As pharma’s therapeutic toolbox continues to evolve, cell and gene therapies (CGTs) are beginning to reach patients at commercial levels. Produced in unique settings—including small, clinical-scale manufacturing operations, dedicated facilities in hospitals, and shared clinical/processing environments—these advanced personalized therapeutics require highly integrated supply chains. These incumbent complexities can pose significant challenges in compliance with current Good Manufacturing Practices (cGMP).

Advanced Therapies on the Horizon, Processing Innovation Required

According to The American Society of Gene & Cell Therapy (ASGCT), there are 3,366 gene and cell therapies in development from the preclinical through pre-registration stages as of Q3 2021.¹ Globally, there are 19 gene therapies (including genetically modified cell therapies), 15 RNA therapies and 54 non-genetically modified cell therapies approved to date.

As with any rapidly growing field, there are mounting challenges for both innovators and their manufacturing partners in building out the commercial process.^2,3 Expanding capacity to address increasing demand and expedite timelines can lead to bottlenecks in raw material supply and critical resources like experienced technical staff. As in the early years of monoclonal antibody development, CGTs are hampered by a lack of standardized processes.⁴

Industrialization of autologous and allogeneic cell therapies is still in its infancy, and as the field matures, so must advancements to increase productivity, safety, and efficacy of treatments and reduce bottlenecks as facilities come online.

Criticality of Fill and Finish

CGTs require complex manufacturing and logistics choreography compared with traditional therapies, making the control of all processes paramount.

Traditional products, both large- and small-molecule, are typically manufactured at scale with at least partly automated equipment lines. Many of these products have extensive shelf lives once manufactured and use raw materials that have similarly long expiration dates.

CGTs require a complete reimagining of this dynamic.

Autologous CGT therapies have patient-specific starting materials such as cell tissue, blood, bone marrow, or sometimes even a tumor sample.⁵ The manufacturer must then generate a therapy that is specific to the starting material. The human leukocyte antigen (HLA) typing and matching phase used to match donors and patients in allogeneic therapies has a similar circular demand chain as opposed to the linear supply chains associated with traditional pharmaceuticals.

New requirements for effective manufacture and delivery of a CGT are now in play. Notably, the starting materials taken from patients are not as stable as synthetic materials, meaning there is a manufacturing window of days instead of years. The tissue is living, which means that there are far tighter specifications regarding temperature, time, and handling throughout processing. Cells require oxygen and nutrients when metabolically active, so these products require either just-in-time delivery to patients or cryogenic storage temperatures to preserve the cells in a metabolically inactive state.

For providers of innovative CGTs, there is little room for anything but best-practice approaches to final product consistency.⁶ Considering the scalability needed to meet these advanced therapies’ commercial potential and the necessity for improving yields at increased throughput, the industry is beginning to understand it must abandon manual processes and adopt automated ones to achieve true reproducibility across operators and operations.

Fill and finish is a very high-value step for many reasons, but two of those top the list.⁷ First, patient impact: CGT treatment is usually a last resort, and fill and finish is the final step before infusion. Any failure will be catastrophic because the patient will not receive the therapy. Second, economic impact: When these therapies are manufactured in GMP environments, great cost is associated with modifying cells during the Chemistry, Manufacturing and Controls (CMC) management stage. If any failure or any misstep happens now, then all money spent to that point has been wasted. Moving formulation and fill–finish from manual, open processes to closed, automated processes reduces manufacturing complexity, cost of goods (COGs), risk of contamination, and cell exposure to DMSO prior to freezing.⁸

Clearly, maintaining potency and viability through fill and finish is vital. Where this step relies on manual processes, there is inherent variability, which is unsustainable in an extremely high-value manufacturing setting. The need to reduce open process steps, ensure traceability, and maintain temperature control calls for automation to help ensure consistent products and reduce risk and manufacturing costs.

Simplifying the day-to-day operations that produce these leading-edge therapeutics is critical to the industry’s future. Advances in automation and machine control now offer new flexibility and optimized production in this exciting segment of biomanufacturing.

Automated Fill and Finish Systems Are Key to Successful cGMP Processes

Successful advanced cGMP processes require attention to operational details across the spectrum of therapeutic process. Every formulation or production step can present new variability and quality control challenges that require innovation, experience, and advanced systems to overcome.⁹

Even experienced cGMP biomanufacturers are likely to face unique hurdles trying to ensure process robustness from the time the patient’s cells leave the clinic to when they reach the processing facility, are processed, and finally are returned to the patient. When the therapy’s delivery systems can consistently achieve verifiable reproducibility at scale, reductions to risk, labor, and other resources are sure to follow.

Integral to the treatment path are the aseptic handling, filling, and finishing of the patient’s blood or cells. A given therapeutic process may require these fill and finish steps, or even more:

1. Mixing: Maintain batch/cell suspension uniformity
2. Cooling: Maintain consistent environmental temperatures  to support cell health
3. Air removal: Remove air that can compromise the final product during cryopreservation
4. Aliquoting: Help ensure consistency with accurate volumes
5. Sealing: Help maintain sterility of the final product
6. Data management: Facilitate cGMP compliance with electronic data recording and reporting

By removing manual handling and introducing automated data management at each step, you reduce human error and other factors impacting process variability and quality. Nevertheless, there are a number of specific challenges that biopharma companies are likely to encounter and that will require advanced technical solutions to overcome. These include:

Accurately Managing Batch-to-Batch and Process Variability

Automating process control at each point of the therapy’s journey facilitates accuracy and quality and sets enterprise-wide process standards. Configured correctly, automated systems reduce variability in fill and finish processes by supporting:

• Greater post-thaw viability for cell products from donors
• Post-formulation inlet-cell viability
• Uniformity of cell concentrations
• Final product temperature meeting user-defined targets

Automation also allows manufacturers to reduce the number of operators and manual processes and reduce the overall cost of goods (COGs) in production, as well as manage occupational and product quality risk.

Setting Critical Quality Attributes Faster, More Accurately

Automated access to data during operations enables transparent trending and tracking of the process and monitoring of key patient-centered attributes across the continuum of care. Automated data acquisition and management can help manufacturers identify critical quality attributes (CQAs) earlier and more accurately at each step in a therapeutic process.

Defining Process Controls Early in Development

Setting process controls early using automated data management methods is another way to leverage the technology for better scaling and compliant, accurate fill and finish operations.

Instilling Data Management and Integrity in Operations

Automating cell processing fill and finish is a secure path to compliance. Combined with automated, digitally controlled fill and finish processing systems, a well-engineered software application can deliver data integrity that facilitates cGMP compliance. Procedure data, for example, can be automatically transmitted between the system and the application while the system is operating. Operators can leverage common, shared software to specify processing protocols, configure materials and the device, define users, and assign permissions.

A common digitized system provides better resource management and compliance. From tracking tubing sets and materials to capturing key compliance data electronically, a digital approach to process monitoring and control promotes cGMP for proactive regulatory compliance.

Managing Skills, Labor Hours, and Materials with Accuracy

For CGTs, scaling is one huge factor for therapeutic success that supports patient access to treatment. However, if scaling is to be a viable aspect of the business plan, it must be cost-efficient — production economies and pricing may depend on it.

Automated, closed fill and finish systems reduce training time and the demands for skilled labor, because they make each point of processing more reliable and faster. That reduces error and risk, as well as improving the ability to track and trace the flow of material, timelines, and operator actions.

Automating for Post-process Consistency and Cell Viability

As mentioned, CGTs need to be carefully managed throughout manufacture and logistics to maintain desired temperature ranges. The most common protocol for cryostoring uses dimethyl sulfoxide (DMSO), a cryoprotectant that permeates cell membranes to reduce intracellular ice crystal formation. The trade-off is oxidative stress and gene expression changes sometimes induced by DMSO. This chemical can also damage organelles, cytoskeletons, and cell membranes, affecting cell viability and functionality. As a result, the period for which cells are exposed to DMSO needs to be carefully managed.

In CGT processing, adding DMSO to media creates an exothermic reaction; to reduce the impact of heat generation and consistent mixing on the product, a manual system of cold packs and syringes has been used to make sure that the cells and DMSO are kept within acceptable temperature ranges.

Air also needs to be efficiently removed from the cryopreservation bags, which must then be sealed properly to prevent embrittlement of the plastic and contamination.

Manual documentation may be paper-based, but even if some separate electronic capture method is used, it still has to be performed by an operator. This leaves the process open to human error in the generation and recording of data which can be essential for batch release.

So how do manufacturers mitigate these risks with automation? As with any manual process, there is a risk of operator-to-operator variability even when operators follow the same procedures. Automation ends this variability, which reduces operator-related errors and ensures workflows are managed as certified and standardized operating procedures.

When DMSO is used, automation can help maintain cell viability by minimizing the effects of the cryoprotectant during processing by automating temperature control. It can also maintain sterility with functionally closed and disposable single-use accessories, which reduces the risk of contamination by decreasing the number of open events.

Finally, it has a direct, positive effect on reproducibility, consistency, and assurance that manufacturers have the right target volumes in the product bags with consistent concentration of cells.

Summary

Adopting automation technologies into fill and finish processing presents many benefits, including consistency, repeatability, sterility assurance, and reduced human error.

These qualities are essential in CGT to deliver a cGMP process that successfully delivers a product for its intended patient.

Ultimately, more robust and efficient fill and finish lines de-risk development and manufacturing for very high-value products. 

References

1. “ASGCT, Informa Pharma Intelligence. Gene, Cell, & RNA Therapy Landscape. Q3 2021 Quarterly Report.  Accessed February 21, 2022.” https://asgct.org/global/documents/asgct-pharma-intelligence-quarterly-report-q3-2021.aspx
2. “The Regulatory Framework for CAR-T Cells in Europe: Current Status and Foreseeable Changes AND Centre Qualification by Competent Authorities and Manufacturers.” 10.1016/j.biotechadv.2021.107735
3. “Automation, Monitoring, and Standardization of Cell Product Manufacturing.” 10.3389/fbioe.2020.00811
4. “Standardization, workforce development and advocacy in cell and gene therapies: a summary of the 2020 Regenerative Medicine InterCHANGE.” 10.1016/j.jcyt.2021.02.004
5. “International alliance and AGREE-ment of 71 clinical practice guidelines on the management of critical care patients with COVID-19: a living systematic review.” 0.1016/j.xphs.2020.07.002
6. “Objectives, benefits and challenges of bioreactor systems for the clinical-scale expansion of T lymphocyte cells.”10.1016/j.biotechadv.2021.107735.” 10.1007/978-3-030-94353-0_37
7. “Regulatory Landscape and Emerging Trends in Advanced Therapy Manufacturing: An EU Perspective.” 10.1007/978-3-030-75537-9_2
8. “Formulation Considerations for Autologous T Cell Drug Products.” 10.3390/pharmaceutics13081317
9. “Automation in cell and gene therapy manufacturing: from past to future.” 10.1007/s10529-019-02732-z

Allison Hoffman is Global Product Manager of Cell Therapy Technologies at Terumo Blood and Cell Technologies.