Development of a sterile gospital-compounded crystalloid cardioplegic solution to ensure continuity care

Introduction and Objective
The discontinuation of Plegisol^® and the supply shortage of CELSIOR^®, two crystalloid cardioplegic solutions used to induce rapid electromechanical cardiac arrest during open-heart surgery, created a major risk of disruption to cardiac surgical care. The aim of this study was to develop and validate a sterile hospital-compounded cardioplegic solution equivalent in composition to Plegisol® in order to ensure continuity of patient care.

Materials and Methods
A sterile hospital-compounded injectable solution reproducing the composition of Plegisol^® was developed in accordance with the French Good Compounding Practices (2023). The cardioplegic solution was filled into 250 mL vials with the following target concentrations : Na⁺ 110.0 ± 11.0 mM, K⁺ 16.0 ± 1.6 mM, Mg²⁺ 16.0 ± 1.6 mM, and Ca²⁺ 1.2 ± 0.1 mM, corresponding to a theoretical osmolality of 302 mOsm/kg and a target pH of 4.0 ± 0.5.

The manufacturing process included preparation of the electrolyte solutions, mixing, pH adjustment, sterilizing filtration through a 0.22 µm filter, aseptic filling, stoppering and crimping, followed by terminal steam sterilization (121°C for 20 minutes). A pilot batch of 120 vials was produced to validate the manufacturing process and initiate a stability study in accordance with International Council for Harmonisation (ICH) guidelines.

Quality controls, performed according to the European Pharmacopoeia requirements, included sodium, potassium, magnesium and calcium assays, pH, osmolality, visible and subvisible particulate matter, bacterial endotoxin testing, and sterility testing including method suitability.

Results
The pilot batch met the formulation specifications, with measured ion concentrations of Na⁺ 103.9 mM, K⁺ 16.1 mM, Mg²⁺ 15.6 mM, and Ca²⁺ 1.3 mM. Measured osmolality was 281 mOsm/kg and pH was 3.6. Visible and subvisible particulate testing, sterility testing, and bacterial endotoxin assay (<0.050 IU/mL) all complied with predefined specifications, validating both the manufacturing process and the pilot batch for the stability study. Interim stability results at six months demonstrated maintenance of the physicochemical compliance of the preparation.

Discussion and Conclusion
This study demonstrates the feasibility and successful validation of a sterile hospital-compounded crystalloid cardioplegic solution in response to the unavailability of Plegisol^®. This temporary alternative ensures continuity and safety of cardiac surgical care while awaiting the implementation of blood cardioplegia or the restoration of CELSIOR® availability. Stability data support the implementation of a sustainable supply strategy based on anticipatory production and the establishment of an emergency stock to mitigate future supply shortages.