Biologic excipients: Importance of clinical awareness of inactive ingredients

Due to the complexity and fragility of biological drug products, several challenges exist in their formulation development. Excipients are added to increase product stability, maintain tonicity, and facilitate drug delivery. The potential implications of these additive substances merit clinical consideration. We assessed the safety risk of excipients on the basis of their type and variability through an assessment framework, which quantifies excipient complexity in 230 biological formulations, and identifies excipient-related adverse events through published case reports.

A biologic on average contained 4.45 excipients, half of that found in oral medications. The frequency distribution was heavily skewed towards the most commonly occurring excipients: water (40.4%), sodium chloride (38.3%), polysorbate 80 (28.7%), sucrose (24.4%), and mannitol (20.9%), with 44.4% of formulations not listing the concentration of the most commonly occurring inactive ingredients. A literature search revealed only 17 case reports of excipient-related adverse events, suggesting the need for more clarity for clinicians on the safety of chemical additives.

These cases included injection site reactions, anaphylaxis, hyperglycemia, and acute renal failure. With the expansion of the biopharmaceutical market, it is important to consider the safety data of biologic excipients, so that therapy can be tailored appropriately for a specific patient.

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Table 1: Excipient functional category, class and types used in biologics.

Functional Category	Excipient Class	Types
pH Modifier (Acidifying/Alkalizing/Buffering Agent)	Bufferung Agents	Acetate, Citrate, Tartrate, Histidine, Glutamate, Phosphate, Tris, Glycine, Bicarbonate, Succinate Sulfate, Nitrate
Tonicity Agent	Tonicity Modifiers	Mannitol, Sorbitol, Lactose, Dextrose, Trehalose, Sodium Chloride, Potassium Chloride, Glycerol, Glycerin
Bulking Agent	Sugars and polyols	Sucrose, Trehalose, Glucose, Lactose, Sorbitol, Mannitol, Glycerol
	Amino Acids	Arginine, Aspartic Acid, Glutamic Acid, Lysine, Proline, Glycine, Histidine, Methionine, Alanine
	Polymers and proteins	Gelatin, PVP, PLGA, PEG, dextran, cyclodextrin and derivates, starch derivates, HSA, BSA
Wetting and/or Solubilizing Agent	Surfactants	Polysorbate 20 (Tween 20), Polysorbate 80 (Tween 80), Poloxamer (Pluronic F68 and F127), Triton X-100, Brij 30, Brij 35
Antioxidant	Antioxidant Preservatives	Histamine, methionine, ascorbic acid, glutathione, vitamin E, poly(ethylenimine)
Antimicrobial Preservative	Antimicrobial Preservatives	Benzyl alcohol, metacresol, phenol, 2-phenoxyethanol
Chelating and/or Complexing Agents	Chelator Preservatives	Edetate disodium, diethylenetriamine pentaacetic acid (DTPA), citric acid, hexaphosphate, thioglycolic acid, zinc

 

Article information: Ionova Y, Wilson L (2020) Biologic excipients: Importance of clinical awareness of inactive ingredients. PLOS ONE 15(6): e0235076. https://doi.org/10.1371/journal.pone.0235076