Study Finds Similar Long-Term Stability Between CT-P6 and Reference Trastuzumab

A recent study looked at the long-term stability of CT-P6 (Celltrion and Teva's Herzuma), a trastuzumab biosimilar referencing Herceptin, to see if it had the same stability as the reference product.

Previous studies have shown that the originator Herceptin, reconstituted in vials or diluted in polyolefin bags, retained stability for up to 1 month at 4°C, but no data are available for its biosimilars. This study examined the extended stability of CT-P6 by several complementary methods, both in reconstituted vials at a concentration of 21 mg/mL and after dilution to bracket concentrations of 0.8 and 2.4 mg/mL in polyolefin bags, after storage at 4°C and 22°C for up to 3 months.

Drug stability studies are typically conducted in standardized conditions, and not in real-world scenarios, where they might be prepared by medical staff in less-than-ideal conditions. This study showed that the trastuzumab biosimilar CT-P6 remained physically and chemically stable for at least 90 days when stored at 4°C and away from light.

The biosimilar was studied in 2 contexts: in vials after reconstitution (21 mg/mL) and after dilution in polyolefin bags for final concentrations of 0.8 mg/mL and 2.4 mg/mL. Two storage temperatures were tested: 4°C and 22°C. Compared to the freshly prepared bags, after 28 days of storage at 4°C and 22°C, no sign of physical instability was observed, including no formation of submicron, micron, or particulate aggregates. Gel exclusion chromatography revealed no oligomer formation or breakdown of the compound’s molecular structure. Ion chromatography did not show any significant change in the distribution of the ionic variants after 90 days storage at 4°C. However, after 28 days storage at 22°C, significant signs of hydrolysis were observed.

Second derivative ultraviolet and fluorescence-derived spectral analysis showed no change to the tertiary structure of the antibody when stored at 4°C for 28 days. While small changes to the tertiary structure were observed after storage at 22°C for 28 days and 90 days at 4°C, thermal denaturation curves were identical between batches and these storage conditions, suggesting no strong destabilization of the 3-dimensional structure after 90 days storage at 22°C.

Identical results were observed for the drug in vials after reconstitution. The consequences of the modification of tertiary structure (possibly the cause of increased hydrodynamic diameter) after 90 days storage at 4°C on pharmacological activity remain unclear, but since there were no signs of chemical degradation nor aggregation, the effects are likely to be very limited.

After 90 days of storage at both 4°C and 22°C, no signs of physical instability, such as the formation of aggregates or oligomers, were observed, regardless of the antibody concentration. After 90 days at 4°C, there was no change in the distribution of the 7 ionic variants of the compound. The tertiary structure of the compound was unaltered after storage for 28 days at 4°C.

However, when stored at 22°C for 28 days, tertiary structure was slightly altered, and there were signs of hydrolysis, but no observable aggregate formation or significant signs of thermodynamic destabilization. The same conclusions can be made for reconstituted vials at 21 mg/mL.

For hospitals and specialists, the findings could help to improve patient management, lessen nurse and pharmacy workload, and avoid losses of the drug. The findings justify advanced preparation and implementation of dose-banding strategies. In addition, the results suggest a way to handle a drug dilution previously prepared but not administered, with implications for the pediatric use of products previously packaged for adult patients. In addition, the extended stability could improve the general acceptability of biosimilars.

Reference

Paul M, Astier A, Vieillard V. Extended stability of a biosimilar of trastuzumab (CT-P6) after reconstitution in vials, dilution in polyolefin bags and storage at various temperatures. GaBI J. 2018;7(3):101-10. doi: 10.5639/gabij.2018.0703.022.