Cell and gene therapies hold immense promise to revolutionise how we think about treatment. However, as our biological innovation and discovery advances, so does the complexity of drug development processes. Currently, drug development costs have risen 140% in the past 10 years, which has imposed severe restraints on the vast opportunity to revolutionise cell and gene R&D.

Whereas existing barriers to making CGT a reality may seem insurmountable, and the thought of cell and gene in the clinic illusory, we at TTP believe that now is the time for change. TTP has devised a series of 8 different innovative strategies to address these issues in a practical and targeted way. Our 8 Innovations are not just theories, but initiatives which TTP is already implementing into our technologies, and which could be key to accelerating your CGT journey.

#1

Miniaturisation can help development of more effective potency assays

Ensuring the consistency and potency of cell and gene therapies presents a significant challenge for developers and regulators.

Reporter cell lines and primary cells are often needed in order to elucidate a biological response.

Traditionally, cell-based assay formats require 100s to 10,000s of cells per data point — which is not always practical when working with rare cell samples. Often, a variety of assays are needed to fully characterise the potency of a sample.

This process increases sample consumption, spending on reagents and cell-based assays, and sample variability. By implication, this leads to concerns surrounding sample shortages, the need for investment for assay development, and the consistency across separate tests.

However, miniaturisation offers a solution, opening the doors to a number of alternatives. Using microwells and droplets would enable assays to be undertaken at nL scale, which helps to conserve samples. Similarly, cutting the number of cells from 10,000+ to between 10 and 100 delivers comparable data quality at a lower cost. A single sample could also be used across multiple assays to provide multiplexed readouts.

#2

Cell encapsulation approaches can enable cell culture scale-up for developing regenerative medicines

Development in regenerative medicine can involve painstaking cell culture processes to ensure the survival of delicate cell types. High quality cells can be manufactured in small quantities, but scale-up requires additional measures — like cell encapsulation in hydrogels — to be undertaken.

Addressing this bottleneck in therapy development requires access to specialised equipment that streamlines workflows (minimising hands-on time while maximising processing capacity to become capable of processing billions of cells), performs reliably across a range of cell types and hydrogel materials, and offers a clear pathway to scalable manufacturing

We partnered with CellFiber Co. Ltd. to develop their R&D cell encapsulation technology into a production-capable system. TTP employed a scalable design which allowed CellFiber to move from a lab scale (only mL to L) into an industrial scale. Whereas the prior maximum capacity was only mL or L of cell culture, the result of our design was that it could hold tens of L. With scientific understanding of CellFiber's technology, we could demonstrate performance under extended operation. This meant that we easily leveraged our experience in designing therapeutics manufacturing equipment to advance CellFiber's plans to supply into GMP environments.

Read more about our work with CellFiber here.

#3

A targeted approach to process automation can enable rapid deployment of scalable solutions with low biological risk

Implementing automation in cell therapy development is best done sooner rather than later. It is possible to reap the benefits of automation by: focusing on single process steps; developing custom equipment that preserves unique cell-handling requirements; and leveraging designing-in ability to scale alongside meeting commercial manufacturing needs

Our targeted approach to process automation involves taking cues from the manufacturing industry to capture and audit PD workflows. This aids in identifying critical features, timings and process bottlenecks.

Another crucial step is to evaluate process architectures before embarking on hardware development. This involves leveraging biophysics, fluidics and modelling to arrive at solutions which are evidence-based, cell-centric and scalable.

Finally, our targeted approach aids development of suitable surrogates of the drug substance using established and/or modified cell lines. Doing so would mitigate the availability of development cell lines at an early stage.

#4

Non-contact cell counting enables in-line, real-time monitoring of manufacturing processes.

Cell counting is performed at numerous points during cell therapy manufacturing, and is normally performed on stand-alone devices requiring several manual preparation steps.

Hence, non-contact cell counting methods that can be implemented in-line are a key innovation to free up operator time and reduce measurement variability.

We spoke to TTP Project Leader James Stein on work he’s been doing to implement imaging as an in-line cell counting method. Read the full insight on non-contact cell counting here.

#5

Digitisation is making it easier to share data, track products and improve manufacturing processes.

What will it take to turn cell and gene therapies into mass-market cures? Could digitisation and AI be the key to improving complex production processes, arduous supply chain, and life-critical logistics? Would more companies be willing to work together on standardisation to provide more flexibility, reduce errors and allow feedback control?

In a recent podcast episode, we spoke to experts about how increased digitisation allows for a more rapid process development in addition to presenting the opportunity to deploy AI.

Critically, confusion in the batch record could be the difference between a patient receiving an effective cancer-fighting therapy, and having to restart the whole process from scratch. Therefore, digitisation could drastically help the industry by reducing the risk of human error, while also serving as an effective means of sharing insights across drug development teams.

Much of the development in other fields of the industry comes from high rates of repetition. Very often in the cell and gene therapy industries, the repetition rate is low, so it's critical that we approach learning in a different way.

Listen to the whole conversation on our podcast, Invent: Life Science, hosted by our very own Stuart Lowe.

#6

Leveraging insights from manufacturing industries can identify and address process bottlenecks.

Casting a critical eye over workflows undertaken in process development laboratories can be a time-saver. Doing so consolidates equipment usage, simplifies the reproducible performance of tasks, and identifies future obstacles towards scale-up.

Analysing how and where process steps are performed is a crucial starting point in designing automation solutions. Conducting a holistic assessment of manufacturing processes includes task time analysis, line balancing and resourcing, pareto cost-analysis of processes, and scale-up designs.

Subsequently, insights from these time and motion studies can be used to inform facility layout, design of consumable sets and fixtures, in addition to developing automation or semi-automation strategies.

This innovative approach to the cell and gene therapy manufacture process helped Achille Therapeutics in their tumour collection workflow. Read about how TTP helped streamline scaled-up manufacturing of transformative autologous cell therapy here.

#7

Gentle cell sorting can allow stem cells to be processed for manufacturing.

In cell therapy manufacturing, cell sorting methods need to be fast, gentle and sterile to deliver the products patients need. Traditionally, cell sorting is limited to specialist facilities and is undertaken by skilled operators.

Gentle and sterile cell sorting is crucial during cell processing for manufacture to ensure cell functionality, reduce perturbation of the cell state, preserve cells' properties, and maintain population uniformity. This amounts to a more reliable sorting process. Harsher methods risk damaging cells, which are particularly sensitive to mechanical stress and temperature changes, and this could lead to cell death or impair other functions. Specifically, stem cell pluripotency and T-cell antigen recognition are critical properties that are liable to damage.

Cellular Highways, a TTP Group company, have developed the Highway1: a fluorescence-based cell sorter for both RUO and GMP use. Target cells are identified by flow cytometry and then sorted using patented VACS (Vortex Actuated Cell Sorting) technology, which separates cells via a gentle vortex as they pass through a microfluidic channel.

Machine vision continually monitors the sorting process (at rates of up to 37 thousand cells per second) automatically adjusting and regulating the process to maximise yield and purity, whilst removing the need for a person to monitor the sorting process.

#8

Automation can reduce labour costs and facility footprint.

Despite the incredible potential for CGTs in the treatment of disease, emerging therapies remain unavailable to many patients due to insufficient expertise and manufacturing capability for affordable production.

Currently, CGT therapy manufacture involves manual process that require a skilled workforce and large, specialised lab facilities. CGT manufacturers must also contend with stringent regulatory requirements. All this means that the manufacturing process is labour-intensive, high-cost, and low-output.

However, advances in automation offer a solution to existing inefficiencies. An automated process could decrease reliance on highly specialised, costly labour, which also improves efficiency by minimising manual processes and human error. This would likewise optimise space with modular, scalable designs, reducing the need for large, expensive facilities. Flexible, automated systems similarly make it easier to adjust production volumes in response to demand without expanding physical facilities.

Cellular Origins, a TTP Group company, has developed Constellation, a full automation platform offering up to 30 times more space efficiency than conventional, manual techniques, alongside a 16 times reduction in labour and 51% reduction in production costs, allowing for more efficient advanced therapy manufacture.

Are you looking to accelerate your Cell and Gene Therapy development?

TTP has unpicked the Cell and Gene therapy development process and has drawn up 8 innovations to resolve obstacles in the CGT revolution - and all while improving quality and compliance. With our previous and ongoing projects spearheading the latest in technological advancement, our expertise and innovative insights mean that we may have the perfect solution for your specific needs.

With TTP, unlock opportunities to streamline therapy development and make cell and gene therapy available to all.