Manufacturing
A diagram showcasing best practice using isolator technology in manufacturing.
The key challenges using isolator
technology are the following: ■ Isolator design with closed isolator or open isolator and air treatment system including HEPA or ULPA fi lers
■ Cleaning, disinfection and decontamination using Vapor Hydrogen Peroxide system (VHP)
■ Interventions and manipulation of the operators using gloves/sleeves systems
■ Management of the transfers inside/outside the isolator for the sterile components (for example primary packaging with container and closure systems), the environmental monitoring devices including media plates and swabs
■ Environmental monitoring program inside isolator and for the surrounding area
■ Maintenance activities that present the minimum contamination risk.
Aseptic processing simulation If a product cannot be sterilised in its final container, the preparation should be sterilised by filtration and the filling operations should be performed in compliance with aseptic processing best practices. The objective is to identify, assess, appropriately control and minimise the risk of microbes, pyrogens and particulates contaminations. The effectiveness of aseptic processing operations should be initially and periodically verified, including the performance of aseptic processing simulation (APS) using a nutrient medium or a surrogate in place of the products.
“Analytical methods are applied to evaluate both viable particulate contamination for the air and surfaces and non-viable particulate contamination of the air.”
The APS procedure is complex to prepare and should consider some key points. Firstly, the simulation of manufacturing activities is performed as closely as possible to the routine aseptic manufacturing process. Further, APS should include all critical steps and personnel interventions known to occur during routine production (inherent and corrective interventions) in a
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manner and frequency similar to a routine aseptic process supported by a risk-based approach. APS protocol should also identify the worst-case conditions and parameters of the filling line with representative sizes of combinations of container/ closure systems, line speed, filled volume, growth conditions of the microorganisms (selection of the medium, incubation temperature and time), holding times from the routine, duration of the filling operations, number of shifts and campaign period. At the initial validation, at least three consecutive APS satisfactory runs should be done; then, periodically, a revalidation should be performed, generally every six months. To note, the number of filled units should be sufficient to effectively simulate all representative activities of the aseptic process in compliance with the CCS. After the incubation step, each filled unit should be visually inspected by qualified personnel – the acceptance criterion for APS is absence of microbial growth. At the end of this APS process, the reconciliation of the total number of units from filling operations to final inspection should be evaluated.
Environmental monitoring programme Environmental monitoring for clean rooms and clean air equipment should consider viable and non-viable particulates contamination and other physical parameters such as temperature, relative humidity and pressure differentials between rooms. This environmental monitoring includes a sampling plan programme for viable and non-viable particulates with three key elements. Firstly, the definition and justification of the sample locations are supported by a risk-based approach in compliance with the CCS. Then the frequency of the samples is defined and justified according to the risk of contamination. After this, analytical methods are applied to evaluate both viable particulate contamination for the air and surfaces and non-viable particulate contamination of the air. The results of this environmental monitoring programme should be evaluated by comparison to action limits and alert levels. The data should also be trended, and when excursions are met, corrective actions and preventive actions should be defined in the objective to minimise the risk of contamination.
Challenge for the future
Environmental monitoring programmes associated with all other parameters and information acquired throughout the manufacture of each batch of sterile processes will generate huge amounts of data. The evaluation and trending of all such data are key challenges for the release of each batch of sterile products for the safety of the patients. To succeed in this objective, a strategy of interpretation using algorithms involving artificial intelligence and a process of archiving these data using data centres must be defined, organised and secured in advance. ●
World Pharmaceutical Frontiers /
www.worldpharmaceuticals.net
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