Impact study of eye drop batch production

Objectives
High concentration antibiotic eye drops administration (Ceftazidime, Amikacin, Vancomycin) are ophthalmic emergencies. The short stability at + 4°C leads to untimely production. A physico-chemical and microbiological^{1, 2} stability study was performed to extend the stability to 90 days at -20°C, protected from light, allowing batch production. Thawing method (room temperature for 20 minutes) was also validated for the dispensation. The aim of our work was to implement batch production and measure added value in comparison to our prior manual on demand production method.

Material and Method
The batch size for quarterly production for each of the 3 antibiotics was determined according to the number of patients treated in 2020 and 2021 and was set at 130 vials per batch. The batch production was performed using premixing in a master bag and transfer to High Density Polyethylene eye drop vials with the help of peristaltic pump (Repeater^®, baxter) in BSC grade A. Additionally destructive controls were implemented in accordance with European Pharmacopoeia i.e., sterility controls (SC) (Merck Symbio Steritest^®), and subvisible particle (SV)counting (Beckmann Coulter HIAC 9703+). The manual production consisted in the transfer of reconstituted solution from vials of antibiotic using syringes to 12 eye-drop vials and process was only controlled by visual observation and final concentration (FC) determination. The time and vials spared were compared.

Results
During 2021, 12 batches were produced, giving a total of 1560 eye drop vials. In comparison, manual production represented a total of 1272 units, for 2020. After one year of production, it was shown that time saved by batch production was around 50%. For 12 batches, time production was 39 hours (3.25h per batch: 2.5h for preparation, 0.75h for controls) against 80 hours during on demand production for 104 series (0.5h per preparation and 0.25h for control).
Additionally, batch production decreased by 9% the wastages with 5% (N=84) and 14% (N = 220) for batch and manual production respectively.
In comparison to manual on demand production, batch production dramatically improved the quality of the preparation produced as it allowed multiples controls including in-process controls on master bag (gravimetric, concentration) and post-process destructive and non destructive controls (gravimetric, FC, SC, SV, pH osmolality). All the batch results were in accordance with the requirement for ophthalmic preparations.

Discussion-Conclusion
Batch production allows to implement additional controls, enhancing the quality of preparations and leads to cost optimization in terms of human resources and stocks. The time spared can lead to double the batch size with equivalent human resources. Alternatively, it can help to envision the development of new ophthalmic preparations for in-house needs or for others healthcare establishments.

1. Chédru-Legros V, Fines-Guyon M, Chérel A, Perdriel A, Albessard F, Debruyne D, et al. Stabilité à – 20°C des collyres antibiotiques renforcés (Amikacine, Ceftazidime, Vancomycine). J Fr Ophtalmol. oct 2007;30(8):807-13
2. Lucile.P. Étude de la stabilité microbiologique de trois collyres renforcés en antibiotiques (Amikacine, Ceftazidime et Vancomycine). Université de Bordeaux ; 2020.

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