Production of major therapeutic interest drugs: example of pancuronium bromide
The COVID pandemic has deeply affected the efficiency of the production and distribution capacity of drugs. The increase in use of certain drugs causes supply tensions, particularly for drugs of major therapeutic interest (DMTIs), as it happened for curares used in intensive care. The COMEDIMS*, in collaboration with the Direction and the College of Specialties, because of a possible drug shortage, have requested the manufacturing unit of the hospital to product injectable curare preparations. This approach was concerted with the Agence Nationale de Sécurité sur le Médicament**. The objective of this work was to rapidly develop the production of an injectable pancuronium bromide (PB) solution.
A feasibility study has been carried out. It was supplemented by a Failure Modes, Effects and Criticality Analysis (FMECA). Then manufacturing procedures and instructions were drafted. Then, the supply of raw materials (drug substances and excipients) and conditioning article was necessary (sterile and apyrogenic type 1 glass vials, self-sealing capsules). Finally, the control laboratory developed and validated the dosage method and then, drafted analysis reports for the raw materials and the finished product in accordance with the European Pharmacopoeia criteria.
The feasibility analysis was favorable with an average criticality index calculated at 126. The formulation was developed from the commercial speciality: BP, water for injection, sodium chloride 20%, sodium acetate and glacial acetic acid. All production steps were carried out in a controlled atmosphere area: weighing under a laminar flow hood, mixing step in class B, filtration in class A and distribution with filtration and capping/sealing under an isolator. The finished product was controlled with the candling method, labelled, packaged and stored between 2 and 8°C. Batches contained between 545 to 1090 vials, with a volume of 6 mL per vial. Physico-chemical controls included: macroscopic aspect, vial leak test, pH, osmolality, invisible particle count, preparation uniformity and content testing by high performance liquid chromatography. Microbiological testing included: bacterial endotoxins, sterility testing and “Bact/alert” vial inoculation. Thus, 5000 units were produced and controlled, 100% of the batches were found to be conformed.
Curares were the frontline DMTIs using during the COVID crisis. The supply tension, which is still extant, requires the import of foreign specialties. Curare production carried out from April 23rd May to 14th 2020, has allowed to build up a stock in the eventuality of a total shortage.
*Commission du Médicament et des Dispositifs Médicaux Stériles and **Agence Nationale de Sécurité sur le Médicament are French commissions