines, through targeted gap analyses, strategy reviews and hands-on execution support.
Contact the 3Biotech team to discuss how this approach could apply to your programme, or explore our CMC strategy and development services on our website.
