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Written by: Jim Sanford, Life Sciences Sector Strategy Manager, Watson-Marlow Fluid Technology Solutions.
Since as early as the 1970s, gene therapy has promised treatments for many diseases, from cancer and HIV to cystic fibrosis and spinal muscular atrophy. With the first patient receiving gene therapy in 1990, the full impact of this therapeutic class is only just starting to be realised. Cell therapy has been around even longer, but as the biopharmaceutical industry grows, so is the understanding of these medicines, and their demand to treat even more patients.
Jim Sanford
Challenges remain in the production of cell and gene therapies (CGTs), especially in the transition from lab manufacture to commercialisation, with complex processing requirements and high costs restricting patient accessibility. As medicines progress from research and development, through clinical trials and on to the market, production must scale to meet this growing demand. A combination of planning and technology can help to overcome these challenges and as approvals in this field continue to accelerate, an official from the FDA has predicted that 2024 will be a “breakout year” in addressing key challenges of cell and gene therapies.
Fill/finish can seem like a straight-forward stage in the manufacturing process, and as it is one of the final actions, it can be overlooked until later. However, it is vital to consider it early on. So how can platform technologies assist in the successful scale up of fill/finish operations in cell and gene therapy processing.
CGT Complexities
The biological nature of CGTs requires precise control of processing conditions and extremely gentle handling in order to maintain product integrity. As traditional sterilisation approaches could damage structure and function, maintaining sterility throughout the manufacturing process is key. Batch sizes are likely to remain small so bench top production methods used for research and development may satisfy the volumes needed but they will not meet the regulatory requirements needed for commercialisation and efficiency. There is a clear need for bespoke technologies that have been designed specifically for these treatments and overcome the challenges reliably and efficiently.
Contamination Prevention
The risk of contamination creates significant challenges in cell and gene therapy production. CGTs are often delivered intravenously straight into vulnerable patients, and even trace levels of contaminants can prove fatal. The biological nature of the therapies prevents any final product sterilisation so a comprehensive contamination control strategy is vital. This is not only key to protect the patient, but also to avoid product loss and the associated costs and time delays. Operator protection is another important consideration as these therapies often use bio-hazardous materials such as genetically modified viral vectors during production.
Containment needs vary dependent on a product’s makeup and application, so a best fit solution is needed, especially for those organisations that produce multiple therapies. These systems will need to meet the scale up timescale and cost plan, while still controlling both viable and non-viable contamination and the associated bioburden. This can be achieved with appropriate barrier technologies or the incorporation of pre-sterilised single-use components.
Human intervention is another potential source of contamination but automation can and should be used to manage this. Sterility can be further enhanced by the use of barrier technologies powered by automation but while complete automation can be appealing, it is also important to incorporate accessibility into process and equipment design. Controlled accessibility allows for interventions to be made to resolve issues when they occur without compromising the aseptic, Grade A environment or ruining batches. Automation brings the added benefits of increased process control and monitoring as well as improved efficiency.
Recent revisions to Good Manufacturing Practices (GMP) Annex 1 require manufacturers to increase contamination control measures, including both barrier technology and automation, to reduce risk to patients and operators. A comprehensive strategy should use a focused, risk-based approach to protect the critical areas. It is therefore vital that developers select the right technology and equipment partners to support the needs and delivery of GMP.
Modular, Flexible Solutions
As a diverse class of therapeutics, CGTs have different manufacturing needs. Processing platforms therefore need to be flexible, incorporating standardised components to ensure regulatory compliance. Platforms also need to accommodate different batch sizes, including container sizes and fill volumes, as required for different therapies.
One way to achieve flexibility is the use of pre-validated, enclosed and automated modular systems. These systems can be fully configurable and arranged to process a range of different products, with or without containment, helping to address many of the issues around regulatory compliance, safety, waste reduction and changeover between products.
Precise Product Selection
As well as considering the overarching attributes of a platform, specific components must also meet the complex requirements of cell and gene therapies. The requirement for gentle processes makes pump selection a key concern. Efficient production relies on high performing pumps, but these can cause large pressure fluctuations that can lead to damage to cells and biologic therapies. Low shear pumps that are specifically designed to minimise this potential damage are a key component of any fill/finish line. To be commercially viable they also need to meet required delivery speeds and offer precise volume control. Peristaltic pumps are a popular choice for cell and gene therapies as they are inherently low shear and as the fluid is completely contained in a tube, usually single-use, it never comes into contact with the pump itself offering improved sterility.
Single-use technology is another clear choice for CGT processing as it provides the opportunity to replace the entire fluid pathway with a new pre-validated system for each batch. This removes the need for clean-in-place (CIP) or sterilise-in-place (SIP) systems and can therefore guarantee sterility in a way that meets the needs of small-batch and bespoke manufacturing needs. Single-use pathways often come pre-validated for regulatory compliance, and this is also true of some automated, modular equipment. Pre-validated systems that meet industry standards bypass the need for a bespoke validation and design processes, providing a key part of a robust Contamination Control Strategy (CCS) and leading to faster regulatory approval.
A Skilled Workforce
Many industries are facing a skills shortage, and the biopharma industry is no different, especially within manufacturing and GMP expertise. There are promising signs that this is changing, with the number of employees joining cell therapy, gene therapy and multifunctional facilities in the UK rising by 23% in 2022, but this growth brings increased training demands. Designing processes which are easy to use and maintain will therefore benefit all organisations, with automation in a process reducing the burden on staffing levels as well as delivering GMP best practice.
Partnering for Success
Often therapies that look promising in early-stage development ultimately fail to deliver in clinical trials, in some cases because processes could not be successfully scaled-up. At the early stages of research and development, manufacturing can seem like a distant concern, but by considering processing needs as early as possible, organisations can avoid later hold-ups.
The value created by choosing a partner that can support scale-up using a common technology base, can be seen from R&D through to cGMP production. The use of benchtop fillers that apply the same technology throughout scale-up in dispense and single-use fluid path technologies can limit the time and cost of validation whilst ensuring consistent output. Selecting a supplier that can scale with the therapy using common technologies, gives producers peace of mind that they can scale safely with tried, tested, validated and supported solutions.
As we see the development of novel treatments accelerate, manufacturing solutions need to match this innovation to ensure this doesn’t become the bottleneck in the delivery of effective medicines. By understanding current and future processing needs early, partners will be better able to deliver the value and expertise required. Current and future challenges will be better navigated by working collaboratively with manufacturing partners who understand the unique demands of this promising industry.