Why CMC Must Shape Critical Decisions Early In Development

By Matthias Gerlach, Ph.D.

There is a reasonable objection to the familiar call to involve every function earlier. If CMC (chemistry, manufacturing, and controls), quality, regulatory, manufacturing, clinical, and commercial all need to be involved from the beginning, what does “early” mean? More meetings are not a development strategy.

This principle applies across therapeutic modalities, even though the two examples in this article come from biologics development.

I would start with the decision, not the organizational chart. Before selecting a clinical construct, discovery and protein engineering need a credible challenge from downstream development: What is the capture route for this molecule, not just its tagged research version?

The following functional perspectives should enter at the decisions they can influence.

• Analytical development should establish whether available assays characterize the intended product and whether apparent differences could be process-related.
• CMC leadership should judge which uncertainties are material at that stage.
• Regulatory expertise belongs in the discussion when product design, safety, or the proposed control strategy creates a question worth taking to scientific advice.
• Quality and manufacturing become essential as material history, the control strategy, and clinical production requirements take shape.
• Commercial input matters when process complexity, scale, or cost threatens the viability of the development path.

Before committing to a clinical construct, I would want a short, decision-focused manufacturability assessment: a plausible capture route, an initial view of recovery and impurity behavior, assays relevant to the clinical molecule, and a clear account of uncertainties that could force a redesign.

The team does not need a fully optimized process. It needs enough evidence to know whether the next commitment is defensible, who owns the remaining questions, and when they must be answered.

Two anonymized examples from actual development programs illustrate where that input becomes critical.

Case Study 1: When The Research Construct Is Not The Clinical Candidate

The purification method worked. The complication was that the molecule being purified was not the one intended for clinical development. In an early fusion protein program, a histidine tag (His-tag) provided a practical affinity-capture route for laboratory material. The proposed clinical candidate, however, was tagless.

Unlike conventional monoclonal antibodies, the fusion protein lacked an Fc domain, so the familiar Fc-mediated protein A capture step was unavailable. Retaining the His-tag could preserve a convenient purification route, but its presence in the therapeutic molecule would require a product-specific justification, including an assessment of potential immunogenicity and other quality risks. Removing it meant establishing a different capture process and determining how much of the analytical evidence generated with the research construct remained relevant.

I have seen how quickly a program can move from a promising scientific result to a much harder question: What exactly are we going to manufacture for the clinic? That is where early CMC input matters — not because every function belongs in every discovery meeting, but because someone needs to challenge a consequential choice before it becomes the basis for the entire development plan.

A missing capture platform changes the questions

Protein A is an effective starting point for many monoclonal antibodies and Fc-fusion proteins. It is not a universal purification platform for therapeutic proteins. Without an Fc domain, the team must establish another credible capture mechanism. Affinity tags can help during discovery, but they are not automatically the right answer for the clinical molecule. Nor is a tag inherently unacceptable; its suitability depends on the construct, its intended use, the process, and supporting evidence.

In this program, the real task was to understand what would change with the tagless candidate. A different purification route could alter the impurity profile, recovery, and composition of the material used in analytical studies. That matters because an apparent difference between constructs may arise from the protein, the process, the buffer, or the assay. It takes targeted experiments to distinguish those possibilities.

The presence of a permanent His-tag in a therapeutic candidate warranted careful, product-specific regulatory consideration, not an assumption that such tags were prohibited. Potential immunogenicity, product heterogeneity, stability, and the ability to characterize the intended clinical product all required consideration. The choice was not simply whether the tag made purification easier; it was whether the development strategy could support the molecule the team proposed to take forward.

Scientific advice belongs in the CMC decision

One analytical question illustrates the point. If tagged and tagless material produce different binding signals, the team cannot assume that removing the tag changed biological activity. Differences in purification conditions, sample matrix, or assay behavior may contribute. Before building a release strategy around that result, the team needs to understand what the assay actually measures in the intended clinical candidate.

In a scientific advice discussion with a regulatory authority, the proposed use of a binding assay for early clinical release and stability testing was considered acceptable in principle, provided the choice was justified and the relationship to biological activity explained. This was not a ruling in favor of tagless molecules or against His-tags. Its value was more practical: It helped define what the analytical strategy needed to demonstrate for the intended clinical product, rather than allowing the team to rely uncritically on work performed with the research construct.

For me, that is the strongest argument for seeking scientific advice early, when molecular design and the control strategy are closely connected. The discussion does not replace experiments or guarantee an outcome. It can help teams ask the right questions while the construct, purification approach, and analytical plan can still be adjusted.

The second case shows why that timing matters beyond regulatory discussions. The absence of a familiar capture platform can create difficult choices even when upstream expression is already established.

Case Study 2: When Upstream Success Meets Downstream Reality

In a separate development program, another Fc-free fusion protein could be produced for process-development work, but the downstream team could not rely on conventional Fc-mediated protein A capture. A product-specific chromatography sequence had to be developed. This was not simply a matter of finding a resin that bound the protein. The complete process had to recover sufficient product while removing aggregates, fragments, host-cell proteins, and other impurities.

The team compared alternative sequences of capture, intermediate purification, and polishing steps. One practical question was whether an intermediate step could be removed to improve overall recovery without sacrificing the required impurity clearance. That is a decision about the process as a whole: A cleaner fraction at one stage is of little value if too much product is lost, and a higher yield is not a success if critical quality attributes are compromised. The process sequence had to be credible before individual steps could be optimized in detail.

The upstream material added another complication. Material produced in different formats did not behave identically during chromatography; elution and recovery differed, even when some analytical observations appeared comparable. Yield estimates also required care because the underlying measurements were not equally reliable. A promising small-scale purification result, therefore, could not be treated as proof of a robust route for the next manufacturing stage.

The lack of an Fc domain did not cause every difficulty in this program, and Fc-free proteins do not necessarily need engineered affinity tags. Ion exchange, mixed-mode, and other product-specific methods can provide effective capture routes. But those routes need to be demonstrated. A producing cell line and an encouraging expression result are not evidence that the clinical molecule can be purified reproducibly at acceptable recovery and quality.

The Limits Of Early Assessment

Of course, discovery teams cannot resolve every manufacturing question before choosing a lead molecule. Data may be scarce, the protein may be available only in small quantities, and a final purification sequence may be impossible to define. Early scientific advice also consumes time and resources and is most useful when the questions are specific enough to support a productive discussion.

Nor should the absence of an Fc domain be treated as a design defect. Many successful biologics rely on product-specific purification strategies. Likewise, a His-tag is not by itself proof of a safety problem. The relevant risks depend on the final construct, its intended use, the process, and the supporting evidence.

The real danger is false certainty. A clean laboratory chromatogram can create the impression that purification is solved. A strong expression result can make a program look more mature than it is. An early binding assay can appear to settle a biological question without establishing that the assay is suitable for the clinical candidate. CMC's early entry can help make those assumptions visible and determine which ones must be tested before the next commitment.

Early Enough To Change The Decision

The two programs in our case studies were different, but they exposed the same gap between research progress and clinical readiness. In one, a His-tag made laboratory purification practical while the intended tagless candidate demanded a different CMC and analytical strategy. In the other, a fusion protein without an Fc domain required a product-specific downstream process, with recovery and impurity clearance pulling in different directions.

Neither example suggests that every novel protein should be redesigned as an antibody or that every manufacturing question must be settled in discovery. The aim is to recognize which uncertainties are acceptable for the next stage and which could undermine the development path itself.

After years of working across development, external manufacturing, and technology transfer, I have become wary of treating a successful laboratory result as proof of manufacturing readiness. Many worthwhile therapeutics present manufacturing challenges; those challenges should not automatically derail a candidate. The mistake is discovering them only after the decisions that could have addressed them are no longer open. CMC does not need to dominate discovery. It needs to be heard before choices that determine the clinical product become difficult to reverse.

About The Author:

Matthias Gerlach, Ph.D., is an independent executive advisor with more than 25 years of experience in the pharmaceutical and biotech industry. His background spans drug discovery, CMC, pharmaceutical development, technology transfer, external manufacturing, global supply chain, and commercialization. He previously served as managing director and SVP of manufacturing and supply chain at Aeterna Zentaris GmbH in Germany. He has worked with international CROs and CDMOs across development stages and manufacturing modalities and advises biotech companies and industry partners on CMC strategy, manufacturing, supplier selection, and operational execution.