This work summarizes our recent efforts to develop lab scale methods that benchmark biological liquid formulations and their susceptibility to interfacial and fluid shear induced physical changes during formulation and filling processes. We have previously found that common unit operations such as pumping, mixing and resuspension during filling processes can cause damage to liquid formulations if not properly designed and monitored. This is further complicated by the diverse array of biological drug products that are currently being developed and include small proteins, monoclonal antibodies, virus-like particles, live viruses, lipoproteins and DNA molecules. Common modes of damage to the drug formulation during processing are clipping, adsorption and aggregation which can compromise product efficacy, quality and safety profiles. A scaled down approach was used to develop the bench experiments that represent various process unit operations used to formulate and fill the final drug product. Data obtained from these studies were used understand the behavior of the drug molecule in various types of flow and mixing conditions and prioritize development efforts to focus on ensuring the drug can be processed without affecting quality.

Bench scale studies were conducted to test formulation robustness and included small mixing vessels, hydrophobic and hydrophilic surface interactions, shaking and recirculation with peristaltic or piston pumps. In addition, a small elongational shear device was added to the recirculation studies and various types of tubing were used to study material specific interactions. We found the most common change was aggregation of the protein molecules during recirculation and mixing. Protein aggregation caused losses in potency and unsatisfactory visual appearances but could be mitigated with proper modifications to the formulation and/or process. The rate and extent of aggregation was a function of the active and/or surfactant concentrations. Our studies revealed that damage resulting in aggregation was a breakdown in the formulation caused by surface related shear phenomena. The rate and extent of aggregation was also strongly dependent on the surface material of construction. Additional work is currently being conducted to understand the mechanisms of damage and how it relates to various materials used in commercial manufacturing. Based on the results of this work, a general approach was developed to characterize the sensitivity of new biologics to process induced physical changes. This approach is enabling the optimal design of processes, formulations, and packages while minimizing the development work required for robust biological formulations.

In conclusion, we took one step closer towards a scientific understanding of how formulation and filling processes may affect complex biological drug molecules. This is a key development component to ensure we can meet the demand for getting life-saving, safe and efficacious drugs to the market faster. Finally, fundamental scientific understanding and prioritization during process development of biological drug formulations will immensely aid biopharmaceutical efforts to develop processes that incorporate a quality-by-design aspect to ensure final product quality.