Chapter 15: Drug Product Formulation Development and Formulation Robustness Criteria for a mAb in a Pre-filled Syringe

Abstract

A majority of monoclonal antibodies (mAbs) are formulated for intravenous (IV) administration. Recently however several subcutaneous (SC) products have been approved that are ready to use in a physician’s office, clinic, or at home using either a pre-filled syringe (PFS), an auto-injector (AI), or patch pumps. AIs have shown to be more convenient for patients and ensure better compliance, especially while treating chronic conditions such as diabetes, rheumatoid arthritis (RA), or asthma. SC products have certain limitations during pharmaceutical development including volume per injection (usually 1–2 mL), short injection times, bioavailability (typically 60–70% of IV dosing), and number of injections per dose cycle (preferably one or two injections). This makes development of high-concentration formulation mandatory if SC administration by PFS is called for in the target product profile (TPP). High-concentration mAb formulation development needs to take several aspects into account, including viscosity due to high concentrations, syringeability, and potential interactions between formulation and device components. Formulation scientists typically use a multivariate study with statistical analysis to comprehend any interactions between the formulation parameters, their ranges, and if there is any impact on protein product quality over time and temperature. This chapter focuses on formulation development of mAb drug products for subcutaneous delivery using a quality by design (QbD) approach. We present a two-pronged approach to (1) design and execute a pre-robustness study to identify worst-case formulations and (2) robustness studies on worst-case formulations to support product development in a PFS. We believe this approach will simplify product development while assuring that formulation robustness can be achieved using a QbD approach.