Crossing the hurdles of translation—a robust methodology for synthesis, characterization and GMP production of cross‐linked high molecular weight hyaluronic acid particles (cHA)

Abstract

Hyaluronic acid (HA) is one of the most widely used extracellular matrix substrate in tissue engineering, drug delivery, and other clinical applications, due to its unique physiochemical properties and ubiquitous biological presence. In the past decade, there has been a surge in research paradigms involving HA products to evaluate their commercial feasibility. Numerous papers and reviews have reported procedures for chemical modifications and cross‐linking of HA, but the intricacies of their scale‐up in the production processes are often not discussed. Protected by confidentiality agreements with industry partners, information on these procedures is exclusive and not accessible within an academic setting. Establishing translatable synthetic protocols of HA would address this significant gap in the field and facilitate their use in other applications. The current method details a reproducible and robust method for producing particles that are composed of high molecular weight hyaluronic acid (cHA) and cross‐linked via a 4‐arm polyethylene glycol amine linker using 4‐(4,6‐dimethoxy‐1,3,5‐triazin‐2‐yl)‐4‐methyl‐morpholinium chloride chemistry. A critical analysis of previously reported procedures for their advantages and limitations (reaction parameters, molar equivalents, and reagents used for cross‐linking), forms the basis for this procedure and its subsequent adaptation to good manufacturing practices requirements. As a component of a Class III medical device, the reported cHA is in the form of non‐sized particles.