Why RoteaHub?

The Gibco™ CTS™ Rotea™ system story — a case study of industry-academia collaboration

Li, James & Lim. Gene Therapy (Nature), 2023.

View

The back story

The Nature article above outlines part of the journey that led to development of the Rotea system.

Roteahub draws on the back story where projects to automate manual processes were pursued.

These projects involved standing beside the process specialists as they conducted open aseptic procedures in the clean room

• observing and asking questions to understand the nuances of the manual methods.

The objective was to translate the procedures into a manufacturing systems capable of carrying each patient’s batch through an environment meeting the demands of commercial therapeutic manufacture.

Building on simple principles

The process is the product for cell-based therapies where the product itself is too complex and diverse for full characterisation.

• Changes to the manufacturing process experienced by the cells may require demonstration of comparability to support continued reliance on existing clinical data.
• Early adoption of preferred methods and process standards therefore becomes an important direction.

Risk based design -

• What can go wrong?
• Can it be detected?
• How can it be prevented or mitigated?

The question is not whether a regulator will permit an approach, but whether the associated risks are understood and appropriately managed.

Recognising strategies to avoid hazards is a powerful tool for robust process design.

Strawman designs to challenge the status quo and build alternative scenarios

The demonstrated procedures were documented as the ‘base case’ commonly ‘manual’ processing option.

Each procedure is reviewed to consider how it might be completed without demanding operator control of the detailed sequence and critical parameters such as liquid dispensing. Automated concepts were created from existing tools such as centrifugation methods and magnetic bead selection systems.

Multiple levels of automation were conceived and compared against the base case.

The commercial imperative

Recommending investment in automation demands evaluation of the alternative options and a commercial view.

A commercial view places further burdens on the process design.

For therapies to reach patients, manufacture must be commercially sustainable.

Patients or healthcare systems must be able to pay for treatment, while investors require a pathway to recover the capital invested in development.

Cost modelling to compare options

Cost models were created to reflect different designs of the process.  These included:

• facility capital and operating costs
• personnel demand
• reagent costs
• single use material costs
• gowning costs
• production equipment utilisation and capital cost
• production equipment and specialist single use kit development cost.

The models were driven by patients per year capacity, so the relative benefits of different investment strategies could be observed playing out. The models were necessarily built upon estimates. Their purpose was not to predict exact costs, but to reveal the relative consequences of different manufacturing strategies.

Hazard Frequency Analysis

While cost-of-goods analysis was providing comparative insights into manufacturing economics, it became clear that an additional measure was needed.

How can alternative process designs be compared from a quality and reliability perspective?

The formal approach would be to perform a comprehensive FMECA. However, FMECA is resource intensive and can be difficult to apply consistently across different conceptual process designs.

A pragmatic alternative was adopted: review the manual methods and count the frequency with which a fixed set of manufacturing hazards occurred.

The resulting hazard list was then updated for each strawman design. Indeed, many of the design modifications were specifically directed toward eliminating or reducing the occurrence of these hazards.  (Reference 2)

In this way, hazard analysis becomes a design tool, translating risk mitigation directly into design requirements.

Early insights and constraints to success

Insight 1. - Manual processing is simply not sustainable:

• The number of highly skilled personnel needed to support modest annual volumes are simply not available. (References 3 and 4.)
• Scaling up demands ongoing capital investment ahead of the income curve. (Again demonstrated in the real world)

Insight 2. - Once the automation has removed the primary manual product interactions, the quality benefits of additional automation diminish.

Insight 3. - Heavy investment in process-specific dedicated automation is difficult to justify.

The need to use the manufacturing methods in early clinical trials for comparability demands early investment in a process without proven efficacy that may need to change as directed by the clinical outcomes. The automation development in turn will likely delay the clinical trials.

Insight 4 — Adopt Scalable Unit Processes Early

The biological imperatives of a therapy should drive process development; Cell selection methods, culture systems, cytokine strategies, fill-finish approaches and dosing regimens should be chosen to optimise patient outcomes.

The role of process design is not to constrain these choices, but to identify manufacturing methods capable of delivering them reliably and at scale.

Wherever practical, existing unit process systems should be adopted early in development and scaled through clinical manufacture into commercial supply.

Early adoption of scalable unit processes reduces comparability risk, accelerates development and provides a clearer pathway to commercial scale-out.

By way of example, the Rotea instrument, and now its companion Compleo product, were specifically developed to support this role: providing standardised unit processes that can be employed during process development and translated into clinical and commercial manufacture.

Insight 5 — Patient scheduling can dominate facility utilisation

Capital equipment and facility utilisation can be massively disrupted by patient material sourcing and dosing plans.
If the process draws on fresh patient material and delivers fresh doses to the patient some simple scheduling exercises highlight a horrible insight. Patients attend the clinic from Monday to Friday.
If the manufacturing process is say 3 days from material arrival to patient delivery, work out which days of the week you can accept patient material. By the way, Patients are ill and may not be able to attend planned appointments.

Insight 6 — Functional closure changes the economics of manufacture

Open suite processing, barrier isolator processing and functionally closed processing were compared in overall capital cost and product cost of goods.

Barrier isolator and functionally closed systems can operate within low grade clean rooms - class D for example, This allows for transport of material into and out of class B space if needed through a class C passthrough. Personnel gowning is dramatically less intrusive on cost and non-productive gowning/degowning time. Personnel can flexibly attend to multiple different patient products that are isolated in the closed process - isolator or single use kit.

Barrier isolator systems however suffer from poor utilisation when the ‘between every procedure’ sterilisation cycle is accounted.

Functional closure in single use kits is challenged by a lack of comprehensive tools to handle all the procedures. The benefits of functional closure can only be realised if the process is comprehensively managed this way. The product being contained in a kit provides pathways for handling process disruptions, through to recovery by open aseptic processing.

Functional closure stands out as the path to deliver uncompromised quality within a productive workspace.

Insight 7 — Commercial success in patient-specific therapies is a scale-out problem.

For patient-specific cell therapies, it is useful to distinguish between scale-up and scale-out.

Scale-up refers to increasing manufacturing throughput within a facility through additional equipment, personnel or process efficiency.

Scale-out refers to replication of manufacturing capability across facilities, organisations or geographic regions while preserving product quality and process consistency.

The ability to process 10,000 patients in a single facility is very different from processing 1,000 patients per year across 10 countries.

Commercial success requires more than manufacturing capacity. Patients gain access to therapies through physicians, hospitals and healthcare networks operating within their local healthcare systems.  (Reference 5)

Reliance upon a single global manufacturing site may substantially increase logistics complexity while diminishing perceptions of local availability, resilience and long-term supply security.

Successful scale-out demands a manufacturing architecture incorporating standardised unit processes, process assurance and appropriate automation that can be transferred reliably between operators, facilities and geographies.

Closing Thoughts

It is a privilege to work with people developing cell therapies.  Across research laboratories, clinics and manufacturing teams there is a shared motivation: to deliver therapies that meaningfully improve patients’ lives.

It is disappointing when therapies that appear capable of helping patients cannot progress because a sustainable commercial pathway cannot be established.

Equally, it is disappointing when substantial investment is directed toward manufacturing approaches that have not been fully explored or stress-tested. The failure of highly visible initiatives risks not only individual programmes, but confidence in the broader field.

Commercialisation should not be viewed as separate from patient benefit. Commercial sustainability is often the bridge that allows promising therapies to become widely available to the patients who need them.

RoteaHub exists in the hope that shared insights into manufacturing architecture, unit processes and robust process design can help strengthen that bridge and contribute, in some small way, to making more of these therapies a reality.

References

1. The Gibco™ CTS™ Rotea™ system story — a case study of industry-academia collaboration — Li A, James D, Lim R. Gene Therapy 30, 192–196 (2023).
2. Tallying Hazards to Compare Automation Options
3. Cellular therapy processing laboratory: a workforce hiring nightmare — Booth GS, Savani BN, Adkins BD, et al. Bone Marrow Transplantation 58, 735–737 (2023).
4. Skilled Labor Shortages Impact Cell and Gene Therapy Manufacturing — Chakraverty A. Labiotech.eu (2021).
5. Investment Insights for Cell Therapy Manufacture