Strategies to overcome challenges can deliver advantages over a monotherapy.
By Mitra Mosharraf, Ph.D., and Rajiv Nayar, Ph.D., HTD Biosystems Inc.
Combination therapy of two or more molecules with complimentary pharmacological effects has led to an increased interest in development of coformulation products. Here, we discuss the challenges and strategies for coformulation development of biologics. Coformulations or fixed-dose combination drugs (FDCs) are defined as products in which two or more separate drug components are combined in a single dosage form.1 These products can often reduce the number and volume of injections, improve patient compliance, reduce discomfort, and lead to patent extension for previously marketed products.2 According to the Food and Drug Administration (FDA),1 “drug and biologic combinations may consist of (1) two or more previously marketed drug products; (2) one or more new molecular entities (NMEs) and one or more previously marketed drug products; or (3) more than one NME.” Coformulation of previously marketed products might appear to be a safer approach than the other two FDC options, because of access to historical data and knowledge of biophysical and biochemical profile and stability indicating assays for each molecule. However, in addition to safety, efficacy, and noninferiority, clinical trials should usually also provide evidence that the combination product has superiority compared to the monotherapy. There are also many chemistry, manufacturing, and controls issues that need to be addressed for a combination biologic. These include analytical challenges in characterization of each molecule in the coformulation, manufacturing issues of formulating higher concentration biologics, and stability problems such as protein-protein interactions, protein aggregation, and subvisible particle formulation.