Validation of a compounding process for injectable dopamine in an anaerobic chamber for a clinical trial
5 October 2022B. Palas1, D. Lannoy1,2, N. Carta2, C. Nassar1, M. Roche1,2, P. Odou1,2
1- Pharmacie CHU Lille, France ; 2- Laboratoire de Biopharmacie, Pharmacie Galénique et Hospitalière, UFR3S, Univ Lille, France
In a clinical trial in Parkinson’s disease, dopamine is directly administered by pump into the cerebral ventricles. Dopamine is unstable in solution, especially when exposed to oxygen, requiring
to be prepared in anaerobic conditions. An anaerobic production workstation (O2 level <100ppm) with laminar flow and overpressure A135 (class A) (Don Whitley Scientific, Bingley, UK) was positioned in a controlled atmosphere area (class D) in our pharmacy. It is coupled to a hydrogen peroxide (H2O2) autonomous decontamination system. The workstation includes an airlock allowing the anaerobic setting of incoming material. The atmosphere is a mixture of N2, CO2 and H2. The objective is to validate the manufacturing process through the 2 aspects of this production: sterility and anaerobia.
Prior to each production, sterile consumables are placed in the previously cleaned chamber. H2O2 solution is nebulized for 1 min and left in contact for 4 hours. H2O2 exposure test strips (Oxy’pharm, France) were placed in order to check the good diffusion of the H2O2 into the chamber. The chamber was then placed in anaerobic conditions for 8 hours. The absence of O2 during use is controlled in two complementary ways: the O2 level is controlled before production and then every 30 minutes with the internal probe, then the absence of degradation product from oxidation (DPO) is checked by colorimetry and by HPLC with UV-visible detector (HPLC-UV). The control of the aseptic process was validated by media fills tests (MFT), performed according to the PIC/S PI 007-6 recommendations of 2011 (in aerobic conditions with filtered air rather than inert gas), with Trypticase Soy Broth (whose fertility was tested beforehand) until the vials were sealed. Quality control of the clinical batches was performed, including dopamine (HPLC-UV) and DPO assays and sterility testing (adapted from Ph.Eur 10.0 monographs 2.6.1 and 5.1.9 - microbiology laboratory).
The H2O2 exposure test strips showed a blind zone, concerned consumables was placed differently. Five MFTs were rejected. Following each positive MFT, corrective actions were undertaken: verification of laminar flow, labeling of vials at the end of production and securing the membrane filtration. The MFT was validated 2 times, with 2 operators. During use, as soon as O2 level is <100ppm, it is maintained below this value. Between October 2020 and June 2022, 16 batches (784 vials manufactured) were accepted, with DPO remaining undetectable.
Discussion – Conclusion
These actions made it possible to obtain negative MFTs and to validate the manufacturing process. We compound hundreds of vials of dopamine, so it is possible to produce inert products in the hospital.