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mAb Downstream Processing

Efficient downstream processing can accelerate mAb manufacturing while containing costs

Optimization of the downstream steps in monoclonal antibody (mAb) processing is critical to ensuring product quality, yield, and sterility. Getting the most out of every step depends on a broad range of products, services, and solutions to meet the different needs of each process.

Accelerating clarification of pretreated feed streams

Increasingly efficient upstream processes enable biopharmaceutical manufacturers to achieve higher cell densities and antibody titers. This improved upstream efficiency has led to new purification challenges resulting from high product and contaminant concentrations. Harvest and clarification technologies are evolving to incorporate feed stream pretreatment, including flocculation and different filtration methods such as normal flow, tangential flow, and depth filtration to improve separation efficiency. The objective is to increase process capacities and filtrate quality, while minimizing biomanufacturing costs.

For example, pretreating feeds with a flocculation reagent followed by depth filtration is an effective clarification solution for harvesting high cell density cultures, with easy integration into current platforms. The flocculation reagent acts as a binder to aggregate cells and cellular debris into larger particles within a solution. Primary clarification filters specifically designed for harvesting of high cell density cultures are now available, removing larger particles by using their depth for sieving while maintaining good adsorption capacity.

Workflow

Monoclonal Antibody Manufacturing

Increased process understanding has led to advancements in mAb manufacturing that include efficiencies in both upstream and downstream processing

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Upstream

The upstream process begins with cell line development and includes all steps up to cell harvest, with the goal of increasing cell densities and product titers to maximize mAb production

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Final Filtration and Filling

Final filling of drug products must meet stringent requirements for sterility, integrity, cleanliness, operational safety, and efficiency

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Viral Safety

Based on the principles of “prevent, detect, and remove,” viral safety combines risk analysis with careful selection of raw materials, extensive testing of raw materials and process intermediates, and implementation of virus reduction steps in downstream processing

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Bioburden Control

All mAb production processes are at risk for microbial contamination, requiring a process design with control strategies to mitigate the risk, as well as bioburden monitoring to assure process control

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Aggregate Removal

Protein aggregates are a concern throughout upstream and downstream mAb manufacturing, and control is key to maximizing process efficiency and robustness

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Intensifying mAb polishing with single-pass TFF and anion exchange chromatography

While it is common for mAb downstream purification processes to use a flow-through anion exchange (AEX) resin as a final impurity adsorption step, this conventional polishing step can lead to process bottlenecks due to large columns with long processing times. A growing number of manufacturers are taking advantage of a new solution: pre-concentrating the mAb feed before the AEX column by connecting inline single-pass tangential flow filtration (SPTFF) with AEX chromatography. This approach improves the AEX resin’s capacity for HCP impurities and minimizes the bottleneck at the AEX polishing step.

Increasing purification efficiency using chromatography membrane

Conventional purification technologies generally require trade-offs in process design. For example, resin-based chromatography columns are often oversized due to throughput limitations and are less compatible with flexible manufacturing. Conventional membrane adsorbers offer faster throughput, but their low binding capacity may not provide sufficient process robustness.

To overcome these limitations, a new generation of high-capacity, high-throughput AEX chromatography membrane has been developed, combining high binding capacity and flow rates in a single-use plug-and-play format. This new option for purification offers the potential of more productive, flexible, and robust process design.

Handling high-viscosity feeds associated with increasing concentration

Converting infusion-based treatments to subcutaneous injections can increase patient comfort and satisfaction. The challenges to development of these solutions include:

Delivering a much higher concentration drug
Designing an efficient ultrafiltration process, using high-quality formulation buffers
Overcoming viscosity limitations with some TFF systems

TFF cassettes designed for high-viscosity operation enable drugs to be concentrated without modifying current systems or replacing pumps.
Excipient combinations to decrease viscosity of highly concentrated protein solutions can be used to improve process economics during TFF. This can ultimately enable a higher final protein concentration in formulation still administrable with standard syringes.

Optimizing reuse and storage of TFF cassettes

Qualification of TFF cassette reuse, lifetime, and storage is important during optimization and qualification of any manufacturing process. Understanding the requirements and risks of TFF cassette storage and reuse is essential to developing a comprehensive validation plan and mitigating potential risks of product recalls or plant shutdowns.

Optimizing cleaning for extended chromatography resin lifetime

Chromatography resins are a major contributor to monoclonal antibody production costs. To improve process economics and maximize resin lifetime, resins should be effectively cleaned before reuse to remove fouling species.

Optimization of resin cleaning procedures over multiple cycles through traditional lab-scale experiments is time-consuming and requires a significant amount of feed material. However, miniaturized, high-throughput screening tools can be used to optimize resin cleaning procedures. Studies at miniaturized scale accelerate the time to results, while minimizing the volume of feed material and buffers required.

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