A review of Formulations of Commercially Available Antibodies

Abstract

the most at 17 each. A total of 136 products were identified of which 36 are lyophilized powders and 100 are solutions. The routes of administration are mainly subcutaneous or intravenous infusion with three intravenous bolus, two intravitreal, and one intramuscular. The subcutaneous products are ready-to-use solutions or reconstituted lyophilized powders that do not require dilution while most intravenous products are concentrates that require dilution into saline or another intravenous fluid prior to infusion. Most are packaged in single-dose units and the exception of multi-use is Herceptin Ò and its biosimilars. The package configurations are vials, prefilled autoinjectors, or prefilled syringes. A typical antibody formulation contains an antibody, an excipient to adjust tonicity or osmolality for solutions or a lyoprotectant for lyophilized powders, a buffer, and a surfactant. The ionic tonicity-adjusting excipient is mainly sodium chloride and the non-ionic osmolality-adjusting excipients include sucrose, trehalose, mannitol, maltose, and sorbitol. The lyoprotectants are trehalose and sucrose. The pH range is 4.8-8.0 and the buffers or pHmodifying agents include histidine, citrate, succinate, acetate, phosphate, glutamate, adipic acid, aspartic acid, lactic acid, tromethamine, and 2-(N-morpholino)-ethanesulfonic acid. The surfactants include mostly polysorbate 20 or polysorbate 80, with four containing poloxamer 188, and one that does not contain a surfactant but contains PEG 3350. One product does not contain a buffer, and 12 do not contain a surfactant. The viscosity-lowering excipients are sodium chloride and the amino acids arginine, glycine, proline, and lysine. Arginine may also function to adjust ionic strength and minimize aggregation. Human serum albumin is used in 2 products for intravenous infusion. Other excipients include methionine as an anti-oxidant, and EDTA or DTPA as chelating agents. The maximum volume of subcutaneous injection is 15 mL administered over 3-5 minutes, but the typically volume is 0.5-2 mL. Five fixed-dose combinations have recently been approved and four contain hyaluronidase to assist the large volume subcutaneous injection of up to 15 mL, while one is a fixed-dose combination for intravenous with three antibodies. Prefilled autoinjectors and syringes are becoming more common and many come affixed with a needle of 27-gauge or 29-gauge, while a few have a 26-gauge or a 30-gauge needle. Recent advancements include hyaluronidase to assist the large subcutaneous injection volume of 5-15 mL, fixed-dose combinations, buffer-free formulation, and smaller subcutaneous injection volume (0.1 mL).

US FDA-approved therapeutic antibodies with high-concentration formulation: summaries and perspectives

“…Consistent with our observation, Robert Strickley and William Lambert suggested this year (2021) in their review article that “a typical subcutaneous solution formulation has 100 mg/mL antibody, sucrose at 50 mg/mL, buffered at pH 6 by 0.01M histidine, has the surfactant polysorbate 80 at 0.01 mg/mL, the viscosity lowered with 10 mg/mL arginine, and is packaged in a prefilled syringe” ( 9 ).…”

“…In fact, multiple literatures as well as our formulation excipient analysis in Fig. 2 consistently concluded that arginine is the most widely used viscosity-lowering excipient because it may reduce both electrostatic interaction and hydrophobic interaction between protein molecules ( 9 , 30 , 35 ).…”

“…Thus, the high viscosity of the high-concentration antibody may result in challenges during manufacturing the drug substance (especially ultrafiltration and diafiltration process) and the drug product (in particular mixing, sterile filtration and filling). If subcutaneous administration is used for administration of high-viscosity antibody drug, large bore size needles may have to be used because of the increase in back pressure, and thus may result in an increased pain for patients ( 9 , 14 ).…”

“…More than one decade later after FDA approved the first mAb, FDA approved in 1998 the first mAb formulated with 100 mg/mL protein concentration (Synagis, Palivizumab) ( 8 ). While drafting this article, we notice that an excellent review of formulations of commercially available antibodies approved by global regulatory agencies was already published in March 2021 ( 9 ). Our article, as indicated in the title, is focused only upon the US FDA-approved therapeutic antibodies with high-concentration formulation.…”

Hybridoma technology; advancements, clinical significance, and future aspects

“…FDA has approved many monoclonal antibodies to be available commercially [ 31 ]. Margetuximab , a drug that is used in conjunction with chemotherapy to treat patients with HER2-positive metastatic breast cancer, was approved in the year 2020 [ 15 ].…”