Authors of a new in vitro study said Sanofi’s biosimilar SAR341402, approved in June 2020 by the European Medicines Agency for use in insulin pumps, had similar stability compared with the originator under stress conditions in their experiments.
The rapid-acting insulin analog insulin aspart, used in Novo Nordisk’s NovoLog and NovoRapid products, was approved in 1999 and 2000 by the European Medicines Agency (EMA) and the FDA, and is frequently used for continuous subcutaneous insulin infusion via insulin pump devices. Authors of a new in vitro study said Sanofi’s biosimilar SAR341402, approved in June 2020 by the EMA for use in insulin pumps, had similar stability under stress conditions in their experiments.
Insulin may be exposed to variations in temperature, humidity, and light, and mechanical agitation from patient movement, while stored in the reservoirs of an infusion system for extended time periods, where it interacts directly with plastic surfaces of the reservoir and pump.
Ensuring stability of the insulin under these conditions and compatibility with the tubing and reservoirs of the pump system is important, the investigators noted. They compared the stability of Sanofi’s biosimilar to NovoLog and NovoRapid in Medtronic insulin pumps under various stress conditions, such as high temperature or mechanical agitation, and potential misuse conditions, for up to 13 days.
Similar physical and chemical stability between insulin aspart biosimilar and reference product
The investigators reported physical and chemical stability were similar over 13 days with no significant decrease in insulin aspart concentrations; concentrations remained within 90% and 100% of the label claim for all products. There was a time-dependent increase in high-molecular weight proteins and other insulin aspart impurities “as expected,” but each remained within an acceptable range.
However, concentrations of the antimicrobial preservatives phenol and metacresol decreased below acceptance criteria after day 4 in pumped samples and day 7 in reservoir samples at elevated temperatures with mechanical stress. The authors wrote that the loss of phenol and metacresol was “presumably due to the exposure to plastics used in the infusion set and reservoirs leading to adsorption and diffusion processes,” adding that loss of these preservatives has also been reported in previous studies after contact with plastic pumps and reservoirs.
Out-of-specification results were also observed for pH; however, the authors did not consider these findings relevant for patient safety, as the pH values were within the range considered acceptable for subcutaneous injections.
During photostability testing, impurities due to light and heat exposure increased over time similarly in samples of the 3 different insulin products. The authors noted that samples from reservoirs generally showed higher concentrations of impurities than pumped samples, and that this finding was most likely due to differences in the composition of the plastics composing the reservoirs and pumps.
Subvisible particle counts were “comparable” and within acceptance criteria in all products following 13 days of use in pumps, and “all leached elements were well below the safety concern threshold of 1.5 µg per person per day.” The concentration of one substance (1,6-dioxacyclododecane-7, 12-dione) was detected above the predefined safety threshold in pumped samples. However, the authors said, no genotoxic potential was found, and the concentrations detected “were not thought to pose any additional risk to patients.”
No occlusion alarms were triggered, and no occlusion events were observed, over 6 days of continuous pump use with mechanical agitation.
The authors also examined 6 potential misuse scenarios, including mixing the different insulin products, reusing reservoirs, storing the device at unintended temperatures, and using infusion sets for longer than intended. “Similar results for all insulin aspart products were seen in each scenario” when used over the recommended reservoir usage time of 6 to 7 days, they reported.
The investigators concluded that SAR341402 “demonstrates appropriate physicochemical stability” when used in insulin pump devices. Although the extreme conditions they tested “may not fully reflect real-life use in clinical practice,” they wrote, their findings suggest the stability of the biosimilar is maintained similarly to that of the originator under simulated worst-case conditions.
Mohnicke M, Blecher A, Beichert K, et al. In vitro stability of biosimilar insulin aspart sar341402 in the medtronic minimed insulin pumps. J Pharm Sci. 2023;112(4):963-973. doi:10.1016/j.xphs.2022.12.006