Implementation of an anticipated reconstitution circuit, and reconstitutions modalities of cyclophosphamide vials using a PharmashakerV3^®

Cyclophosphamide (CYP) is an alkylating agent used in pneumology and hematology. In our sterile production unit (SPU) approximately 26 vials are reconstituted per week. The dissolution of CYP is time consuming, contributes to the development of musculoskeletal disorders for the manipulator (MSD) and can impact the fluidity of the production and the quality of the preparation. During preliminary tests, the use of an automatic shaker PharmashakerV3^® (PS) (Fresenius) didn’t show an optimal dissolution in all the programming conditions. The aim of this work was to study the feasibility of an early reconstitution of CYP vials via the PS, and the reconstitutions modalities in order to fluidify the circuit while guaranteeing the manipulator’s comfort and the patient’s safety.

The organization of our SPU allowed us to propose several circuits (placement of the PS, method for reconsitution of the CYP, etc). The advantages and disadvantages were rated by the pharmacists and compounders (from -2 to +2 points). The CYP vials were reconstituted and shaken via 4 methods: manually (a), with PS© for 2 (b), 4 (c), 6 (d) minutes (3 vials for each condition). Visual check determined if it was necessary to repeat the shaking in case of incomplete dissolution. 3 samples per vial were collected. For each sample, 3 samples were collected and diluted. Then, they were assessed by High Performance Liquid Chromatography method (HPLC-UV)(1) (C18 RP; H20/ACN 50/50; 50mmx4mmx3µm; 200nm).

3 scenarii were performed: the average rating of advantages and disadvantages was +5 for scenario 1, -5.5 and -9.25 for scenarii 2 and 3. The scenarii evaluation shows that scenario 1 (CYP was reconstituted, shaken on sterilized PS under isolator then kept at 4°C) was the most suitable for our SPU. Only the vials shaken for 2 minutes in PS required an additional 2 minutes programmation in order to be visually clear. The HPLC assay showed an average compliance of 97.83% +/-0.003% for method (b), compared to 96.13% +/-0.012, 96.36% +/- 0.053 and 96.55 +/ -0.041, for method (a), (c), (d) respectively.

Our study showed a similar dissolution quality to manual stirring (3min40 on average in our SPU) after 2x2min. The 2x2min programming allows us to observe the dissolution progression, to shake the vial between each 2min session and limit the formation of aggregates. The introduction of PS in our SPU limited TMS and associated with a human action, optimizes the dissolution and fluidify the production. It remains to be seen if this process can be applied to others products in the future.

(1) A. Delmas. Quantitative and qualitative control of cytotoxic preparations by HPLC-UV in a centralized parenteral preparations unit. J Pharm Biomed Anal 2009 Jul 12 ;49(5):1213-20

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