Dr. Joe Gallagher, technical applications manager, Avantor navigates the fill and finish challenges in cell and gene therapy manufacturing.
Avantor
Cell and gene therapies (CGTs) are redefining the healthcare landscape, offering new treatment options for many challenging diseases. These advanced therapies, including autologous and allogeneic cell therapies and viral vector–based gene therapies, present unprecedented complexity in their development and manufacturing. Fill and finish steps are also complex and critical to a successful therapeutic.
How do fill and finish challenges for CGTs compare with traditional biologics like monoclonal antibodies?
The foundational imperatives of the manufacturing process, such as maintaining sterility, minimising product loss and ensuring consistency, are shared across traditional and advanced biologics. But there are also many differences. Traditional biologics, like monoclonal antibodies (mAbs), are relatively stable proteins often produced in large volumes for large patient populations. Their fill and finish processes are well-established, templated and largely automated after decades of optimisation.
In contrast, CGTs are far more complex and present unique operational and logistical requirements related to sterility and product integrity, shelf-life and storage and in some cases, the need to support individualized dosing. These therapies often involve small batch sizes, temperature-sensitive components and, depending on the cell or viral vector type, highly variable product characteristics.
As is the case for most biologics, terminal sterilisation isn’t suitable for CGTs due to their heat sensitivity. Sterile filtration also presents challenges with yield loss, typically observed in gene therapy products, and may not be possible in cell therapies due to their size and sensitivity. Therefore, it is important to maintain sterility in all steps of the production process. Additionally, cryopreservation of cell therapies can require temperatures of –130°C to –196 oC, a distinct difference from mAbs, which have less challenging cold chain requirements of 2-8 °C or -20 °C to -80 °C for longer term storage.
While batch sizes for viral vectors tend to be larger than those for autologous cell therapies, the need for sterility, precise dosing and cryo-compatibility remains.
What types of excipients are used with CGTs, and how do they differ from traditional biologics?
Cell therapies rely on specialised excipients to maintain viability, most notably dimethyl sulfoxide (DMSO) for cryopreservation. While DMSO is effective for protecting cell viability during the freezing process, prolonged exposure is toxic, which means exact dosing and removal are critical. Biological excipients such as human and bovine serum albumin are also used in the final formulation and cryopreservation media, acting as stabilisers and protecting cells during the stress of processing, especially during freezing and thawing.
Similar to conventional biologics like mAbs, gene therapies use stabilisers like sucrose and trehalose, along with other excipients, including buffers, salts, polymers and surfactants.
Given their direct contact with the final product, all of these materials must be of excipient grade quality, conforming to the local pharmacopeia and International Council for Harmoniation of Technical Requirements for Pharmaceuticals for Human Use (ICH) regulations, and consistently available from reliable and trusted suppliers to minimize the risk of delaying the manufacturing process.
Why is early planning around excipients so critical in CGT production?
There is intense pressure on speed to market in CGTs, and excipients are not always an early focus area. Using non-regulated raw materials in development, however, can lead to supply chain and regulatory challenges later. Early consideration of raw material usage can ensure that you can secure sources, validate grades and consider scalability so there are no surprises on the path to the clinic.
Partner with a supplier that offers excipients in multiple grades, including non-GMP options for early testing, which gives customers flexibility to build scalable, compliant processes from the start. Always inquire if the supplier manages raw material sourcing in-house or through vetted partners to ensure consistent, reliable availability.
How do you ensure speed and flexibility when designing assemblies for complex CGT workflows?
When it comes to CGT manufacturing, no two workflows are exactly alike, so while some level of customisation is often required, it doesn’t necessarily mean that one has to start from scratch. Instead of reinventing the wheel each time, consider configuring proven, validated systems to meet the unique requirements of each application.
This is especially important in CGT, where development timelines are tight and therapies are high-value and patient-specific. Fully customised assemblies can sometimes require extended lead times for design, testing and validation. As an alternative, adaptable, pre-designed assemblies built from pre-qualified components provide the functionality and performance customers need, without the longer timelines of full custom development.
Configurable elements like tubing length, filter placement or port configurations are small but impactful adjustments to fit the customer’s exact process. It’s a streamlined way to get a tailored solution with faster turnaround and lower development risk.
Ultimately, whether it’s a fully bespoke assembly or a smartly configured standard, find a supplier who works with CGT developers to ensure the right solution is in place that delivers precision, process compatibility and speed to market.
What other factors are important to consider in CGT fill and finish?
Some of the most important drivers in CGT development and manufacturing are the need for scalability and efficiency.
One of the most important factors shaping CGT manufacturing is the focus on scalability. Early decisions about materials, equipment and workflow design can have major downstream consequences and should support commercial success. Using consistent technologies from early development to commercial production helps reduce variability and accelerate scale-out and scale-up readiness. For example, modular equipment platforms that offer the same user interface and performance at different volumes can provide operators with a seamless transition as production scales.
When it comes to efficiency, CGT manufacturers are laser-focused on reducing timelines and streamlining costly, labour-intensive steps. Because these therapies are often made-to-order and time-sensitive, even small delays or inefficiencies can impact patient access. Innovations like pre-configured assemblies, low-hold-up volume sampling systems and gentle pumping technologies all contribute to faster, more reliable operations. In many cases, the bottleneck isn’t the cell expansion or vector production; rather, it’s the support processes like solution prep, sterile connection or manual fill-finish steps. Addressing these areas with smart, scalable solutions is essential to enable faster, more agile CGT manufacturing.
Undoubtedly, CGTs are transforming medicine. They're also transforming how we think about manufacturing. As the field continues to evolve, success will depend not just on scientific breakthroughs but on practical, scalable and efficient technologies that can bring those breakthroughs to life.