A Comprehensive Scientific Survey of Excipients Used in Currently Marketed, Therapeutic Biological Drug Products

Abstract

Purpose The steady development of biotechnology-derived therapeutic biologics over the last few decades has generated drugs that are now standard medical treatments for a range of indications. While the development of protein products has surged in recent years, the formulation and delivery of these complex molecules have relied on drug-specific studies and, in some instances, data from non-proteinaceous drug products. The commonalities, trends, and gaps in excipient technologies used to support the development of therapeutic proteins largely remain unexplored due to the drug-specific nature of many formulations. Methods Using a comprehensive and relational database approach, we aimed to provide a scientific survey of all approved or licensed biotechnology-derived drug products with the goal of providing evidence-based information on common attributes and trending features in protein product excipients. We examined 665 formulations, and 395 unique formulations based on having unique excipients within them, that supported 211 therapeutic proteins as of June 2020. Results We report the prevalence of each excipient class and excipient chemical used in eight different drug types including monoclonal antibodies, antibody conjugates, cytokines and growth factors, enzymes, polypeptide hormones, pulmonary surfactants, recombinant fusion proteins, and toxins. We also report the prevalence by excipient type among all therapeutic proteins, in the context of each drug’s recommended pH range, concentration ranges for excipients, and route of administration. Conclusions The results of our analyses indicate certain excipients common to monoclonal antibodies, cytokines, and polypeptide hormones. We also report on excipients unique to protein drug products, such as amino acids, solubilizers, and lyoprotectants. Overall, our report summarizes the current landscape of excipients used in marketed biotechnology-derived therapeutic biologic products.

Detection of innate immune response modulating impurities (IIRMI) in therapeutic peptides and proteins: Impact of excipients

“…Most therapeutic peptides and proteins are formulated using excipients to enhance manufacturability, stability, and delivery, however some excipients, like polysorbate 80, have been shown to modulate cell viability ( 33 , 36 , 37 ). To examine whether excipients impact the sensitivity of cell-based assays to detect IIRMI, we selected several commonly used excipients: polysorbate 80 and poloxamer 188 (surfactants), albumin (stabilizers), sucrose, trehalose and, mannitol (sugars), and histidine and arginine (amino acids) ( 31 ). Their impact on cell-based assays to detect IIRMI using Raw-Blue and THP-1-Blue cells was explored.…”

“…The formulation of biologics can be complex and different therapeutic products contain a wide range of excipients to stabilize and protect the API ( 31 ). Most commonly used excipients have a long history of safety, but some, including mannitol ( 50 – 52 ), polysorbates and its degradants have been associated with changes in product immunogenicity, injection site reactions, and hypersensitivity responses ( 33 , 46 , 53 – 55 ).…”

“…Thus, a drug product consists of the active pharmaceutical ingredient (API) and its excipients. For aqueous-based injectable formulations, some of the most commonly used excipient types include buffering agents, stabilizers, tonicity adjustment agents, lyoprotectants and antioxidants as recently reviewed ( 31 , 32 ). Sodium chloride, polysorbate 80, sucrose, and mannitol are the most common excipients after water, but most biologics have at least 4 components in their formulation ( 32 ).…”

Effect of Poly(trehalose methacrylate) Molecular Weight and Concentration on the Stability and Viscosity of Insulin

“…Excipients have been employed extensively to maintain biopharmaceutical activity through the environmental stress DOI: 10.1002/mame.202100197 caused by manufacturing, transportation, and storage. [8,9] Small molecules such as amino acids, [10,11] osmolytes, [12,13] and carbohydrates [14] all successfully stabilize proteins through buffering, preferentially hydrating, and binding interactions. Macromolecules, both natural and synthetic, have been used to stabilize biopharmaceuticals through various mechanisms including preventing protein adsorption, unfolding, and aggregation.…”

Editorial: Formulation and Delivery of Biologics

“…Towards more rapid development of biologics, Rao et al took a different approach, namely analyzing the trends in the use of excipients in commercially available drug products (12). In their review, they examined 395 unique formulations for 221 therapeutic proteins.…”