Since the first immunotherapies were developed in the 1980’s, the production of monoclonal antibodies (mAb) to treat a wide variety of diseases has grown rapidly. The number of approved biologic therapies continues to increase and the total volume of mAb production grows, but the economy of production has remained relatively unchanged, keeping many therapies out of reach of much of the global population.
To meet the full potential of these therapies and to extend the current access, the evolution of processing methods to deliver improvements in economy and productivity are essential.
Continuous processing methods are widely understood as having the potential to streamline bioprocessing, reduce costs and safeguard quality. To achieve this, novel technology is required to enable this evolution and Pall has developed key enabling technologies to make continuous processing a reality.
Taking The Continuous Path
Whether you are ready to develop a fully continuous process, or prefer to adopt islands of continuity to intensify your existing process, we have a range of Continuous Ready products that will help you.
Beyond individual technologies we can help you combine these to create robust, but flexible integrated bioprocessing platforms and to take the next step in accelerating production and can also be provided in a prefabricated flexible POD® cleanroom from G-CON.
Supporting Your Journey
Pall Biotech has the knowledge and facilities to help accelerate your process development, This is especially true for the adoption of continuous processing where our continuous development laboratory has been processing up to 100 g/day since 2016. This give us first-hand insight into the unique challenges and opportunities that continuous processing brings.
We are happy to share our knowledge and together we can rapidly optimize your process, prove its readiness for industrial scale production and help increase your speed to market.
The technology decision will be driven by the cell culture characteristics and the process scale however for most processes that are relevant to continuous processing, single-use depth filtration is a viable solution. This may be optimized for each process where the optimal grades will differ between low cell density, high viability cultures and higher cell densities or lower viability. Solutions that offer robust performance across a wide range of culture conditions make the best platform choice and can support both batch and continuous processes.
High throughput depth filtration is an effective solution on its own for low cell density applications or in combination with other harvest technology for very high cell densities. Scalable, easy to use and single-use formats ensure simple operation and changeout if needed.
Bioburden control, especially within long running processes, is critical to the final drug product quality. Presterilized products with high thoughput and low binding, maximize yields while 0.2 µm validated membranes assure the retention of bacteria and provide a high level of particulate control securing the efficacy and life of downstream processes.
Multiple purification steps integrate seamlessly to deliver a streamlined purification platform that can operate as part of a traditional batch process and with other technology within an integrated continuous manufacturing process.
Multicolumn counter current chromatography delivers high throughput and very efficient media utilization when compared to single column, batch processes. When coupled with single-use valve cassettes these solutions deliver highly flexible configurations for both continuous and batch processing.
From the engine of protein capture using protein A affinity sorbents, to the simplicity of membrane based ion exchange chromatography and the unique selectivity of mixed mode chemistries, our robust purification platform delivers the purity required across a range of mAbs without the need for buffer exchange, dilution or pH adjustment. This platform works perfectly within a continuous process or delivers simple process intensification when operated in a traditional batch mode.
Traditional concentration and diafiltration using ultrafiltration systems requires the pooling and recirculation of complete batches and does not lend itself to integration within any form of continuous or intensified processing. Single-pass solutions avoid the need for batch pooling and reduce the shear damage and heat input associated with prolonged recirculation.
Simple in-line concentration without the need for complex controls permits the easy inclusion anywhere in the process where concentration can improve the performance or productivity of other unit operations. Over concentration of drug substance.
Multiple orthogonal virus reduction steps are mandated by regulators to assure robust clearance of a wide variety of viruses. Together, chromatographic purification, virus inactivation and virus filtration combine to deliver a validated, high log reduction to assure patient safety and the unit operations remain largely unchanged in a continuous process.
Virus inactivation using a low pH hold step is typically a manual batch operation reliant upon operator accuracy to maintain product quality and safety. The Cadence VI system is fully automated and can be configured to adjust, hold and readjust the pH of an incoming elution stream, with minimal operator involvement to support batch and continuous processing.
Robust, high virus retention under the challenging low-flow and high throughput conditions associated with continuous processing is a must. Add to this the retention resilience against stop-start conditions and the simplicity of pre-sterilized formats and you have a virus filtration platform that integrates perfectly with all monoclonal antibody and recombinant protein processes.
Validating robust virus removal for re-usable sorbents, while demonstrating the absence of batch to batch contamination can be a challenge. Single-use, disposable, membrane based ion exchange solutions simplify this challenge and can easily be incorporated into a continuous purification process to provide additional virus controls that are readily validated.
Bioburden control, especially within long running processes like continuous processes, is critical to the final drug product quality. Presterilized filters with high though put and low binding permit the use of smaller capsules to reduce product loss while 0.2 µm validated membranes assure the retention of bacteria at critical points in the process.
For low bioburden processes, the highest level of bacterial retention may not be necessary to maintain very low process bioburden. Where practical, the use of 0.2 µm filters documented as for bioburden control rather than sterile filtration may reduce the regulatory burden for activity such as filter integrity testing.
The use of closed, single-use processing solutions reduces the need for the venting of product hold containers but may be necessary where the process design requires venting such as for post sterilization integrity testing, inert gas overlay or where hard walled surge vessels are desired. Sterilizing grade air filters that are compatible with gamma irradiation permit the design of presterilized process solutions that control cleanliness and bioburden.
The preparation, storage and transport of media and buffers is an ever-present challenge and the provision of these is just as important when making the move to continuous processing. Single-use solutions, support all volumes and provide the flexibility and portability required to keep critical processes running.
Available in a wide variety of volumes, these combine with other carefully selected components to create the right system to deliver essential process fluids and to secure the storage of process intermediates and drug substance.
The mixing of buffers and cell culture media using single-use technology streamlines their preparation and delivery to the process
Monitoring and documenting simple operations such as sterile filtration and pH adjustment can be a time-consuming activity and can be simplified through the adoption of multipurpose automated systems.