Challenges and Considerations in Development and Manufacturing of High Concentration Biologics Drug Products

With the advent of novel biotherapeutics in indications such as oncology, the attention has moved to making these therapies patient centric, potentially available for self-administration. Given the volume limitations of the other convenient routes of administration such a subcutaneous, intramuscular, there is a need for high concentration drug products. Along with the concerns of inherent protein instability at high concentration, there are other practical challenges during the development of these drug products. This review focuses on the considerations in formulation screening, process development, manufacturing, analytical methods and stability for high concentration liquid drug product. For the scenarios where, high concentration liquid drug product is not feasible, alternate approaches can be undertaken to obtain high concentration drug product during administration. The discussion on the current available alternate technologies with an overview of their advantages and disadvantages are covered here. The scope of the overall discussions is introductory and limited to cautionary notes and experiences as opposed to prescriptive recommendations and detailed literature reviews: our primary goal is to provide a compiled set of considerations that can guide a detailed literature research and a to-do list for high concentration development and manufacturing activities. This manuscript aims to highlight the motivations to develop high concentration parenteral protein drug products, a wide range of -commonly known or sometimes overlooked- challenges associated with their development and manufacturing, as well as some approaches towards mitigation of said challenges.