CAR-T CMC strategy under time pressure

Early-stage CAR-T programmes often operate to tight timelines, shaped by clinical need,

competition and limited capital. Whether those programmes reach patients, however, is

usually determined by a different set of factors: the readiness of manufacturing processes, quality systems and regulatory Chemistry Manufacturing and Controls (CMC)

documentation.

In this case, the Sponsor was an emerging biotech developing an autologous CAR-T therapy for oncology. The early scientific data justified continued development, and there was a clear intention to move quickly. What was missing was a development framework that could support that pace. Much of the programme still relied on research-grade documentation, and the route to clinical entry had not been brought together into a single, coherent CAR-T CMC strategy.

Although a scientific interaction had taken place, written feedback and decision records were incomplete, leaving uncertainty over which risks had been addressed and which remained open.

This pattern is common in advanced therapy development. Promising data can point the way forward, while the CMC pathway that turns laboratory work into a controlled, compliant product remains only partly defined. In CAR-T programmes, that lack of definition can have direct consequences for timelines and execution.

To address this, the Sponsor engaged 3Biotech to introduce structure to the development pathway, reduce uncertainty and support the planned timeline, while recognising the limits of what could realistically be resolved at this stage. The agreed scope covered leadership of the CMC plan for both vector and CAR-T products from preclinical development through to clinical supply, including CDMO selection, supply chain and logistics, QA-aligned analytical implementation, and preparation of regulatory CMC documentation.

Assessing the risk profile

The programme reached a stage at which its underlying assumptions needed to be tested. A structured risk review indicated that the programme’s risk profile was not aligned with the pace at which it was expected to progress.

3Biotech reviewed the available preclinical data alongside the planned construct evolution, noting that much of the supporting documentation remained limited and research-grade.

Risks were assessed in terms of likelihood and potential impact, with particular attention to their implications for execution, sequencing and regulatory readiness.

Three areas were identified as requiring immediate attention.

1. Safety package uncertainty Early tissue reactivity findings required further interpretation. The key questions extended beyond whether staining was observed to include which cell types were involved, whether the signal was functionally relevant, and how it would be investigated further.
   

   In CAR-T programmes, this is not a peripheral issue. While potency can often be adjusted during development, safety concerns are far less flexible. If off-target and cross-reactivity risks are not addressed early, delays are more likely to arise later, when manufacturing slots, toxicology studies and regulatory sequencing are already constrained.
   

2. A development plan that was not execution-ready The overall development plan reflected strong scientific work but lacked the level of

   operational detail expected for an IND- or CTA-enabling package. There was limited clarity on which studies would be conducted, what materials would be used, how activities would be sequenced, what quality standards would apply, and how long each step would take.
   

3. A construct change with CMC consequences

   A third construct iteration, incorporating an additional control or safety feature, was under consideration. This raised questions around the underlying scientific rationale, the absence of a defined comparability approach, and potential intellectual property or freedom-to-operate exposure.

   In CAR-T development, a construct change is not solely an R&D decision. It has direct implications for analytical methods, critical quality attributes, vector and cell manufacturing campaigns, and the way the nonclinical safety package is constructed.
   

   At this stage, the aim was not to resolve every open question. Instead, the focus was on identifying the most consequential risks, prioritising them, and translating them into mitigation actions that could be aligned with the timeline before irreversible commitments were made.

Putting a CAR-T CMC strategy in place

Once the risk profile had been defined, attention shifted to execution. The programme

required a functioning CMC strategy and framework that could support continued scientific development while enabling progress towards clinical supply.

Governance and planning

The agreed scope included ownership of the CMC development plan, tranche-based

execution, structured gap and risk analysis, mitigation tracking, and maintenance of a live

Gantt covering resources and lead times.

This governance layer made it possible to manage multiple critical paths in parallel, including starting materials, vector and plasmid readiness, cell manufacturing, analytics, QA documentation and regulatory alignment. Risk management was treated as a practical execution tool rather than a reporting exercise. Each identified risk was linked to a mitigation action, a responsible owner, a decision point, and a defined impact on schedule and cost.

Defining the product early

One of the first deliverables was a Target Product Profile developed through a structured

review of existing data and a formal risk assessment. For autologous CAR-T products, an

early TPP serves as a technical alignment tool rather than a commercial statement. It links

clinical intent to measurable product characteristics, such as patient population, route of

administration, dose concept, shelf-life expectations and acceptable variability for early

clinical phases.

The TPP informed early CMC targets, including identification of critical quality attributes

related to identity, purity, potency and safety, and clarity on what would need to be

measurable at the point of clinical release.

Starting materials and raw materials

Early control of starting materials and critical reagents was essential. The scope included

oversight of supply chain and logistics and confirmation that CROs and CMOs were

operating within appropriate regulatory expectations.

This required early decisions on starting material definitions, acceptance criteria, critical

reagents, vector-related materials and their quality grades, and documentation requirements such as traceability and change notification. Availability alone was not sufficient. Materials needed predictable supply, controlled change and QA visibility to avoid late disruptions to comparability and process understanding.

Manufacturing strategy for vector and cells

The tranche plan covered plasmid activities, vector engineering runs and GMP manufacture, and an engineering CAR-T batch, with explicit attention to manufacturing slots and sequencing.

Engineering runs were used to reduce risk in unit operations under near-GMP conditions

before committing to full GMP manufacture. Vector and plasmid campaigns were aligned

with the selected construct and the emerging comparability strategy, balancing technical

requirements with slot availability and lead times.

Analytics and quality readiness

Release-enabling analytics defined the feasible CMC timeline. The scope, therefore, included implementation of phase-appropriate analytical methods, preparation and review of batch records, and generation of CMC and quality documentation.

The analytical package supported identity testing, fit-for-purpose potency measures,

assessment of process-related impurities, an appropriate sterility strategy, and relevant

vector-related attributes. Methods were developed to suit the development phase while

remaining defensible for regulatory review, with documentation captured in a way that would support future comparability arguments.

CDMO selection and oversight

CDMO engagement was treated as an extension of the Sponsor’s quality system. Selection focused on technical capability, documentation maturity, deviation management practices and the ability to operate within phase-appropriate GMP expectations.

Ongoing oversight covered manufacturing readiness, slot protection and contingency

planning, and alignment between CDMO output and the regulatory narrative being

developed. This level of control is often critical for maintaining momentum in early CAR-T

programmes.

The construct decision

As anticipated, the programme reached a point at which a construct decision could no longer be deferred. Proceeding with the new version offered potential advantages but carried clear CMC implications. Delaying the decision reduced uncertainty but placed additional pressure on the timeline.

From a CMC perspective, the implications were well defined. These included potential

changes in expression and potency, questions around the behaviour of the control or safety feature, the suitability of existing analytical methods, and the coherence of the nonclinical safety strategy.

The mitigation plan avoided a binary choice by introducing defined decision gates supported by targeted data. Tranche activities included construct characterisation, strengthened cross-reactivity assessments, and execution of plasmid, vector and engineering CAR-T activities designed to generate decision-quality evidence.

Comparability was treated as a structured argument supported by aligned testing and

documentation, rather than a single study. Where possible, long-lead activities were initiated in parallel, with contingencies in place, to protect the critical path without committing prematurely.

Regulatory engagement formed part of this approach, with plans for scientific advice focused on comparability, safety and toxicology strategy ahead of key execution steps.

What changed, and why it mattered

The outcome was not a sudden transformation, but a change in how the programme was

managed. By the end of the tranche, the programme had moved from a research-led

approach to one that could be executed with greater predictability.

There was a defined Target Product Profile supported by an active risk and mitigation

framework, clearer safety framing, an ordered CMC sequence covering plasmids, vector and CAR-T activities, embedded CDMO oversight, and QA-aligned analytics and documentation suitable for clinical progression.

Most importantly, the CMC pathway was explicit. Activities, dependencies and decision

points were visible and could be actively managed. For early CAR-T programmes, this

visibility is often what determines whether momentum is maintained or lost.

Next steps

If you are developing a CAR-T or other advanced therapy and facing similar CMC,

manufacturing or regulatory challenges, 3Biotech works with Sponsors to bring structure and clarity to early-stage development.

To discuss how this approach could apply to your programme, contact the 3Biotech team or explore our CMC strategy and development services on our website.