Stability of factor VIII concentrates after reconstitution

Abstract

Adjusted-dose continuous infusion of factor VIII (F VIII) has recently been shown to reduce the doses of the factor in patients undergoing surgery by 50-75%. The main limitation of this method has been the instability of factor concentrates. All manufacturers are recommending infusion of the concentrate within hours after reconstitution. We studied the stability of 15 different lyophilized F VIII products. Reconstituted samples were stored for periods of 4, 24, and 72 hr and 1, 2, 3, and 4 weeks at temperatures of 4-8 degrees C, 20-23 degrees C, and 37 degrees C in their original glass containers and in plastic tubes and then frozen. Assays were performed in duplicate, using a one-stage clotting method and a chromogenic assay for F VIII, with all samples from a single concentrate in the same run. Activation of the coagulation factor occurred in some concentrates, more often at 4-8 degrees C than at 20-23 degrees C or 37 degrees C. The stability of all products was substantially better than that declared by the manufacturers. Several concentrates maintained factor activities above 80% of baseline for the entire period of 4 weeks at 4-8 degrees C or at 20-23 degrees C. The results demonstrate that many of the F VIII concentrates may be used for continuous infusion.

Evaluation of recombinant factor VIII (Kogenate®) stability for continuous infusion using a minipump infusion device

“…Although product labelling information indicates that FVIII preparations must be used within 3 h of reconstitution (based on sterility issues), a variety of FVIII concentrates, including recombinant product, have been shown to be stable (retaining> 80% of initial activity) up to 30 days following reconstitution when stored at room temperature in plastic or glass [19, 20]. However, the recovery of both plasma‐derived and recombinant FVIII concentrates has been shown to be variable, presumably related to dilution of the protein or adsorption to the material comprising the infusion set when measured after flow through some infusion set‐ups, the amount of exogenous heparin and the duration of the infusion [21].…”

Efficacy and safety of continuous infusion of Mononine® during five surgical procedures in three hemophilic patients

“…Further studies using immunopurified or recombinant factor VIII confirmed the advantages of this method compared to bolus injections [3][4][5][6][7][8][9][10][11].…”

Continuous Infusion of Coagulation Products in Hemophilia

“…not cause bacterial overgrowth and the thousands of cultures performed from mini-pump reservoirs after completion of the infusion were all negative [1,4,11,18]. Similarly, studies employing simulated CI with mini-pumps failed to find any microbial contamination of the infusion sets used for up to 6-7 days [1,15], and the bacterial safety of CI is also confirmed by clinical trials [4,16].…”

“…The experiments focused on the risk of contamination and bacterial overgrowth during prolonged incubation of concentrates in the pump reservoir and proved that many FVIII and FIX concentrates are poor growth mediums for most bacterial strains [1,2,11]. Inoculation of the reservoirs of mini-pumps, containing factor concentrates, with common contaminants did have been tested and proven to comply with the stability requirements for CI [12][13][14][15][16][17].…”

“…Extensive stability studies conducted in the early 1990s demonstrated that most plasma-derived concentrates (pdFVIII/FIX) available at that time remained stable for several days after their reconstitution, and sometimes even for weeks [1,11]. after reconstitution, in the reservoir of the infusion pump at room temperature.…”