A Comprehensive Scientific Survey of Excipients Used in Currently Marketed, Therapeutic Biological Drug Products
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.
Table 5: Common Excipients Among Unique Formulations for Different Molecule Type of Active Pharmaceutical Ingredients
| Excipients | Monoclonal Antibody (n = 118) | Excipients | Polypeptide Hormone (n = 109) |
| Polysorbate 80 | 61.86% | sodium phosphate | 58.72% |
| Histidine | 51.69% | sodium hydroxide | 57.80% |
| Sucrose | 38.98% | hydrochloric acid | 42.20% |
| Polysorbate 20 | 27.97% | metacresol | 42.20% |
| Sodium chloride | 25.42% | glycerin | 36.70% |
| Trehalose | 16.10% | zinc | 36.70% |
| Sodium phosphate | 15.25% | mannitol | 33.03% |
| Citric acid | 11.86% | phenol | 33.03% |
| Sodium citrate | 11.86% | glycine | 22.94% |
| Sorbitol | 10.17% | phosphoric acid | 17.43% |
| Excipients | Cytokine and Growth Factor (n = 83) | Excipients | Enzyme (n = 48) |
| Sodium phosphate | 49.40% | sodium chloride | 50.00% |
| Sodium chloride | 43.37% | sodium phosphate | 45.83% |
| Polysorbate 80 | 38.55% | polysorbate 80 | 20.83% |
| Albumin human | 26.51% | mannitol | 16.67% |
| Mannitol | 20.48% | citric acid | 12.50% |
| Sodium acetate | 20.48% | sodium hydroxide | 12.50% |
| Polysorbate 20 | 18.07% | polysorbate 20 | 10.42% |
| Sucrose | 16.87% | ||
| Citric acid | 16.87% | ||
| Sodium citrate | 15.66% | ||
| Excipients | Recombinant Fusion Protein (n = 18) | Excipients | Antibody Conjugate (n = 8) |
| Sucrose | 61.11% | sodium chloride | 50.00% |
| Sodium chloride | 44.44% | sucrose | 50.00% |
| Sodium phosphate | 44.44% | polysorbate 80 | 37.50% |
| Mannitol | 33.33% | citric acid | 25.00% |
| Citric acid | 27.78% | polysorbate 20 | 25.00% |
| Polysorbate 80 | 27.78% | sodium citrate | 25.00% |
| Sodium citrate | 27.78% | sodium phosphate | 25.00% |
| Polysorbate 20 | 22.22% | ||
| Excipients | Toxin (n = 10) | Excipients | Pulmonary Surfactant (n = 3) |
| Albumin human | 100.00% | sodium chloride | 100.00% |
| Sodium chloride | 50.00% | colfosceril palmitate | 33.33% |
| Sucrose | 30.00% | palmitic acid | 33.33% |
| Lactose | 20.00% | sodium bicarbonate | 33.33% |
| Sodium succinate | 10.00% | tripalmitin | 33.33% |
Read more
Rao VA, Kim JJ, Patel DS, Rains K, Estoll CR. A Comprehensive Scientific Survey of Excipients Used in Currently Marketed, Therapeutic Biological Drug Products. Pharm Res. 2020 Sep 24;37(10):200.
doi: 10.1007/s11095-020-02919-4.
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