Did our fabrication process impact on azacitidine stability?
(2) ARNA Laboratory-ChemBioPharm U1212 INSERM - UMR5320, CNRS - University of Bordeaux, France
(3) Department of Pharmacokinetics, Groupe PK/PD, INSERM U1034 - Bordeaux University Hospital, France
Stability of azacitidine was found to be 48 hours when stored at 4°C1, and when cold water for injection (WFI) was used for the reconstitution step. In routine production, our process includes 15 minutes of sterilization with peracetic acid at 45°C and transfer of the preparation to ward and finally administration to the patient is usually done more than one hour after the beginning of the preparation. Elevation of temperature may occur along the process compromising the stability of azacitidine. So, our goal was to monitor temperature during the whole process and to assess the stability of azacitidine in real life condition.
Materials and methods
Temperature was monitored during 3 different sterilization processes with temperature sensor (VWR®). Temperature of water before and after sterilization for 20 ml and 250 flasks is kept with partial immersion thermometer (Brannan®). All temperature measurements were done in triplicate. Azacitidine syringe 25mg/ml were prepared as usually, azacitidine concentration were determined by HPLC–UV stability indicating method1, immediately after reconstitution T0, T+30 minutes, T+45 minutes and T+1 hour store at ambient temperature, and on one syringe returned from ward (cold chain not respected).
Results and discussion
At the end of sterilization process temperature was 24°C in the pass-through, 16.6°C in the vial, 18°C and 10°C in 20 ml WFI flask, and 250ml WFI flask respectively. At T+45 min Concentration maximal variation was - 2.3mg/ml (-11.9%). On the returned syringe variation was -3.65 mg/ml (- 18.8%) in comparison to reference initial concentration in prepared syringes complying with cold process.
This work showed that a non- neglictable elevation of temperature occurs in the water for injection flask and in vials. Immediate corrective measure was implemented i.e. exclusion of 20 mL WFI flasks for reconstitution of azacitidine and operators were reminded about good process for this drug i.e. immediate storage in fridge after preparation and systematically discarded if returned from ward. Additional tests are ongoing to assess whether or not we have to use BSC instead of isolator due to temperature elevation during the sterilization process.
1. Legeron R, Xuereb F,et al. Chemical stability of azacitidine suspensions for injection after cold-chain reconstitution of powder and storage. Am J Heal Syst Pharm. 2013;70:2137–42.