Production Difficulties for Biologics with High Potency
In the realm of biologics, the surge in demand for drugs to be administered subcutaneously has brought forth a host of challenges, particularly with high concentration biologics such as monoclonal antibodies (mAbs).
One of the primary concerns is the increased risk of aggregation during freezing. To mitigate this, control measures are essential to prevent variable freezing kinetics from affecting quality. This is especially true for drug substances that are often frozen for storage and transportation.
The production of high concentration mAbs relies heavily on sterile filtration processes, with throughput being a key consideration when selecting filters. Single-pass tangential flow filtration (SPTFF) offers benefits over recirculation, including preconcentration using in-line concentration and in-line diafiltration devices, a lower hold-up volume, leading to enhanced product recovery and a higher step yield at higher concentration.
The manufacturing process for high concentrations of mAbs is overseen by companies like Sartorius, with more information available on their website. Filtration processes for mAbs must be validated to ensure the desired level of bacterial retention can be achieved, with filter selection driven by a full assessment of process risk, especially for process fluids with known risk factors such as higher viscosity.
Fill and finish can present problems with higher concentration and viscosity, as filling needles may drip and clog. To address this, robust process operations are crucial, and optimizing filling needle size and filling flow regime can also guard against drips and clogging. Hydrophobic filling needles have been found to reduce drip formation during fill and finish.
Maintaining product homogeneity in viscous fluids requires mixing systems that provide power without shear. Powerful mixers that transfer torque into a fluid at reduced speeds combined with levitation technology create an ideal mixing environment.
Excipients in formulations are optimized to inhibit aggregation, promote product stability, control viscosity, protect against shear stress, enhance absorption and bioavailability, and support improved and faster dispersal of therapeutics.
Preparation of high concentration mAbs begins with product concentration, which can be extended to delivering HCmAbs, posing a risk of aggregation and shear-related damage. To tackle this, plate freezing systems using 2D bags have more control over freezing than 3D bottles. Additionally, smaller filters, enabled by high-throughput characteristics, lead to lower non-recoverable fluid losses.
In conclusion, addressing the challenges associated with high concentration biologics requires a multi-faceted approach, encompassing filtration, mixing, freezing, and formulation strategies. By optimizing these processes, we can ensure the production of safe and effective high concentration biologics for patients.
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