Adaptation of hospital aseptic processes to face national shortage of curare
1- Pharmaceutical Technology Department, Bordeaux university hospital (CHU de Bordeaux), France
2- ARNA Laboratory-ChemBioPharm U1212 INSERM - UMR5320, CNRS - University of Bordeaux, France
3- Pharmacokinetics and PK/PD Group, INSERM 1034, University of Bordeaux, France
4- Hospital Hygiene Service, Bordeaux university hospital (CHU de Bordeaux), France
In the context of essential drug shortages during the Covid-19 pandemic, we were involved in the network driven by ANSM1 for studying feasibility of hospital pharmacy production of curare. One of the main differences in comparison to current hospital pharmacy process was the use of non-sterile raw material, open system transfer of the solution via 0.22µm filtration method and the use of pyrogen-free vials. The objective of our work was to validate the possibility to produce final ready-to-use curare solution, using our current hospital aseptic methods and final containers i.e. bags and syringes. Benefits expected would be to improve the national capacity in case of major industry shortage.
Material and Method
For this proof of concept we used Cisatracurium Besilate raw powder. Our method consisted of two steps: making a bulk solution (BS) of Cisatracurium Besilate at 5mg/ml and then aseptic repartition, using 0.22µm double filtration in unit doses using the Baxa Repeater® peristaltic pump. Only hospital commonly available materials were used: the intermediate BS container was a sterile, pyrogen-free water for injection canister (Aguettant) extemporaneously emptied and the final containers were 50mL syringes (BD PlastipakTM) and 50mL bags (Easyflex+).
Validation of the aseptic process was simulated using TSB culture media (Media Fill Test, MFT) by 3 production campaigns of 100 syringes and 100 bags.
An HPLC stability indicating assay was used to establish the stability of the BS at D14, and the stability distributed in bags and syringes until D60. All the controls required by the European Pharmacopoeia (EP) were performed on finished products (i.e. pH, osmolality, visible and non-visible particle test, packaging tightness, extractable volume, sterility and endotoxin) completed by process controls (i.e. filter integrity test, determination of the bioburden before filtration).
Results and Discussion
No microbial growth was observed after 14 days of incubation of the MFT, validating the aseptic preparation process in bags and syringes.
First tests performed demonstrate physicochemical stability of +/-5% of the initial BS concentration at D14 and compliance against all EP requirements.
Assays are still in progress to demonstrate the stability of the finished products until D60.
Our method allows the production of EP-compliant products, avoiding the cost and delay associated with the use of more specialized equipment.
The stability of our BS opens the possibility of subcontracting its repartition to other centers that have less technical and/or human resources.
1. Agence Nationale de Sécurité du Médicament et des produits de santé