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Monoclonal Antibodies (mAbs) and Recombinant Proteins

Flexible, scalable solutions to support process development and clinical production.

 

The number of licensed immunotherapies based upon monoclonal antibodies (mAb) and recombinant proteins has grown rapidly over the last 30 years. Despite this growth, most current production processes remain closely related to those established by the early processes pioneers.  However, the productivity of a typical mAb process has changed significantly over this same period.  The optimization of cell lines and cell cultures, the intensification of downstream purification, and the adoption of new technology, continue to drive productivity increases and reduce the cost of production.  This in turn, helps meet the changing demands of a growing and ageing population in an increasingly competitive industry.

 

Robust mAb manufacturing platforms can accelerate speed to clinic and can quickly develop processes and support a swift transition to full scale production.  Making the right technology choice accelerates, and de-risks, this transition. The same choice may also enable the redeployment, or reuse, of hardware across multiple development and clinical processes.  This further dilutes financial risks relating to capital investments at all stages of production.

 

Other antibody constructs such as Fc fusion proteins, bispecific monoclonal antibodies (bsmAb) and antibody-drug conjugates (ADCs) require unique modifications to these model platforms.  However, these, and future therapeutic modalities, still share similar production and purification challenges. The same solutions can be reorganized and optimized to form the foundation of any future process.

 

New process developments will always have the greatest scope to adopt new technology but existing processes still have opportunities to evolve within the constraints of the manufacturing approval.  The benefits of single-use technology can be applied to most unit operations and may make significant differences even for non-critical processes.

 

Together with single use, the Integration and automation of unit operations, not excluding the adoption of continuous processing elements, all contribute to increasing the productivity, flexibility and economy of production.  Whatever you need, the right choice for your process can be found among our complete process solutions.

 

Choose Your Journey

 

There is no single, best manufacturing solution. What is right for one process, or one manufacturing site, may not be right for every other.  Pall has a unique breadth and depth of portfolio to support all your manufacturing choices, supporting traditional manufacturing methods and single-use alternatives with technologies for further intensification through automated, continuous processing and integrated processing.

 

 

 

 

 

Helping You On Your Journey

 

Beyond just the technology, Pall Biotech has the knowledge and portfolio to help accelerate mAb process development, and to intensify existing processes through automation, integration and the adoption of single-use technology.

 

Let us 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.  

 

process development services

Cell Culture

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While historic mAb based blockbuster processes may use multiple, multi-thousand litre stainless steel stirred tank production bioreactors, higher culture titres mean that an increasing number of processes do not require greater than 2000 L for any single batch. These volumes are within the capability of single-use alternatives and the benefits that this can deliver.  Even for very large-scale processes, the benefits of single-use may still be achieved when applied within the seed train and can deliver productivity improvements as part of a hybrid, single-use and stainless steel upstream process.

 

Single-use Bioreactors

 

Preirradiated consumables combine with process monitoring, hardware and software to control and simplify the preparation and growth of cell cultures.   This simplicity minimizes contamination events and supports rapid turnaround for higher levels of productivity.

 

Biaxial rocking bioreactors for volumes of 2 L - 25 L

Stirred tank bioreactors for volumes of 10 L – 2000 L

 

Process Control and Data Acquisition

 

Maintaining control is critical to maintaining the productivity of the cell line and to assure the critical quality attributes of the final drug product.

 

Benchtop control tower for the flexible control of single-use cell cultures.  Available with software for supervisory control and data acquisition (SCADA)

 

 

Media Preparation

 

Upstream processes need the timely provision of volumes of sterile process media.  The preparation, transfer and connectivity all need to be carefully controlled to minimize process risks.

 

0.1 µm filters for mycoplasma control

Mixers for media preparation

Sterile connectors to simplify the aseptic connection of single-use components

 

 

Air Filtration

 

Critical to the security and sterility of cell cultures, the sterile filtration of gaseous additions and exhaust is easy to overlook when focusing on the details of complex upstream processes.  Making a robust air filter choice means you can confidently focus on these details.

 

Steamable filters with PTFE membranes

Autoclavable capsules with PTFE membranes

Irradiatable capsules with PVDF membranes

 

Cell Harvest

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The classical combination of centrifugation and filtration for the cell harvest and clarification demands repeated optimization during scale-up and can require a large capital investment. Depth filtration, often used to clarify fluid post-centrifuge supports several cell harvest options. These include optimized single-use depth filtration platforms to replace centrifugation that can deliver simple, scalable solutions with a robust performance across a wide range of mAb processes.

 

 

Depth Filtration

 

The simplest technology is often the right choice for many processes, providing the performance meets the process needs.  A wide range of depth filtration media can be optimized for each process or as a platform technology for the clarification across a wide range of cell density and viabilities.

 

Lenticular depth filters for installation in reusable stainless-steel housings

Single-use depth filtration

Allegro MVP for control and automation of filtration processes.

 

 

 

Body Feed

 

When the addition of diatomaceous earth (DE) or other process additives is preferred, these can be prepared and removed using single-use solutions to provide the necessary cleanliness and simplicity.

 

Stax CF single-use depth filtration with increased spacing to retain large volumes of permeable solids.

Magnetic Mixer for DE slurry preparation

 

Chromatography

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Multiple stages of chromatographic purification combine to deliver consistent purity of antibody to meet the critical quality attributes needed to assure the safety of the drug product.  This requires a combination of chemistry, hardware and process controls and can be selected to work to any desired manufacturing scale and method.

 

Resins and Membranes

 

The capture and purification of antibodies and recombinant proteins requires a range of ligand chemistries and substrates with unique specificities to achieve the desired purity as simply and as economically as possible.  The ideal purification platform can deliver this purity across a wide range of processes with minimal buffer adjustments.

 

Protein A affinity resin

Cation exchange, mixed mode resin

Anion exchange membrane

 

 

Hardware

 

The right systems are the backbone of a reproducible, well optimized and efficient purification process.  Options exist to support traditional, single-use and continuous manufacturing preferences.

 

Single-use chromatography systems for volumetric flows of 10 – 900 L/hr to work with prepacked and traditional columns

Chromatography Columns 280 mm – 2000 mm diameter

Chromatography Systems such as packing skids and process control hardware

 

 

Continuous Chromatography

 

Multicolumn counter-current chromatography can be applied as part of an integrated, continuous downstream process or simply used to minimize resin volumes throughout process development and small scale clinical manufacturing in batch mode.

 

Process development systems for process flows of 0.5 to 100 mL/min

Production systems for 8 to 350 L/hr

 

Virus Safety and Control

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Securing the viral safety of final drug substance is mandated by regulatory bodies with a minimum of two dedicated orthogonal technologies required to provide robust viral clearance and ensure drug safety.  While multiple unit operations in a typical mAb process, including chromatographic purification, may be validated to contribute to this safety, dedicated and complementary virus control steps are needed.

 

 

Virus Inactivation

 

Taking advantage of the low pH conditions used for the elution of protein A affinity resins, viral load is reduced by applying a process hold at a low target pH for the validated time.

 

Virus Inactivation system for the automated pH adjustment and mixing to support both batch inactivation and integration with continuous processes.

 

 

Virus Filtration

 

Removal of all viruses by size exclusion is a robust virus control that can be simply added to most processes to achieve a high viral log reduction value (LRV).

 

High flow virus filters for robust, high LRV across a wide range of mAbs and fluid conditions.

Virus prefilter to secure and extend the performance of your virus filter.

Steady flow virus filters for complex fouling fluids

 

Ultrafiltration (Concentration and Diafiltration)

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Adjusting the fluid properties of process intermediates using ultrafiltration (UF) is common throughout typical mAb processes.  The applications range from simple diafiltration (DF) for buffer exchange, in support of chromatographic purification, to establishing the optimal concentration and fluid conditions of the drug substance in readiness for final formulation and product filling.  Where practical, additional concentration stages may also enhance the performance of other unit operations where these are volume or flow dependant.

 

 

Reusable cassettes and TFF systems

 

Recirculating UF/DF solutions with cleanable cassettes and flowpaths may be validated for reuse within a manufacturing campaign and can be controlled and monitored using systems that meet your exact requirements.

 

Regenerated cellulose membrane cassettes for cleanability

PES membrane and cassettes for low protein fouling

TFF systems for all production scales and automation needs

 

 

Single-use cassettes and systems

 

Single-use flowpaths and cassettes simplify the installation and reduce process preparation times.  The non-product contact hardware can be deployed across multiple unit operations for process flexibility, reduced capital investment and rapid turnaround times between processes.

 

Single-use TFF modules are pre-sterilized and ready to use

Single-use TFF systems for areas of 0.5 m2 to 10 m2

 

 

Continuous

 

Single-pass UF processes minimize shear forces to maximize process yield.  They are key enablers of continuous processing and can be easily added to intensify batch processes.

 

Inline concentration for volume reduction and concentration

Inline diafiltration for the formulation of drug substance

 

 

Filtration plays an important role in controlling bioburden throughout the process and is critical when protecting the cell culture and ensuring the sterility of the final drug substance and final drug product.

 

 

Sterile Filtration

 

For critical points in the process and for the highest assurance of bioburden control, 0.2 µm, sterilizing grade filtration delivers the sterility assurance needed.

 

Supor® EX ECV capsule filters

Supor EKV capsule filters

 

 

Bioburden Control

 

For non-critical fluids such as buffers, bacterially retentive filtration, not qualified as fully meeting the demands of a sterilizing grade, may be sufficient and can deliver an appropriate level of controls.

 

Bioburden reduction filter capsules

 

 

Mycoplasma Control

 

Where potential contaminants are known to penetrate traditional 0.2 µm filters or for when additional sterility assurance is sought, 0.1 µm filters deliver the level of retention required.

 

0.1 µm filter capsules for mycoplasma control

 

 

Performance Validation

 

The final filtration of drug product is carefully regulated.  Process specific validation confirms the performance under the process conditions and ensures that product contact does not impact the safety of the drug.

 

Filter validation testing and consultancy