COVID-19 essential medication: hospital production of rocuronium bromide 50mg/5mL

B. Dessane1, 2, J. Heloury1, A. Venet1, V. Servant1, JM. Bernadou1, F. Xuereb1, 3, Crauste-Manciet1, 2
1 Pharmaceutical Technology Department, Bordeaux University Hospital, France
2 ARNA ChemBioPharm U1212 INSERM – UMR 5320 CNRS, Bordeaux University, France
3 Univ. Bordeaux, Biologie des maladies cardiovasculaires, U1034 INSERM, F-33600 Pessac, 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. The use of non-sterile raw material was one of the main difference in comparison to current hospital pharmacy processes. The objective of our work was to validate the possibility to produce final ready to use curare solution in glass vials using our current hospital aseptic methods and to implement new quality controls to release batches of injectable solutions.

Materials and Methods
We worked on rocuronium bromide (RB) (50mg/5mL) hospital process implementation according to European Pharmacopeia (EP) and good preparation practices. Critical steps were highlighted before production with a feasibility analysis using FMECA method. Raw RB was provided by French Health Minister through a safety national stock stored at AGEPS2. Excipients and conditioning articles were purchased from various approved suppliers. All the quality controls required by the EP were performed on finished products (i.e. pH, osmolality, content testing, visible and non-visible particle test, vial leak test, extractable volume, sterility and endotoxin) completed by process controls (i.e. filter integrity test, determination of the bioburden before filtration). Media fill tests (MFT) were conducted in triplicate with trypticase soybean medium to validate our process.

Results and Discussion
Feasibility analysis was favorable to develop the production process. The formulation was based on commercial formulation: RB, trihydrated sodium acetate, glacial acetic acid, sterile sodium chloride 20% and sterile water for injection. All conditioning articles were chosen sterile pyrogen-free to limit the microbiological risk. All preparation steps were carried out in controlled atmosphere areas: weighting and mixing drug and excipients in grade A biosafety cabinet in a grade D environment; 0.22µm double filtration, aseptic transfer in sterile pyrogen-free glass vials and capping-sealing in a grade A unidirectional airflow surrounded with a grade B environment. Final preparation in sealed vials were then submitted to final heat sterilization cycle for liquid solution at 121°C for 15min. MFT showed no microorganism growth validating our aseptic process. A stability indicating dosage method was developed by high performance liquid chromatography and validated according to ICH recommendations. In total, 500 vials were successfully produced with and 100% of our batches were found in conformity.

The hospital production of RB has been implemented. All controls required by EP for sterile injectable forms were developed and validated to release EP-compliant products. This allowed us to build up a safety stock in case of a total curare shortage.

ANSM1 : Agence Nationale de Sécurité du Médicament et des Produits de Santé
AGEPS2 : Agence Générale des Equipements et Produits de Santé

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