For cell therapies, raw material quality hinges on the human touch

When it comes to cell-based therapy manufacturing, the concept of quality management carries important distinctions from more traditional therapeutics production. Of course, the same rigour is needed, and quality assurance (QA) / quality control (QC) is conceptually the same, in that it aims to prevent anything that could compromise the process and/or contaminate the final cellular drug product. Someone moving from a traditional pharma environment into cell therapies would instantly recognise the pieces related directly to specifications and compliance.

The difference comes from the sourcing of raw materials and the functioning – and even nature – of supply chains. Because the cellular starting materials come directly from patients or donors, far from a well-controlled manufacturing facility, there is an element of the manufacturing process that is effectively done in public.

Quality management seeks to control as much as can be controllable, so, cell therapy must account for those unique elements that are not controllable and still mitigate associated risks. Stakeholders have been increasingly turning to experienced partners in the blood banking field, which have already developed quality solutions that parallel the needs of the cell therapy space.

Quality challenges with human-sourced starting material

Cell therapies start from living, biological raw materials that carry inherent variability. Even compared to traditional biologics, cell therapy production comes with additional unknowns and risks.

Although both require cells for manufacturing, the need to collect products from a living person, versus growing cells in culture or bioreactors that is more predictable, adds a new layer of complexity. There are factors like potency that are impacted by source variability. The starting material comes from different people – maybe patients or donors, healthy or with a particular disease state, immunocompromised or “superdonor”. These and dozens of other variables can affect manufacturing outcomes before seeing a single drop of blood.

Another consideration is the health of a donor or patient. There are unique concerns associated with collection for certain groups, like patients at late stages of certain diseases. And interest is growing in the recruitment of donors with certain stable diseases, whose cells may more closely match a recipient with a similar condition. That means we must assure the collection itself does not add unnecessary risks to the health of a donor, and make special considerations for the health of the cellular product.

Some inconsistency will be inherent, particularly with today's marketed CAR T-cell therapies, which are all autologous and mostly sit third or fourth in line under standards of care. By the time cells are collected from these patients, raw materials have most likely been compromised, either because of the late-stage disease itself or from rounds of treatment with chemotherapy or radiation. It becomes critical to control what you can: optimise collections and minimise cellular loss.

Allogeneic therapies carry unique risks due to their novelty, requiring all new QC processes to ensure final product potency and effectiveness. That includes understanding which donor characteristics affect the cells of interest, comprehensive health screening (such as for infectious diseases) to ensure the safety of the donor and the donation, and codifying appropriate behaviour during recruitment.

Locking down logistics

It can be incredibly difficult to manage quality over the long logistics chains necessary to source, make, and deliver a cell therapy. Because commercial manufacturing is typically centralised, the process generally requires moving materials over a large geography, twice. This involves collection, preparation for transport (which often means cryopreservation), time-sensitive and temperature-controlled shipping, controlled thawing at the site of manufacturing, and many of the steps repeated to get the finished therapy back to a patient.

There are now solutions that ensure robust storage end to end and software solutions that ensure full traceability. Bar coding and logistics software is often needed to make sure that the products are in the right place and in the right state, at the right time. But further investment and innovation are necessary to meet the rising demand of cellular therapy logistics. This may be the biggest challenge to overcome, along with expanding the collection capacity itself.

Because there’s no precedent for this in pharma, it has required building new models and quality paradigms from the ground up. That process is still ongoing and will require a high level of partnership between biopharma authorisation holders, CDMOs, collection and logistics service providers, and regulatory agencies to build the capacity and robust processes to meet the volume necessary, with equivalent safety of legacy pharma and biologics products.

Integrating quality systems

Despite hospitals’ extensive quality management experience, hospitals often lack the experience or the systems to manage QA and QC in a drug manufacturing environment. Documentation practices and built-for-purpose software systems related to documenting manufacturing are generally not operated in hospital systems. That is one of the most overlooked capital items, along with the labour costs of an independent QA function overseeing biopharma processing to meet manufacturing regulatory requirements.

To address this, some well-resourced hospitals may bring in personnel with pharmaceuticals expertise, who can help develop an internal quality management approach. The needed investment is a challenge for many mid-size hospitals and healthcare systems, and a huge roadblock for smaller hospitals, which may lack the number of eligible patients to generate enough demand to justify the investment. Mid-size to smaller community hospitals may also lack the capacity to move beyond manual document control or deviation management systems, making quality management a lot more difficult and more labour intensive.

Hospitals also may not be equipped to oversee multiple cell therapies from different drug companies simultaneously. Each drug company has its own required hardware and validation processes, as well as documentation and manufacturing data input processes, requiring specific concomitant training and ongoing performance reporting programmes. In addition, overburdened hospital staff might not be prepared to handle the significant administrative burden that comes with operating each pharma’s system, inviting more opportunities for error. As with many emerging enterprises, there are not consistent data standards and, in their absence, each new cell therapy – sometimes from the same manufacturer – will come with additional administrative overhead that small and even mid-sized hospitals may not be able to shoulder without a partner to help manage the process for them.

Partnership path

Pharma and hospitals have access to experienced partners. Traditional blood banking organisations have decades of experience collecting products for transfusion from healthy donors, making them uniquely positioned to manage quality. They have the cGMP compliant processes, training, logistics, and hospital relationships to excel in this space.

Hospitals are seeking to expand existing partnerships with blood banking organisations. Many leverage their long experience with blood collection, including apheresis and stem cell collections, blood/biologics manufacturing management, and logistics to develop more robust cell therapy manufacturing and QA processes. Blood centres are uniquely positioned to add strategic value due to their experience operating in regional, and some even in large, national networks. They have well-established quality management systems built for large, distributed operations with complicated logistics, and the scale and flexibility of their operations leave them better positioned to meet each drugmaker's distinct documentation and quality management and oversight requirements.

Cell therapy stakeholders are clear-eyed about the quality challenges, but recognise the right capabilities already exist – ready to be leveraged through broad partnerships between pharma, hospitals, and blood centre networks.

About the author

Robert Marriott is an experienced executive specialising in clinical and research quality services, regulatory compliance, and operational excellence. As vice president at Vitalant, he leads enterprise-wide quality and regulatory initiatives, overseeing the organisation’s biotherapies (processing and collections), clinical laboratory, and research services. Previously, he established GMP manufacturing and ISO-compliant quality systems at Isolere Bio by Donaldson and founded Marriott Quality and Performance Solutions, LLC, providing FDA compliance and healthcare compliance consulting. His extensive career includes senior roles at Alliance Pharmaceuticals, RTI Health Solutions, Dayton Children's Hospital, Versiti, BloodCenter of Wisconsin, GE Healthcare, and Abbott Laboratories. Marriott holds a BSc in Biochemistry and actively contributes to industry publications on operational, quality, and regulatory practices.