At the lowest concentration and highest temperature (e.g., 153 mg/mL at 25 ☌), viscosity is ∼9 cP. Figure 1 shows that range for a formulation of 170 mg/mL ± 10% at temperatures between 5 ☌ and 25 ☌. Viscosity increases exponentially with decreasing temperature, so a significant range of viscosity values may be encountered for high‑ concentration MAb drug products when they are stored at 2–8 ☌ and at ambient temperature of ∼25 ☌. Because viscosity is exponentially dependent on protein concentration, it can vary considerably from lot to lot in this concentration specification range. Subsequently, we placed the samples in a 20 ☌ incubator and recorded their temperature over the course of 190 minutes.Ī high‑concentration MAb drug product with a specification for protein concentration of 90–110% around a target concentration of 170 mg/mL can range from 153 mg/mL to 187 mg/mL. We stored prepared samples in a cold room overnight to allow thermal equilibration. The beakers were fitted with temperature probes in the center of the liquid and covered with aluminum foil.
We filled four equivalent glass beakers with equal amounts of water, normal saline, formulation buffer, and drug substance (170 mg/mL MAb in formulation buffer), respectively. By fitting the data in Sigmaplot and plotting them in a three‑dimensional mesh diagram (Systat Software), we generated a concentration– temperature–viscosity profile. We measured the viscosity of a MAb drug substance at select protein concentrations between 150 mg/mL and 190 mg/mL and at temperatures between 5 ☌ and 25 ☌ using a mVROC microviscometer with an attached water bath (Rheosense). However, the effect of temperature on manufacturability of high‑concentration parenteral formulations has not been sufficiently examined. Some studies describe challenges to manufacturability from high viscosity as a function of protein concentration as well as the influence of protein rheology on combination products for parenteral delivery ( 6, 8– 10). A decrease in temperature will cause viscosity to increase exponentially ( 4– 7). Parenteral drug products are typically stored refrigerated at 2–8 ☌. Temperature also can influence viscosity.
But the same specification applied to a high‑concentration drug product can lead to significant variability in viscosity within its design space. Thus, a specification for a protein concentration 90–110% of target has little effect on viscosity of a low‑concentration drug product. But at high concentrations (>100 mg/ mL, depending on the molecule), viscosity increases exponentially ( 2, 3). At low concentrations, an antibody solution’s viscosity increases moderately as a function of protein concentration.
Monoclonal antibodies (MAbs) often have high dose requirements, so they must be formulated at very high concentrations ( 1). JIM DELILLO (Patient preference and a competitive landscape in the parenteral market have fueled the need for convenient delivery systems and a desire for less‑frequent dosing injections.
0 kommentar(er)
