A systematic review of commercial high concentration antibody drug products approved in the US: formulation composition, dosage form design and primary packaging considerations

Figures & data

Figure 1. Number of product approvals each year among HCAPs between 1998–2021. (n = 46).

A consistent increase in the number of approved antibody products since 1998 with the greatest annual number of initial US approvals have occurred since 2015.

Figure 2. Routes of administration among approved HCAPs (n = 46).

Among the 46 HCAP, Subcutaneous (SC) route of administration is the most used for HCAPs (n = 34), followed by intravenous (IV) (n = 6), both SC and IV (n = 2), intravitreal (n = 3) and intramuscular (IM) (n = 1).

Figure 3. Different therapeutic areas for which HCAPs are approved and marketed (n = 46).

The number of products (n) in parentheses, and the total number of products is 46.

Among the 46 HCAP products, a majority of approved HCAPs are indicated for immunology indications, with 20 products prescribed in Immunology, 4 each for Infectious diseases and Cardiology, 5 for Respiratory, 6 for Neurology, 3 for Ophthalmology, 1 for Hematology, and 3 for Oncology.

Figure 4. Antibody isotypes and subtypes amongst approved HCAPs.

Most antibody products are Immunoglobulin G 1 (IgG1) (30 products). Among the IgG1 antibodies, there are 2 chimeric IgG1, 9 human IgG1, 13 human IgG1k (kappa subtype), and 3 human IgG1λ (lambda subtype).

Figure 5. Dosage forms of the approved HCAPs (n = 46).

Among the 46 HCAPs reviewed here, the most prominent type of dosage form is the Ready-to-Use Solution (SOL) (n = 41), and only four products are marketed as Lyophilized solid (LYO) (n = 4).

Table 1. List of excipients generally used in protein formulations and their functions.

Excipients	Function	Examples
Buffer	Maintain stable pH environment	Histidine, Phosphate, Acetate, Citrate, etc.
Sugar and polyol stabilizers	Conformational stabilizer for the antibody	Disaccharides – Sucrose, Trehalose, Maltose. Polyols – Sorbitol, Mannitol
Tonicity Agent	Maintain iso-tonicity	Sucrose, NaCl, Trehalose, Mannitol
Surfactant	Reduce interfacial stress	Polysorbate 20 and 80, Poloxamer 188
Amino acid stabilizers	Stabilize the antibody by buffering or charge interactions or blocking hydrophobic interactions	Arginine, Proline, Glycine, Histidine, Methionine
Chelating agent	Prevent metal induced degradation	DTPA, EDTA
Viscosity Modifiers	Reduce solution viscosity	Arginine, Proline, Glycine, NaCl
Antioxidants	Inhibit oxidation	Methionine

Figure 6. Tonicity agents utilized in formulation of approved HCAPs (n = 46).

The number of products that contain the tonicity agent (n) in parenthesis and the total number of products is 46.

Among the 46 HCAPs, sucrose is the most frequently utilized tonicity agent for HCAP formulation and found in 18 of 46 products. Trehalose can be found in five products. The polyols sorbitol and mannitol were found in four and two products, respectively. Sodium chloride is found in 4 products. Thirteen of the products do not contain a disaccharide, polyol, or sodium chloride as tonicity agent, but some of these products contain amino acids L-arginine, glycine, and L-proline.

Figure 7. Disaccharide sugars and polyols utilized in formulation of approved HCAPs (n = 46).

The number of products that contain the disaccharide or polyol (n) in parenthesis and the total number of products is 46.

Among the 46 reviewed HCAPs, 18 products contain sucrose, 5 contain trehalose, 4 contain sorbitol and 2 contain mannitol. Seventeen products do not contain a sugar or polyol stabilizer.

Figure 8. Buffers utilized in formulations of approved HCAPs (n = 46).

The number of products that contain a buffering agent (n) in parenthesis and the total number of HCAPs is 46.

Figure shows the prevalence of different buffers in the formulation of the 46 HCAPs, where Histidine, individually or in combination with other amino acids or inorganic buffers, is the most prevalent buffer system used to stabilize HCAPs (n = 32). In addition, glycine (n = 3), glutamate (n = 1), L-Proline (n = 1), lactic acid (n = 1), phosphate buffer (n = 2), acetate buffer (n = 3), citrate buffer, and its combination (n = 2) have been used as alternate buffers. Formulation of 1 product is bufferless.

Figure 9. pH of stabilized formulations amongst approved HCAPs (n = 46).

Among the 46 reviewed HCAPs, 6 products have pH in the range of 4.5–5.0, 12 products have pH in the range of 5.1–5.5, 21 products have pH in the range of 5.6–6.0, four products have pH in the range of 6.1–6.5, one product has pH in the range of 6.6–7.0, and two have pH in the range of 7.1–7.5.

Figure 10. Surfactants in formulations of approved HCAPs (n = 46).

The number of products that contain a surfactant (n) in parenthesis and the total number of HCAPs is 46.

Among the 46 HCAPs reviewed here, polysorbate 80 was the most used surfactant (n = 28) followed by polysorbate 20 (n = 10) and poloxamer 188 (n = 3). Four products have no surfactant.

Figure 11. Amino acids utilized in formulations of approved HCAPs (n = 46).

Number of products that contain an amino acid (n) in parenthesis.

Among 46 HCAPs, L-histidine was used in 30 products, L-histidine hydrochloride monohydrate was used in 23 products, L-methionine was used in 8 products, L-arginine hydrochloride was used in 6 products, glycine and L-proline both were used in 4 products each, L-arginine was used in 3 products, L-aspartic acid in 2 products, and L-lysine hydrochloride was used in 1 product.

Figure 12. Number of amino acids used in each formulation for stabilization of HCAPs (n = 46).

Among the 46 HCAPs, 9 products do not utilize any amino acid for stabilization of the formulation. These products are stabilized using sugars, non-amino acid buffers (e.g., acetate and phosphate), and surfactants. Another nine products utilize one amino acid to stabilize the formulation

Figure 13. Viscosity reducing agents used in formulations of approved HCAPs (n = 23).

The number of products that contain a viscosity reducing agent (n) in parenthesis.

Among the reviewed 46 HCAPs, there are 23 instances wherein viscosity reducing agents (i.e., arginine and its hydrochloride salt, proline, lysine hydrochloride, glycine, and sodium chloride) were used.

Figure 14. Primary packaging configuration of approved HCAPs (n = 46).

The primary packaging configuration for each of the HCAP, number of products (n) in parentheses, and the total number of HCAPs is 46.