Developing Compliant Systems to Modernise the Cell Therapy Manufacturing Workflow

Samantha outlines some of the complex challenges associated with compliance in cell therapy manufacturing systems, before describing how Merck is developing tools to help overcome key obstacles.

Could you briefly introduce yourself and your role within the life sciences business sector of Merck?

I am Samantha Sbardella, a Senior Product Manager responsible for the organisation’s cell therapy manufacturing portfolio of products and services. These include cell therapy manufacturing instruments, cell culture media as well as process development services.

What are some of the critical stages in the cell therapy manufacturing workflow where compliance is a key challenge?

I think with cell and gene-modified cell therapies, they’ve proven quite successful in terms of their effectiveness and recorded response rates – particularly relating to CAR-T therapies to treat haematological cancers. Nevertheless, it’s crucial that the industry is able to address several of the challenges that we’ve experienced within the manufacturing of these living therapeutics to ensure that we can achieve the promise of them.

When I think of some of the challenges that we’ve experienced, particularly in relation to compliance, some of those mainly relate to things like closing the manufacturing workflow, access to and the sourcing of suitable and GMP-compliant raw materials. On a similar topic of supply chain, it’s also related to therapeutic production and considerations for where that occurs, whether it’s localised, decentralised, or centralised. The fourth one is that the data demands continue to increase because of the autologous nature of these therapeutics.

I would say that those four buckets all experience some challenges with compliance.

Why do you think it is the case that there are so many areas where compliance remains a key obstacle?

I think the main part of it is because we have retrofitted a lot of products from the bioprocessing industry. We have leveraged these tools, particularly with that autologous-based therapies or low volume preclinical Phase I allogenic programs, that require some of these scaled-down products, and because of that we have relied on tools available to us from bioprocessing.

In that case, those tools were never required to be compliant as these are benchtops tools for scale-down, process development activities, not intended for manufacturing. So in our field we have adopted a lot of solutions that generally are not compliant for the reasons I’ve just mentioned, or are not the right tool as they don’t really support the true manufacture and collection of cells for therapeutic purposes.

What are the limitations in current technologies or workflows that allow compliance to be as important an issue?

Closing the manufacturing workflow really manifests itself in a mixture of ways where we have seen a lot of manual and automated processing steps still occurring. The more manual operating steps that you have, the more operator intervention risk there is for contamination.

In other cases we have an added complexity in that multiple pieces of equipment are needed within the entire workflow. In some of those cases, there could be two pieces of similar equipment that are required to conduct the same operating step – that is a challenge when it comes to compliance.

With access to and the sourcing of suitable GMP-compliant raw materials, we have seen a large number of ancillary materials in our field that are not intended to be part of the final product. In the case of cell therapies, where we’re actually collecting the cells, as opposed to bioprocessing where there are several downstream processing steps to purify the product, there could be a risk that that material makes it back into the patent, even to a residual level. In this case, it’s really important that products are carefully selected and qualified for cell therapy production for safety, purity and quality considerations in mind.

Some of the supply chain considerations related to therapeutic production strategies, whether it’s localised, decentralised or centralised, include challenges associated with the fact that we don’t necessarily know as a field where we’re where we’re going. We are testing a lot of different things, but ensuring that our systems and tools are compliant for whatever strategy we move forward with it is really critical.

For data demands, manufacturers and regulatory agencies are not able to rely on the typical batch records that we get out of bioprocessing or mAb production where a batch record really can support thousands of doses. In the case of cell therapies, each run is distinct, each run is a patient, and therefore require individual batch records and so data requirements do grow.

How are you working to overcome these issues, limitations, and overall challenges that you have just described at Merck?

We are working on developing an autologous manufacturing system platform. In this case, we have the ekko™ System, which is an acoustic wash and concentration system. We are also developing a sister product called ekko™ Select for the selection of T cells, namely CD4 and CD8. We do think that this is a platform technology that can work for other cell types for selection.

But in this case we believe that we’re addressing a lot of the compliance challenges that we’ve seen within the industry. We’re ensuring that we have automated solutions to address the production process. The more automated solutions that we have, the less operator intervention is required, reducing the risk of contamination or potential failed batches due to incorrect operator decision making.

We are also working on ensuring that we have GMP-compliant raw materials that have been qualified for cell therapy which is critical. And then on a similar topic of the supply chain, we are ensuring that we have a solution that can be used in localised, decentralised, or centralised production schemes.

In terms of data demands based on an increase need due to the autologous based-nature of these therapeutics, we are ensuring that we have the right data capture tools and functions in place within our systems so that information can funnel up to our customers’ MES systems, for example, through an OPC connection.

What should we be expecting to hear from you about this software over the coming months?

The ekko™ System that will be launching is our acoustic cell processing system, a breakthrough technology that provides freedom from process limitations. It is quite a unique technology because it uses acoustics to process cells, with unmatched ease of use and flexibility to support a variety of cell applications, processing steps and scales.

What we’re working on, which really underpins some of the work that we’re doing regarding data generation and general compliance, is software that is both 21 CFR Part 11 compliant and developed under GAMP 5 guidelines. For those who are not fully aware of GAMP 5, it is an ISPE standard. It is a risk-based approach to developing compliant good manufacturing, computerised systems.

We are quite excited in releasing this because it underpins the compliance we are supporting our customers with.

Should we be able to overcome the challenges associated with compliance that you have described today, what do you think the future of cell therapy or gene-enabled cell therapies looks like?

I think that the future of cell therapy looks quite promising.

My organisation is a firm believer that the key to solving industry challenges and the toughest problems is through collaboration, and I think a key piece to success in this field will be continued and deeper collaboration across the industry. So suppliers working with other suppliers, therapeutic developers working with other therapeutic developers, and then suppliers and therapeutic developers working hand in hand with one another. I think that these collaborations really support transformation within our field.

Should this transformation occur, is that growth and expansion sustainable? If we found ourselves existing in our harmonious and compliance future workflow, what would be the next frontier to overcome?

I do think that growth and expansion in this industry is sustainable. I think the biggest thing is working on some of these allogeneic programmes, as well as making progress on programs focused on solid tumours, and ensuring that we have success there. I think that those are going to be the next frontiers and challenges that we need to overcome as an industry.

Looking ahead, I know that you will have a team in Miami for Advanced Therapies Week in January 2022. What should we be looking out for from you at this event?

Yes, we’ll have a lot of activity there from our organisation.

My colleague – Nina Bauer, Director, Head of Commercial, Gene Editing and Novel Modalities – will be giving a presentation actually relating to one of the new frontiers that mentioned previously. It’s titled, ‘Technical Solutions: Cell Therapies for Solid Tumours’, so that will be a great talk focusing on manufacturing paradigms for tumour therapeutics, how gene editing approaches can support efficient tumour targeting and then the dynamics of technology development to meet market needs.

The team will be at booth 704, which will be showcasing our ekko™ Acoustic Cell Processing System with our new compliant ekko™ Software and ekko™ architect tool that I was talking about earlier.

We will also have representatives there to discuss the rest of our cell and gene therapy portfolio, including our gene therapy and viral vector CDMO, CRISPR tools, our producer cell lines for viral vector production as well as our cell culture and media.

Click here to discover more about joining us at Advanced Therapies Week 2022.

This feature was developed in partnership with Merck.